bluuebunny/crossref_metadata_2025 huggingface dataset:
General Coding and Analysis in Qualitative Research
Authors: Pratt Michael G.
Published: January 2023

Coding and analysis are central to qualitative research, moving the researcher from study design and data collection to discovery, theorizing, and writing up the findings in some form (e.g., a journal article, report, book chapter or book). Analysis is a systematic way of approaching data for the purpose of better understanding it. In qualitative research, such understanding often involves the process of translating raw data—such as interview transcripts, observation notes, or videos—into a more abstract understanding of that data, often in the form of theory. Analytical techniques common to qualitative approaches include writing memos, narratives, cases, timelines, and figures, based on one’s data. Coding often involves using short labels to capture key elements in the data. Codes can either emerge from the data, or they can be predetermined based on extant theorizing. The type of coding one engages in depends on whether one is being inductive, deductive or abductive. Although often confounded, coding is only a part of the broader analytical process.

In many qualitative approaches, coding and analysis occur concurrently with data collection, although the type and timing of specific coding and analysis practices vary by method (e.g., ethnography versus grounded theory). These coding and analytic techniques are used to facilitate the intuitive leaps, flashes of insight, and moments of doubt and discovery necessary for theorizing. When building new theory, care should be taken to ensure that one’s coding does not do undue “violence to experience”: rather, coding should reflect the lived experiences of those one has studied.
BDNF-Induced Plasticity of Spinal Circuits Underlying Pain and Learning
Authors: Garraway Sandra M.
Published: January 2023

Understanding of the various types of plasticity that occur in the spinal cord, as well as understanding of spinal cord functions, has vastly improved over the past 50 years, mainly due to an increase in the number of research studies and review articles on the subject. It is now understood that the spinal cord is not merely a passive conduit of neural impulses. Instead, the spinal cord can independently execute complex functions. Numerous experimental approaches have been utilized for more targeted exploration of spinal cord functions. For example, isolating the spinal cord from supraspinal influences has been used to demonstrate that simple forms of learning can be performed by spinal neuronal networks. Moreover, reduced preparations, such as acute spinal cord slices, have been used to show that spinal neurons undergo different types of modulation, including activity-dependent synaptic modification. Most spinal cord processes, ranging from integration of incoming sensory input to execution of locomotor outputs, involve plasticity. Nociceptive processing that leads to pain and spinal learning is an example of plasticity that is well-studied in the spinal cord. At the neural level, both processes involve an interplay of cellular mediators, which include glutamate receptors, protein kinases, and growth factors. The neurotrophin brain-derived neurotrophic factor (BDNF) has also been implicated in these processes, specifically as a promoter of both pro-nociception and spinal learning mechanisms. Interestingly, the role of BDNF in mediating spinal plasticity can be altered by injury. The literature spanning approximately 5 decades is reviewed and the role of BDNF is discussed in mediating cellular plasticity underlying pain processing and learning within the spinal cord.
Kisama Sobados in West Central Africa, 16th and 17th Centuries
Authors: de Carvalho Flavia Maria
Published: January 2023

The population of Kisama, south of the Kwanza River in what is today Angola, was composed of formerly enslaved individuals who escaped and resettled there to avoid deportation to the Americas. Throughout the 17th and 18th centuries, several battles took place in the territories of Kisama, as the Portuguese military, following instructions they received from Portuguese crown officials, sought to subdue local leaders. Slavery was one of the motivations for many of these military attacks, as was the punishment of Kisama leaders who hosted fugitive slaves. Kisama acquired a reputation as a safe haven for fugitives and anyone who resisted Portuguese advances, which led to increased attacks from colonial forces. This region was politically fragmented into groups led by several leaders, whom the Portuguese referred to as sobas. These leaders used defensive strategies that guaranteed the autonomy of Kisama territories until the final decades of the 19th century. Sources from the 17th and 18th centuries describe Kisama’s sobas as rebels and fierce enemies of the Portuguese colonial administrators who successfully cut off land communication between the two Portuguese colonial towns of Luanda and Benguela. The sobas maintained their political autonomy until the first decades of the 19th century, when they fell under colonial rule. The protagonism of the people of Kisama is important in the history of Angola, particularly the history of resistance among west Central Africa peoples. Because Kisama was an obstacle to Portuguese advances in west Central Africa, it should be considered one of the most important areas of insubordination and resistance to Portuguese domination before the 20th century.
Climate Change and Water-Related Diseases in the Mekong Delta Region
Authors: Tran Nu Quy Linh , Connell Des , Hieu Nguyen Trung , Phung Dung
Published: January 2023

