bluuebunny/crossref_metadata_2025 huggingface dataset:
Weakened Bayesian Calibration for Tactile Temporal Order Judgment in Individuals with Higher Autistic Traits
Authors: Wada Makoto , Umesawa Yumi , Sano Misako , Tajima Seiki , Kumagaya Shinichiro , Miyazaki Makoto
Published: January 2022

Previous psychophysical studies reported a positive aftereffect in tactile temporal order judgments, which can be explained by the Bayesian estimation model (‘Bayesian calibration’). We investigated the relationship between Bayesian calibration and autistic traits in participants with typical development (TD) and autism spectrum disorder (ASD). Bayesian calibration was weakened in TD participants with high autistic traits, consistent with the ‘hypo-priors’ hypothesis for autistic perceptions. The results from the ASD group were generally observed as a continuation of those from the TD groups. Meanwhile, two ASD participants showed irregularly large positive or negative aftereffects. We discussed the mechanisms behind the general results among TD and ASD participants and two particular results among ASD participants based on the Bayesian estimation model.
Landing Site Detection for Autonomous Rotor Wing UAVs Using Visual and Structural Information
Authors: Chatzikalymnios Evangelos , Moustakas Konstantinos
Published: January 2022

The technology of unmanned aerial vehicles (UAVs) has increasingly become part of many civil and research applications in recent years. UAVs offer high-quality aerial imaging and the ability to perform quick, flexible and in-depth data acquisition over an area of interest. While navigating in remote environments, UAVs need to be capable of autonomously landing on complex terrains for security, safety and delivery reasons. This is extremely challenging as the structure of these terrains is often unknown, and no prior knowledge can be leveraged. In this study, we present a vision-based autonomous landing system for rotor wing UAVs equipped with a stereo camera and an inertial measurement unit (IMU). The landing site detection algorithm introduces and evaluates several factors including terrain’s flatness, inclination and steepness. Considering these features we compute map metrics that are used to obtain a landing-score map, based on which we detect candidate landing sites. The 3D reconstruction of the scene is acquired by stereo processing and the pose of the UAV at any given time is estimated by fusing raw data from the inertial sensors with the pose obtained from stereo ORB-SLAM2. Real-world trials demonstrate successful landing in unknown and complex terrains such as suburban and forest areas.
Low-cost Imaging of Fluorescent DNA in Agarose Gel Electrophoresis using Raspberry Pi cameras
Authors: Abid Hassan Ali , Ong Jian Wern , Lin Eric Shen , Song Zhixiong , Liew Oi Wah , Ng Tuck Wah
Published: January 2022

Low-cost analytical solutions built around microcomputers like the Raspberry Pi help to facilitate laboratory investigations in resource limited venues. Here, three camera modules (V1.3 with and without filter, as well as NoIR) that work with this microcomputer were assessed for their suitability in imaging fluorescent DNA following agarose gel electrophoresis. Evaluation of their utility was based on signal-to-noise (SNR) and noise variance metrics that were developed. Experiments conducted with samples were subjected to Polymerase Chain Reaction (PCR), and the amplified products were separated using gel electrophoresis and stained with Midori green. Image analysis revealed the NoIR camera performed the best with SNR and noise variance values of 21.7 and 0.222 respectively. In experiments conducted using UV LED lighting to simulate ethidium bromide (EtBr) excitation, the NoIR and V1.3 with filter removed cameras showed comparable SNR values.
A Comparative Study on Methods of Distinction Between Near- and Far-Side Defects as Techniques Used Alongside with the Magnetic Flux Leakage Testing
Authors: Usarek Zbigniew , Chmielewski Marek , Piotrowski Leszek
Published: January 2022

Results of the finite element analysis show that a far-side defect in a steel plate, with the depth greater by 10% of the plate thickness than a near-side defect, can produce a very similar magnetic flux leakage (MFL) signal. Due to the fact that a measurement of MFL itself can lead to misclassification of a far-side defect as a near-side one, and thus to underestimation of its depth, a comparative study of three complementary magnetic techniques was performed. The following techniques were studied: surface topology air-gap reluctance system (STARS), residual magnetic flux leakage (RMFL) and stray magnetic flux leakage (SMFL). Numerical results showed that in the case of the STARS and SMFL, defect signatures in signals were observed for investigated near-side defects, but not for far-side defects. The signature of the far-side defect in the RMFL was observed, however its peak-to-peak value was only about 8% of the value corresponding to the near-side defect.
Minding our Minds: Obsessive-Compulsiveness, Psychiatry, and Psychology
Authors: Blum Lawrence D.
Published: January 2022