The Mekong Delta Region (MDR) in Vietnam, located at the downstream end of the Mekong River, is highly affected by climate change and extreme weather events, such as floods, droughts, soil erosion, and salinization. Due to the specific characteristics of climate, topography, river systems, and population, water-related diseases (WRDs) have been a disease burden in the Mekong Delta. This article aims to critically review the evidence of existing studies on the association between climatic conditions and WRDs in the MDR. Dengue was found to be most sensitive to the changes in ambient temperatures, humidity, and rainfall at a lag of 2 months. The climate-based prediction model was recommended for an early warning system to enhance dengue prevention. Diarrheal diseases are highly correlated with extreme weather events such as high temperatures and floods, but the evidence on the association between climatic conditions and cause-specific WRDs is limited and inconclusive. Despite the preliminary evidence for the development of climate change adaptation strategies in the MDR, studies on other WRDs (i.e., water-washed, water-scarce, and water-contaminated diseases) should be conducted. In addition, future studies should investigate the effects of interaction between climatic factors and sociodemographic, household, and individual factors in predicting climate-sensitive diseases. How to translate and integrate the scientific evidence to the policy and practices that protect the MDR residents from the elevated extreme weather events due to climate change should be warranted.
The Paraguayan Illustrated Press during the War of the Triple Alliance
Authors: de Oliveira Silva Leonardo
Published: January 2023

The War of the Triple Alliance converted Paraguay into a scene of devastation. The conflict with Argentina, Brazil, and Uruguay—the Triple Alliance—resulted in innumerous killings and the destruction of Paraguay’s economy as well as its natural and urban spaces. Halfway through the war, when the imminent collapse of the country was evident, Paraguayan president Francisco Solano López brought together a group of intellectuals to establish an illustrated press to boost the troops’ morale while criticizing and ridiculing the enemy. In only a few months, Paraguay saw the creation of three illustrated periodicals: El Centinela (April 1867–February 1868), Cabichuí (May 1867–August 1868), and Cacique Lambaré (July 1867–September 1868). Publishing texts and cartoons, these newspapers played a crucial role in engaging the heterogenous Paraguayan population while solidifying racial discrimination against Afrodescendants. The legacy of these illustrated publications was the increased valorization of the Paraguayan identity (which was fundamental during the reconstruction years). On the other hand, this state-controlled press promoted discrimination against groups portrayed as not belonging to the Paraguayan self-image.
(High) German
Authors: Pickl Simon
Published: January 2023

(High) German is both a group of closely related West Germanic varieties and a standardized language derived from this group that comprises a wide range of dialects and colloquial varieties in addition to its standardized form. The two terms have related, and to an extent overlapping, but distinct meanings: German refers to a Standard Average European language spoken predominantly in Central Europe by some 96 million speakers and by minority speech communities around the globe. High German has a double meaning: On the one hand, it is another term for Standard German. On the other hand, it refers to the High German linguistic group within West Germanic, the linguistic basis for the German language. As such, it is defined by the High German consonant shift, a sound change that affected Germanic obstruents and set it apart from its immediate neighbors within (West) Germanic, that is, Low German and Low Franconian. The High German consonant shift around the 7th century, together with the onset of written transmission in the 8th century, marks the beginning of the history of (High) German. Traditional dialects perpetuate patterns of areal variation that arose in the wake of this sound change. Standard German developed out of High German written varieties, especially based on East Central German, through processes of leveling, koineization, metalinguistic reasoning, and codification. During that process, the emergent supra-regional norm superseded Low German in northern Germany and Upper German regional norms in the south, as well as influencing spoken registers, but (Standard) German remains a pluricentric and pluriareal language. Today, colloquial, regional varieties that combine features of Standard German and traditional dialects dominate oral language use, and in social media the written language, too, is developing new colloquial forms that build on standard orthography as well as on regional, informal forms of spoken language usage.
IWRM: Ideology or Methodology?
Authors: Swatuk Larry , Qader Adnan Ibne Abdul
Published: January 2023

Integrated water resources management (IWRM) was introduced as a conceptual solution to solve complicated problems of water management; however, since its inception, practitioners remain divided on its utility. Critics argue that it lacks practicable and working examples and that ongoing support is tantamount to little more than an ideological position. Supporters counsel patience and point to a variety of positive—if partial—outcomes, while aiming to address some of the most meaningful criticisms involving the devolution of decision-making authority, stakeholder participation, and gender mainstreaming. While the notion of “integrated management” resonates positively across the water world, critics and supporters alike are quick to note that in application it will play out differently depending on physical, sociocultural, economic, and political factors. Put differently, while the idea has universal appeal, the means and methods of achieving IWRM will vary. Comparative analysis reveals some common characteristics of performance well known across the development industry. In particular, direct engagement of resource users from project and program conception through to implementation, monitoring, and evaluation increases the likelihood of long-term positive outcomes. In contrast, top-down, elite-driven actions are likely to be resisted. Far from a panacea, IWRM is most usefully regarded as a “sensibility,” offering practitioners a set of signposts to guide actions and loose parameters within which to set policy.
Water Resources Planning Under (Deep) Uncertainty
Authors: Singh Riddhi
Published: January 2023

Public investments in water infrastructure continue to grow where developed countries prioritize investments in operation and maintenance while developing countries focus on infrastructure expansion. The returns from these investments are contingent on carefully assessed designs and operating strategies that consider the complexities inherent in water management problems. These complexities arise due to several factors, including, but not limited to, the presence of multiple stakeholders with potentially conflicting preferences, lack of knowledge about appropriate systems models or parameterizations, and large uncertainties regarding the evolution of future conditions that will confront these projects. The water resources planning literature has therefore developed a variety of approaches for a quantitative treatment of planning problems. Beginning in the mid-20th century, quantitative design evaluations were based on a stochastic treatment of uncertainty using probability distributions to determine expected costs or risk of failure. Several simulation–optimization frameworks were developed to identify optimal designs with techniques such as linear programming, dynamic programming, stochastic dynamic programming, and evolutionary algorithms. Uncertainty was incorporated within existing frameworks using probability theory, using fuzzy theory to represent ambiguity, or via scenario analysis to represent discrete possibilities for the future.

As the effects of climate change became palpable and rapid socioeconomic transformations emerged as the norm, it became evident that existing techniques were not likely to yield reliable designs. The conditions under which an optimal design is developed and tested may differ significantly from those that it will face during its lifetime. These uncertainties, wherein the analyst cannot identify the distributional forms of parameters or the models and forcing variables, are termed “deep uncertainties.” The concept of “robustness” was introduced around the 1980s to identify designs that trade off optimality with reduced sensitivity to such assumptions. However, it was not until the 21st century that robustness analysis became mainstream in water resource planning literature and robustness definitions were expanded to include preferences of multiple actors and sectors as well as their risk attitudes. Decision analytical frameworks that focused on robustness evaluations included robust decision-making, decision scaling, multi-objective robust decision-making, info-gap theory, and so forth. A complementary set of approaches focused on dynamic planning that allowed designs to respond to new information over time. Examples included adaptive policymaking, dynamic adaptive policy pathways, and engineering options analysis, among others. These novel frameworks provide a posteriori decision support to planners aiding in the design of water resources projects under deep uncertainties.
Pomeroy, Elizabeth
Authors: DiNitto Diana M. , Steiker Lori K. Holleran
Published: January 2023

Elizabeth C. (Beth) Pomeroy, PhD, was a social work practitioner, educator, and researcher known for her work on social work assessment, diagnosis of mental disorders, and practice in the areas of grief and loss, HIV/AIDS, and fetal alcohol spectrum disorders.
Identification of species-specific RNA N6-methyladinosine modification sites from RNA sequences
Authors: Wang Rulan , Chung Chia-Ru , Huang Hsien-Da , Lee Tzong-Yi
Published: January 2023

N6-methyladinosine (m6A) modification is the most abundant co-transcriptional modification in eukaryotic RNA and plays important roles in cellular regulation. Traditional high-throughput sequencing experiments used to explore functional mechanisms are time-consuming and labor-intensive, and most of the proposed methods focused on limited species types. To further understand the relevant biological mechanisms among different species with the same RNA modification, it is necessary to develop a computational scheme that can be applied to different species. To achieve this, we proposed an attention-based deep learning method, adaptive-m6A, which consists of convolutional neural network, bi-directional long short-term memory and an attention mechanism, to identify m6A sites in multiple species. In addition, three conventional machine learning (ML) methods, including support vector machine, random forest and logistic regression classifiers, were considered in this work. In addition to the performance of ML methods for multi-species prediction, the optimal performance of adaptive-m6A yielded an accuracy of 0.9832 and the area under the receiver operating characteristic curve of 0.98. Moreover, the motif analysis and cross-validation among different species were conducted to test the robustness of one model towards multiple species, which helped improve our understanding about the sequence characteristics and biological functions of RNA modifications in different species.
Phylogeographical analysis and phylogenetic inference based on the cytochromebgene in the genusCaiman(Crocodylia: Alligatoridae) in Central and South America
Authors: Amavet Patricia S , Pacheco-Sierra Gualberto , Uhart Marcela M , Prado Walter S , Siroski Pablo A
Published: January 2023

The genus Caiman is one of the most taxonomically conflicted among crocodilians. Caiman crocodilus has four subspecies: Caiman crocodilus crocodilus, Caiman crocodilus fuscus, Caiman crocodilus chiapasius and Caiman crocodilus apaporiensis, but some studies recognize Caiman yacare as a subspecies of C. crocodilus or as a C. crocodilus–C. yacare complex. In Argentina, Caiman latirostris and C. yacare are present and included in sustainable use programmes, although they have hardly been studied at the genetic level. The present study had two main objectives: (1) to study the genetic diversity, structure and phylogeny of C. yacare and C. latirostris in Argentina; and (2) to perform a phylogenetic analysis of the genus Caiman throughout its entire distribution. The results show high haplotype diversity for both species but low nucleotide diversity for C. latirostris. Phylogenetic analysis shows a clear separation between both species but, surprisingly, a well-differentiated clade belonging to the Chaco region was observed. The phylogenetic analysis exhibited clades made up of the sequences of each Caiman species, with some inconsistencies: in the clade of C. crocodilus, one sequence of C. yacare is included, and one clade is observed including sequences from C. c. fuscus and C. c. chiapasius. These data indicate the need to undertake interdisciplinary studies to clarify the taxonomic status of these crocodilian species.
Community assembly of tropical Fagaceae-dominated forests in Thailand dates back at least to the Late Palaeogene
Authors: Malaikanok Paranchai , Grímsson Friđgeir , Denk Thomas , Phuphumirat Wongkot
Published: January 2023