Obsessive–compulsive features are commonly found in high-achieving people including psychiatrists, psychologists, and scientists. These traits have a substantial but unrecognized cultural influence on psychiatric and psychological science and practice. This article reviews obsessive–compulsive mechanisms and discusses the ways they both promote and impede psychiatric and psychological science and practice. It examines them in relation to two of the dominant psychiatric and psychological paradigms of our era, the Diagnostic and Statistical Manual (DSM), and Cognitive-Behavioral Therapy. Finally, the article suggests that better awareness of our collective obsessive–compulsive tendencies can facilitate a cultural shift toward a broader, more useful science of mind and brain, as well as therapies informed by more comprehensive scientific understanding.
The Effectiveness of Two Implementation Strategies for Improving Teachers’ Delivery of an Evidenced-based HIV Prevention Program
Authors: Wang Bo , Deveaux Lynette , Cottrell Lesley , Li Xiaoming , Adderley Richard , Dorsett Barbara , Firpo-Triplett Regina , Koci Veronica , Marshall Sharon , Forbes Nikkiah , Stanton Bonita
Published: January 2022

Background

Effective implementation strategies are needed to enhance the success of evidence-based prevention programs. The current study evaluates the effects of two implementation strategies on teachers’ implementation of an evidenced-based HIV intervention.

Methods

Using our 7-item pre-implementation school screening tool, we identified teachers who were at-risk for not implementing the Focus on Youth HIV-risk reduction intervention curriculum which targets grade six through grade 8 students. After completing a two-day curriculum workshop, 81 low- and moderate-performing teachers were randomly assigned to one of four experimental conditions and were asked to teach the two-month intervention curriculum. This optimization trial examines the impact of two implementation strategies: biweekly monitoring/feedbacks (BMF) and site-based assistance/mentorship (SAM). The primary outcome is implementation fidelity defined as number of core activities taught. Linear mixed-effects model was used to examine the association of the implementation strategies with implementation fidelity.

Results

BMF and SAM were significantly associated with teachers’ implementation fidelity. Teachers who received both BFM and SAM taught the greatest numbers of core activities (15 core activities on average), followed by teachers who received either BMF (6.9 activities) or SAM (7.9 activities). Teachers who did not receive BMF or SAM taught the lowest numbers (4.1 activities). Teachers’ sustained implementation of FOYC in the prior school year was related to increased implementation fidelity during the optimization trial. Teachers’ confidence in implementing five core activities, attitudes toward sex education in schools, and perceived principal support were significantly related to increased self-efficacy, which in turn was related to teachers’ fidelity of implementation before the optimization trial.

Conclusion

BMF and SAM are effective in promoting teachers’ implementation of youth evidence-based interventions. Researchers and future program implementers should consider teacher training, teachers’ attitudes toward sex education, perceived principal support, and self-efficacy when attempting to maintain the effects of teacher-delivered interventions in schools.
Unconstrained binary models of the travelling salesman problem variants for quantum optimization
Authors: Salehi Özlem , Glos Adam , Miszczak Jarosław Adam
Published: January 2022

Quantum computing is offering a novel perspective for solving combinatorial optimization problems. To fully explore the possibilities offered by quantum computers, the problems need to be formulated as unconstrained binary models, taking into account limitation and advantages of quantum devices. In this work, we provide a detailed analysis of the travelling salesman problem with time windows (TSPTW) in the context of solving it on a quantum computer. We introduce quadratic unconstrained binary optimization and higher-order binary optimization formulations of this problem. We demonstrate the advantages of edge-based and node-based formulations of the TSPTW problem. Additionally, we investigate the experimental realization of the presented methods on a quantum annealing device. The provided results pave the path for utilizing quantum computer for a variety of real-world tasks which can be cast in the form of travelling salesman problem with time windows.
Two Filtering Methods of Forecasting Linear and Nonlinear Dynamics of Intensive Longitudinal Data
Authors: Hunter Michael D. , Fatimah Haya , Bornovalova Marina A.
Published: January 2022