The Late Oligocene to Early Miocene flora of the Ban Pa Kha Subbasin (Li Basin, northern Thailand) provides a record of montane dry tropical oak-pine forests. The rich ensemble of Fagaceae typical of these forests might have existed in the wider region of Southeast Asia since Eocene times and various fossil plant assemblages represented both lowland (Fagaceae, Dipterocarpaceae) and upland (Fagaceae, Pinaceae) tropical forests. These findings are in conflict with previous interpretations of vegetation development in northern Thailand, which stressed that stratigraphically older (possibly Late Oligocene) spore and pollen assemblages in northern Thailand were markedly different from the modern tropical flora and had a distinct northern temperate character. A major change in climate would have caused a dramatic shift to tropical conditions since the Mid-Miocene. Considering palaeobotanical data from adjacent regions in Southeast Asia, we suggest that differences in spore and pollen assemblages in intermontane basins in northern Thailand are more likely to represent different facies and lowland/upland settings. Assembly of these forest ecosystems, typically comprising Quercus sections Cyclobalanopsis, Ilex and Quercus, pollen of Castaneoideae with affinities to Castanopsis and Lithocarpus, and extinct fagaceous genera such as Eotrigonobalanus, most probably dates back to the Eocene. The absence of oaks of Quercus section Cerris in the spore and pollen assemblage of the Ban Pa Kha Subbasin, despite this group being part of the modern vegetation, might reflect the late arrival (secondary radiation) of this chiefly temperate group in tropical Southeast Asia.
SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes
Authors: Smits Daphne J , Schot Rachel , Krusy Nathalie , Wiegmann Katja , Utermöhlen Olaf , Mulder Monique T , den Hoedt Sandra , Yoon Grace , Deshwar Ashish R , Kresge Christina , Pletcher Beth , van Mook Maura , Ferreira Marta Serio , Poot Raymond A , Slotman Johan A , Kremers Gert-Jan , Ahmad Abeer , Albash Buthaina , Bastaki Laila , Marafi Dana , Dekker Jordy , van Ham Tjakko J , Nguyen Laurent , Mancini Grazia M S
Published: January 2023

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC).

We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions.

We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.
The Influence of Rapid Influenza Diagnostic Testing on Clinician Decision-Making for Patients With Acute Respiratory Infection in Urgent Care
Authors: Stamm Brian D , Tamerius John , Reddy Sush , Barlow Shari , Hamer Caroline , Kempken Ashley , Goss Maureen , He Cecilia , Bell Cristalyne , Arnold Mitchell , Checovich Mary , Temte Emily , Norton Derek , Chen Guanhua , Baltus Jeffrey , Gurley Emily S , Temte Jonathan L
Published: January 2023

Background

The potential benefits of using rapid influenza diagnostic tests (RIDTs) in urgent care facilities for clinical care and prescribing practices are understudied. We compared antiviral and antibiotic prescribing, imaging, and laboratory ordering in clinical encounters with and without RIDT results.

Methods

We compared patients with acute respiratory infection (ARI) symptoms who received an RIDT and patients who did not at 2 urgent care facilities. Primary analysis using 1-to-1 exact matching resulted in 1145 matched pairs to which McNemar 2 × 2 tests were used to assess the association between the likelihood of prescribing, imaging/laboratory ordering, and RIDT use. Secondary analysis compared the same outcomes using logistic regression among the RIDT-tested population between participants who tested negative (RIDT(−)) and positive (RIDT(+)).

Results

Primary analysis revealed that compared to the non-RIDT-tested population, RIDT(+) patients were more likely to be prescribed antivirals (OR, 10.23; 95% CI, 5.78–19.72) and less likely to be prescribed antibiotics (OR, 0.15; 95% CI, .08–.27). Comparing RIDT-tested to non-RIDT-tested participants, RIDT use increased antiviral prescribing odds (OR, 3.07; 95% CI, 2.25–4.26) and reduced antibiotic prescribing odds (OR, 0.52; 95% CI, .43–.63). Secondary analysis identified increased odds of prescribing antivirals (OR, 28.21; 95% CI, 18.15–43.86) and decreased odds of prescribing antibiotics (OR, 0.20; 95% CI, .13–.30) for RIDT(+) participants compared with RIDT(−).

Conclusions

Use of RIDTs in patients presenting with ARI symptoms influences clinician diagnostic and treatment decision-making, which could lead to improved patient outcomes, population-level reductions in influenza burden, and a decreased threat of antibiotic resistance.
gyrA Mutations in Mycoplasma genitalium and Their Contribution to Moxifloxacin Failure: Time for the Next Generation of Resistance-Guided Therapy
Authors: Murray Gerald L , Plummer Erica L , Bodiyabadu Kaveesha , Vodstrcil Lenka A , Huaman Jose L , Danielewski Jennifer A , Chua Teck Phui , Machalek Dorothy A , Garland Suzanne , Doyle Michelle , Sweeney Emma L , Whiley David M , Bradshaw Catriona S
Published: January 2023

Background

Although single nucleotide polymorphisms (SNPs) in Mycoplasma genitalium parC contribute to fluoroquinolone treatment failure, data are limited for the homologous gene, gyrA. This study investigated the prevalence of gyrA SNPs and their contribution to fluoroquinolone failure.

Methods

Samples from 411 patients (male and female) undergoing treatment for M. genitalium infection (Melbourne Sexual Health Centre, March 2019–February 2020) were analyzed by Sanger sequencing (gyrA and parC). For patients treated with moxifloxacin (n = 194), the association between SNPs and microbiologic treatment outcome was analyzed.

Results

The most common parC SNP was G248T/S83I (21.1% of samples), followed by D87N (2.3%). The most common gyrA SNP was G285A/M95I (7.1%). Dual parC/gyrA SNPs were found in 8.6% of cases. One third of infections harboring parC G248T/S83I SNP had a concurrent SNP in gyrA conferring M95I. SNPs in gyrA cooccurred with parC S83I variations. Treatment failure was higher in patients with parC S83I/gyrA dual SNPs when compared with infections with single S83I SNP alone from analysis of (1) 194 cases in this study (81.2% vs 45.8%, P = .047), and (2) pooled analysis of a larger population of 535 cases (80.6% vs 43.2%; P = .0027), indicating a strong additive effect.

Conclusions

Compared with parC S83I SNP alone, M. genitalium infections with dual mutations affecting parC/gyrA had twice the likelihood of failing moxifloxacin. Although antimicrobial resistance varies by region globally, these data indicate that gyrA should be considered as a target for future resistance assays in Australasia. We propose a strategy for the next generation of resistance-guided therapy incorporating parC and gyrA testing.
Immunotherapy in oncology and the kidneys: a clinical review of the evaluation and management of kidney immune-related adverse events
Authors: Rao Ullur Avinash , Côté Gabrielle , Pelletier Karyne , Kitchlu Abhijat
Published: January 2023

Immune checkpoint inhibitors (ICI) are now widely used in the treatment of many cancers, and currently represent the standard of care for multiple malignancies. These agents enhance the T cell immune response to target cancer tissues, and have demonstrated considerable benefits for cancer outcomes. However, despite these improved outcomes, there are important kidney immune-related adverse events (iRAEs) associated with ICI. Acute tubulo-interstitial nephritis remains the most frequent kidney iRAE, however glomerular lesions and electrolytes disturbances are increasingly being recognized and reported. In this review, we summarize clinical features and identify risk factors for kidney iRAEs, and discuss the current understanding of pathophysiologic mechanisms. We highlight the evidence basis for guideline-recommended management of ICI-related kidney injury as well as gaps in current knowledge. We advocate for judicious use of kidney biopsy to identify ICI-associated kidney injury, and early use of corticosteroid treatment where appropriate. Selected patients may also be candidates for re-challenge with ICI therapy after a kidney iRAE, in view of current data on recurrent rates of kidney injury. Risk of benefits of re-challenge must be considered on an individual considering patient preferences and prognosis. Lastly, we review current knowledge of ICI use in the setting of patients with end-stage kidney disease, including kidney transplant recipients and those receiving dialysis, which suggest that these patients should not be summarily excluded from the potential benefits of these cancer therapies.
Resident wild koalas show resilience to large-scale translocation of bushfire-rescued koalas
Authors: Beaman Julian E , Mulligan Connor , Moore Claire , Mitchell Dana , Narayan Edward , Burke da Silva Karen
Published: January 2023

Wildlife translocation is increasingly utilized as a conservation management action, to mitigate the immediate negative effects of habitat loss and fragmentation (e.g. from land clearing or bushfires). Previous research has shown that stress responses can help or hinder survival in translocated wildlife and determine the efficacy of translocation as a conservation action. Yet these translocated animals are only one side of the equation, with translocation also potentially impacting the animals in the recipient population. We measured physiological markers of stress (faecal cortisol metabolite concentrations and neutrophil-lymphocyte ratios) and assessed health condition in a wild koala population one year after a major translocation of bushfire-rescued koalas on Kangaroo Island. We expected to find a high population density at the site (>0.75 koalas per hectare) and that resident koalas would show signs of chronic stress and ill health as a result of territorial conflict over food trees and reproductive opportunities. In contrast, we found that only one-fifth of the population remaining at the site were translocated koalas. The overall population density was also much lower (0.21 koalas per hectare) than anticipated. With no evidence of mass mortality at the site, we suggest that the majority of translocated koalas dispersed away from the site. Our stress marker measurements did not differ between the wild koalas and a sample of captive (non-display) koalas at the nearby Kangaroo Island Wildlife Park and were generally low compared to other studies. Veterinary examinations found that most koalas were in good body condition with very few diagnostic indicators of systemic ill health. Overall, our results suggest that, if there is adequate landscape-scale habitat connectivity and opportunity for dispersal, translocated koalas are likely to disperse from the site of release, with limited impacts on recipient koala populations at translocation release sites.
Haematology, biochemistry and morphological features of peripheral blood cells in captive Boa constrictor
Authors: Dervas E , Michalopoulou E , Liesegang A , Novacco M , Schwarzenberger F , Hetzel U , Kipar A
Published: January 2023