With the advent of new data collection technologies, intensive longitudinal data (ILD) are collected more frequently than ever. Along with the increased prevalence of ILD, more methods are being developed to analyze these data. However, relatively few methods have yet been applied for making long- or even short-term predictions from ILD in behavioral settings. Applications of forecasting methods to behavioral ILD are still scant. We first establish a general framework for modeling ILD and then extend that frame to two previously existing forecasting methods: these methods are Kalman prediction and ensemble prediction. After implementing Kalman and ensemble forecasts in free and open-source software, we apply these methods to daily drug and alcohol use data. In doing so, we create a simple, but nonlinear dynamical system model of daily drug and alcohol use and illustrate important differences between the forecasting methods. We further compare the Kalman and ensemble forecasting methods to several simpler forecasts of daily drug and alcohol use. Ensemble forecasts may be more appropriate than Kalman forecasts for nonlinear dynamical systems models, but further forecasting evaluation methods must be put into practice.
Prevalence of FRAX risk factors and the osteoporosis treatment gap among women ≥ 70 years of age in routine primary care across 8 countries in Europe
Authors: McCloskey Eugene , Rathi Jeetandera , Heijmans Stephane , Blagden Mark , Cortet Bernard , Czerwinski Edward , Hadji Peyman , Payer Juraj , Palmer Kerry , Stad Robert , O’Kelly James , Papapoulos Socrates
Published: January 2022

Summary

We studied whether elderly women at risk for fractures receive primary care treatment to prevent fracture. We found that across Europe, women at risk are often not identified, and less than half of such women receive appropriate treatment. Finally, women diagnosed with osteoporosis are much more likely to receive treatment.

Purpose

To examine the relationship between risk factors for fragility fracture (FF) and osteoporosis (OP) treatment gap in elderly women across Europe, and compare the prevalence of risk factors between countries.

Methods

Demographic and clinical information was collected from women ≥ 70 years visiting primary care physicians in Belgium, France, Germany, Ireland, Poland, Slovakia, Switzerland, and the UK. Increased risk of FF was defined by the presence of 1 or more criteria (history of fracture, 10-year fracture probability, or T-score ≤  − 2.5).

Results

There were 3798 women in total. Treatment gap (proportion at increased risk of FF not receiving treatment for OP) varied from 53.1 to 90.8% across countries, and the proportion of patients at increased risk of FF varied from 41.2 to 76.1%. Across countries, less than 50% of patients with increased risk of FF had a diagnosis of OP. Previous fracture was the most common risk factor, with similar prevalence across most countries; other risk factors varied widely. The treatment gap was reduced in patients with an OP diagnosis in all countries, but this reduction varied from 36.5 to 79.4%. The countries with the lowest rates of bone densitometry scans (Poland, France, and Germany; 8.3–12.3%) also had the highest treatment gap (82.2 to 90.8%).

Conclusions

This study highlights differences across Europe in clinical risk factors for fracture, rates of densitometry scanning, and the rates of OP diagnosis. More emphasis is needed on risk assessment to improve the identification and treatment of elderly women at risk for fracture.
Intraoperative margin assessment by wireless signals in thoracoscopic anterior (S3) segmentectomy using a radiofrequency identification marker
Authors: Yutaka Yojiro , Ohsumi Akihiro , Nakajima Daisuke , Hamaji Masatsugu , Menju Toshi , Date Hiroshi
Published: January 2022

Despite the use of near-infrared thoracoscopy with intravenous indocyanine green, intraoperative assessment of the surgical margin for the resection of non-palpable tumors located near the intersegmental plane requires highly advanced surgical skill for the prevention of local recurrence. Because the demarcation line is limited to the pleural surface, to overcome uncertainty in tumor palpation for deeply located small-sized lesions, other supplemental localization techniques have been proposed. Here, we present a novel surgical technique using radiofrequency identification markers for intraoperative assessment of the lateral surgical margin in segmentectomy.
Students’ collaborative creative process and its phases in mathematics: an explorative study using dual eye tracking and stimulated recall interviews
Authors: Schindler Maike , Lilienthal Achim J.
Published: January 2022