The common boa (Boa constrictor) belongs to the family Boidae and represents one of the most popular traded and kept snake species in captivity. The early diagnosis, prevention and prophylaxis of diseases in this species, and in reptiles in general, still pose major challenges, also due to the lack of reliable reference values. This prompted us to conduct a study on clinically healthy captive B. constrictor to assess their basic health parameters in the blood (haematological and biochemical values, stress markers). Several parameters differed significantly between younger (<3 years) and older (≥3 years) boas; in the latter, the percentages of eosinophils, the haemoglobin and haematocrit levels, as well as the albumin and total protein levels, were higher. In male snakes, cholesterol levels were significantly higher than in females. Light and electron microscopy as well as immunohistochemistry served to identify and determine the morphological features of peripheral blood cells, that is, heterophils, basophils, eosinophils, azurophils, monocytes, lymphocytes, thrombocytes and erythrocytes. Leukocyte subpopulations, that is, T and B cells and monocytes, were also identified based on specific marker expression. The study provides data on haematological, biochemical and stress hormone levels, suitable as reference values, and on the blood cell morphology of B. constrictor which can serve as a guideline for further research on this species.
OP04 Efficacy of upadacitinib in ulcerative colitis: A phase 3 post hoc analysis of biologic- and anti-TNF-inadequate response patients
Authors: Vermeire S , Danese S , Hébuterne X , D’Haens G , Takeuchi K , Finney-Hayward T , Klaff J , Holweg C T J , Rubin D T
Published: January 2023

Background

Upadacitinib (UPA), an oral selective and reversible Janus kinase inhibitor, has demonstrated efficacy with a well-characterised safety profile in patients (pts) with moderately to severely active ulcerative colitis (UC) in a Phase 3 clinical trial program.1,2 This post hoc analysis evaluated UPA in pts with an inadequate response (IR; persistently active UC despite ≥1 induction regimen of infliximab, adalimumab, golimumab, vedolizumab or ustekinumab), loss of response, or intolerance to ≥1 biologic (bio-IR) or anti-TNF agent (anti-TNF-IR) in the Phase 3 trials.

Methods

Pts with a clinical response to UPA 45 mg once daily (QD) following 8-week (wk) induction therapy in U-ACHIEVE or U-ACCOMPLISH were subsequently randomised to placebo (PBO), UPA 15 mg or UPA 30 mg QD in U-ACHIEVE Maintenance.1,2 Here, we evaluated the efficacy of UPA after 8-wk induction and 52-wk maintenance therapy in non-bio-IR pts, bio-IR pts and the subset of anti-TNF-IR pts within the bio-IR population.

Results

Overall, 508 bio-IR pts (51% overall) and 464 anti-TNF-IR pts (91% of bio-IR population) were analysed after induction, and 336 bio-IR pts (49% overall) and 306 anti-TNF-IR pts (91% of bio-IR population) were analysed after maintenance. UPA was significantly more efficacious than PBO across all endpoints analysed at Wk 8 of induction in the non-bio-IR, bio-IR and anti-TNF-IR subgroups (Figure 1; Table 1). At Wk 52 of maintenance, both UPA doses were more efficacious than PBO across subgroups for the primary endpoint of clinical remission per Adapted Mayo score (Figure 2). Adjusted response rate differences for both UPA doses vs PBO were generally similar across most endpoints at Wk 8 of induction and Wk 52 of maintenance for the non-bio-IR, bio-IR and anti-TNF-IR subgroups. At Wk 52 of maintenance, UPA 30 mg QD had numerically better efficacy than 15 mg QD across all endpoints except change from baseline in faecal calprotectin in non-bio-IR patients, with generally similar results for non-bio-IR, bio-IR and anti-TNF-IR pts (Table 2).

Conclusion

In pts with UC, significantly more pts achieved clinical remission after 8-wk induction and 52-wk maintenance therapy with UPA than PBO in non-bio-IR, bio-IR and anti-TNFIR pts. Generally similar efficacy was observed between the bio-IR and anti-TNF-IR pts, which was consistent with the previously published overall population.1,2 These findings suggest that UPA is efficacious for UC regardless of prior therapy with anti-TNF agents or other biologics.
OP17 Upadacitinib Improves Endoscopic Outcomes in Patients with Moderate to Severely Active Crohn’s Disease Irrespective of Previous Failure to Respond to Biologics or Conventional Therapies
Authors: Feagan B G , Horst S , Dryden G , Lindsay J O , Ferrante M , Dubenco E , Lacerda A P , Ford S , Anyanwu S I , Zhou Q , Liu J , Chen M , Schreiber S
Published: January 2023

Background

Upadacitinib (UPA), an oral, reversible JAK inhibitor, demonstrated superior efficacy compared to placebo (PBO) in patients with moderate to severe Crohn’s disease (CD) in 2 multicentre, phase 3 induction (U-EXCEL and U-EXCEED), and 1 maintenance (U-ENDURE) trial.1-3 This sub-analysis assessed endoscopic outcomes in patients with or without a history of biologic failure (inadequate response or intolerance) among those receiving UPA treatment.

Methods

Eligible patients had average daily stool frequency [SF] ≥4 and/or abdominal pain score [APS]≥2, plus a Simple Endoscopic Score for CD (excluding the presence of narrowing component) ≥6 [≥4 for isolated ileal disease]). Patients received UPA 45 mg once daily (QD; UPA45) or PBO (2:1) for 12 weeks (wks). Patients that achieved SF/APS clinical response after 12 weeks of treatment with UPA45 (≥ 30% decrease in daily very soft/liquid SF and/or ≥ 30% decrease in daily abdominal pain APS with neither worse than baseline) were re-randomized (1:1:1) to UPA 30 mg QD (UPA30), UPA15 mg QD (UPA15) or PBO for 52 wks of maintenance. Endoscopic response\ remission were evaluated by central reading at wk 12 induction and wk 52 maintenance. Adverse events (AEs) were assessed through wk 52. Statistical significance in comparisons was not assessed due to an inability to control for type I error in subgroup analysis.

Results

Baseline characteristics/demographics were similar across treatment groups. In the pooled induction population (U-EXCEED+U-EXCEL), 72.0% UPA45 and 71.5% PBO patients had history of prior biologic failure. In U-ENDURE, 73.4% UPA15, 75.6% UPA30, and 76.4% PBO patients had history of prior biologic failure. In patients without or with biologic failure, UPA demonstrated higher rates for endoscopic response compared to PBO at wk 12 (52.0%, 35.7% UPA45 vs 16.2%, 5.3% PBO, Figure 1A) and wk 52 (Figure 1B). Similarly, in patients without or with a history of biologic failure, UPA exhibited higher rates of endoscopic remission at wk 12 (36.0%, 19.6% UPA45 vs. 10.1%, 2.8% PBO, Figure 1A) and wk 52 (Figure 1B). Differences from PBO were found in endoscopic response or remission in patients that remained in response/remission from the entry of maintenance to wk 52 for either dose, regardless of prior history of biologic failure (Figure 1C). UPA treatment was well-tolerated, with no new safety risks observed compared to the known safety profile of UPA (Tables 1-2).

Conclusion

Upadacitinib achieved clinically meaningful endoscopic outcomes, which were maintained up to 1 year, irrespective of a patient’s prior biologic treatment, with an acceptable safety profile.
OP40 PRA023 Demonstrated Efficacy and Favorable Safety as Induction Therapy for Moderately to Severely Active UC: Phase 2 ARTEMIS-UC Study Results
Authors: Sands B , Peyrin-Biroulet L , Danese S , Rubin D T , Vermeire S , Laurent O , Luo A , Nguyen D , Lu J D , Wiechowska-Kozlowska A , Leszczyszyn J , Kempinski R , Kierkus J , Ma C , Ritter T , Feagan B G , Targan S
Published: January 2023

Background

Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases using a precision medicine approach with a companion diagnostic (CDx). This Phase 2 placebo-controlled, multi-center, double-blind study aimed to assess the efficacy and safety of PRA023 for induction treatment in adults with moderately to severely active ulcerative colitis (UC).

Methods

Key eligibility criteria included a modified Mayo Score of 4-9, a centrally read (with adjudication) endoscopy subscore of ≥ 2, a rectal bleeding subscore of ≥ 1, and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced (approved biologics and JAK inhibitors/S1P modulators) therapies (≤ 4 advanced agents from ≤ 3 classes). Patients were stratified by prior biologic exposure status (yes/no) and CDx status (yes/no) and randomized 1:1 to placebo or intravenous PRA023 (1000mg on Day 1, 500mg at Weeks 2, 6, and 10). The primary endpoint was clinical remission at week 12. Analyses of all ranked secondary endpoints, the first being endoscopic improvement (endoscopy score of ≤ 1), were multiplicity controlled.

Results

Of the 135 patients in the full analysis data set, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week Induction Period. Baseline characteristics were similar with minor differences in the proportion of patients with baseline endoscopy score of 3 and prior exposure to ≥ 3 advanced therapies (Table 1). A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs. 1.5% placebo, ∆25.0%, p < 0.0001) at Week 12 (Table 2). In addition, substantially more patients who received PRA023 achieved the key secondary endpoint of endoscopic improvement (36.8% PRA023 vs. 6.0% placebo, ∆30.8%, p < 0.0001). All remaining ranked secondary endpoints were met (Table 2). The rates of treatment-emergent adverse events (AEs) were similar between the two arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm (Table 3). There were no safety signals identified from the study.

Conclusion

PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A Phase 3 study will be conducted to confirm these findings. Recruitment is ongoing for the CDx+ expansion cohort of the study to assess the effectiveness of the CDx, designed to select patients with a higher probability of responding to PRA023.
DOP03 Unfermented β-fructan fibres can induce gut inflammation and tumorigenesis in select Inflammatory Bowel Disease patients mediated by gut microbiota
Authors: Voisin A , Mahmood R , Jeanson T L , Bernstein C , Armstrong H ,   IBD Clinical and Research Centre
Published: January 2023

Background

Dietary fibres are not digested in the bowel; they are fermented by microbes, typically promoting gut health. However, IBD patients have altered gut microbiota composition and can experience sensitivity to consumption of fibres. Our previous findings offered the first mechanistic evidence that if dietary β-fructans (inulin and oligofructose) are not fermented by gut microbes in IBD patients, these fibres can induce inflammation. This diet-induced inflammation could have serious repercussions as chronic inflammation creates a mutagenic environment that promotes progression to colorectal cancer (CRC). We hypothesized that unfermented β-fructans cause tumorigenesis and promotion of IBD progression to CRC.

Methods

We examined pathways associated with response to β-fructan in a randomized controlled trial examining β-fructan supplementation (15g/day) in UC patients in remission (RNA sequencing). We validated pathways of interest in IBD patient colonic biopsies cultured ex vivo with β-fructans (targeted proteomics and mesoscale discovery). We examined structural changes (microscopy; e.g., tumorigenic architecture) in these biopsies. Further, cell invasion, migration, and proliferation were examined using scratch wound assays and chick chorioallantoic membrane assays (CAM; n=10 embryos per treatment).

Results

CRC-related pathways (SLIT2/MAPK and SOS1) were induced and anti-tumour gene RPS27A was reduced only in biopsies from remission UC patients who entered relapse following consumption of β-fructans (endpoint versus baseline), not those in the placebo arm who relapsed. Pathways were validated in IBD patient colonic biopsies cultured ex vivo demonstrating oligofructose produced more significant effects than inulin; response correlated with disease severity. Inulin and oligofructose further influenced the processes of migration and invasion reflective of the tumorigenic process of epithelial to mesenchymal transition and risk of CRC.

Conclusion

Our findings suggest that intolerance and avoidance of fibres in select IBD patients occurs specifically in patients whose gut microbiota do not support fermentation of dietary fibres resulting in increased presence of unfermented dietary fibres in the gut. Here we show that these β-fructan fibres commonly touted as beneficial prebiotics can elicit gut inflammation and tumorigenesis in this subset of IBD patients, suggesting consumption of these fibres should be avoided in these patients.
DOP10 Early intestinal resection in Crohn’s Disease is not associated with severe long-term disease course
Authors: Grellier N , Kirchgesner J , Uzzan M , Mclellan P , Stefanescu C , Lefèvre J H , Panis Y , Sokol H , Beaugerie L , Treton X , Seksik P ,   ERIC
Published: January 2023

Background

Crohn’s Disease patients (CD) with early complicated behaviour (stenosis and/or fistula) are thought to have a more severe long-term disease course. To address this question, we focused on ileal CD that requires early intestinal resection after diagnosis. We aimed to assess the impact of the time to surgery from diagnosis on the risk of severe disease course in patients with ileal CD undergoing a primary ileocecal resection (ICR) or ileal resection (IR).

Methods

All CD patients who underwent ICR or IR between January 2001 and December 2015 and followed in two Inflammatory Bowel Disease (IBD) tertiary centres in France were included. Data were retrieved using dedicated IBD database and patients’ medical records. Early resection was defined as a surgery performed within 6 months after diagnosis. Two control groups with patients who underwent the first surgery between 6 months and 2 years and between 2 and 5 years after diagnosis were enrolled. The primary outcome was second intestinal resection. Secondary outcomes included the need for biologic treatments after initial intestinal surgery. Patients were followed from the date of first surgery until September 2022. Kaplan Meier survival analysis and log-rank test were used to estimate the survival without second intestinal resection and biologic initiation according to the time of first intestinal resection to diagnosis.

Results

Among 404 patients who underwent ICR or IR within 5 years after diagnosis, 130 (32.2%) patients had undergone surgery within 6 months after diagnosis (Group A), 138 (34.2%) patients between 6 months and 2 years (Group B) and 136 (33.7%) patients between 2 and 5 years (Group C). Clinical data are shown in Table 1. The cumulative risk of a second ICR or IR ten years after the first surgery was 25.2% (95% CI 12.5 - 40.2) in group A, 16.6% (5.1 - 33.9) in group B and 22.8% (9.8 – 39.1) in group C, without statistically significant difference (p = 0.25) (Figure 1). The risk of biological exposure after the first surgery was not significantly different in the three groups (p = 0.12) (Figure 2). The cumulative risk to start a biologic therapy at ten years was 46.2% (35.0 – 56.6) in group A, 39.0% (26.2 – 51.5) in group B and 48.0% (36.3 – 58.8) in group C.

Conclusion

In a bicentric cohort with long-term follow-up, intestinal resection within 6 months of CD diagnosis was not associated with an increased risk of second surgery as compared to patients with primary ICR/IR later after diagnosis. Furthermore, patients with early intestinal resection did not need more biological therapies after the first surgery. These data suggest that early intestinal resection in CD is not a predictor of poor long-term prognosis compared to late resection.