In the age of artificial intelligence where standard problems are increasingly processed by computers, creative problem solving, the ability to think outside the box is in high demand. Collaboration is also increasingly significant, which makes creative collaboration an important twenty-first-century skill. In the research described in this paper, we investigated students’ collaborative creative process in mathematics and explored the collaborative creative process in its phases. Since little is known about the collaborative creative process, we conducted an explorative case study, where two students jointly worked on a multiple solution task. For in-depth insight into the dyad’s collaborative creative process, we used a novel research design in mathematics education, DUET SRI: both students wore eye-tracking glasses during their collaborative work for dual eye-tracking (DUET) and they each participated in a subsequent stimulated recall interview (SRI) where eye-tracking videos from their joint work served as stimulus. Using an inductive data analysis method, we then identified the phases of the students’ collaborative creative process. We found that the collaborative creative process and its phases had similarities to those previously found for solo creative work, yet the process was more complex and volatile and involved different branches. Based on our findings, we present a tentative model of the dyad’s collaborative process in its phases, which can help researchers and educators trace and foster the collaborative creative process more effectively.
Ultrasensitive Protein Concentration Characterization Based on Weak Measurements
Authors: Song Bowen , Chen Binglin , Yu Chen , Yang Hua
Published: January 2022

An optical rotation bio-sensor based on the photonic spin Hall effect was established and applied to detecting the concentration varieties of chiral molecules. The optical rotation, introduced by sample solutions, was exploited to modulate the postselected polarization of a weak measurement system. Much work has been done in the case of glucose and fructose. However, little attention has been paid for biomolecules, such as proteins and amino acids. With this modulation, the optical rotation can be determined through the direction and spin accumulation of light spots, thus mirroring the concentration of solutions. A resolution of 2×10−4 degree was achieved.
Association Between Adverse Childhood Experiences, Resilience and Mental Health in a Hispanic Community
Authors: Dominguez Maribel G. , Brown Louis D.
Published: January 2022

This study explores the relations between adverse childhood experiences (ACEs), mental health and resilience among Hispanic adults living in the United States – Mexico Border region. Numerous studies have investigated the negative impact of ACEs on adult mental health, but the concept of resilience as a protective factor for mental health in the Hispanic communities has limited consideration in ACE treatment interventions. The proposed study addresses this gap in knowledge by investigating relations between ACEs, resilience, and mental health. An online survey was administered to 221 university students to assess the relationship between ACEs, mental distress and resilience. Using hierarchical linear regression, three models were estimated. First, including demographics, second including ACEs and low resilience, followed by the interaction of ACEs and resilience. Analyses indicate that ACEs were associated with mental distress (B = 1.02, 95% CI 0.37 – 1.68, p < 0.01) and low resilience was associated with mental distress (B = 5.37, 95% CI 3.15 – 7.59, p < .01). The interaction between ACEs and low resilience was also related to mental distress (B = 1.32, 95% CI 0.17 – 2.47, p = 0.03), indicating that ACEs had a larger association with mental distress among respondents with low resilience. Findings highlight the importance of the direct association between resilience and mental distress, along with the moderating influence of resilience on the relation between ACEs and mental health. Interventions promoting resilience may be effective in reducing mental distress, especially among individuals with a history of ACEs.
Allosteric modulation of dopamine D2L receptor in complex with Gi1 and Gi2 proteins: the effect of subtle structural and stereochemical ligand modifications
Authors: Żuk Justyna , Bartuzi Damian , Silva Andrea G. , Pitucha Monika , Koszła Oliwia , Wróbel Tomasz M. , Matosiuk Dariusz , Castro Marián , Kaczor Agnieszka A.
Published: January 2022

Background

Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays one of the hot topics in drug discovery. In particular, allosteric modulators of D2 receptor have been proposed as potential modern therapeutics to treat schizophrenia and Parkinson’s disease.

Methods

To address some subtle structural and stereochemical aspects of allosteric modulation of D2 receptor, we performed extensive in silico studies of both enantiomers of two compounds (compound 1 and compound 2), and one of them (compound 2) was synthesized as a racemate in-house and studied in vitro.

Results

Our molecular dynamics simulations confirmed literature reports that the R enantiomer of compound 1 is a positive allosteric modulator of the D2L receptor, while its S enantiomer is a negative allosteric modulator. Moreover, based on the principal component analysis (PCA), we hypothesized that both enantiomers of compound 2 behave as silent allosteric modulators, in line with our in vitro studies. PCA calculations suggest that the most pronounced modulator-induced receptor rearrangements occur at the transmembrane helix 7 (TM7). In particular, TM7 bending at the conserved P7.50 and G7.42 was observed. The latter resides next to the Y7.43, which is a significant part of the orthosteric binding site. Moreover, the W7.40 conformation seems to be affected by the presence of the positive allosteric modulator.

Conclusions

Our work reveals that allosteric modulation of the D2L receptor can be affected by subtle ligand modifications. A change in configuration of a chiral carbon and/or minor structural modulator modifications are solely responsible for the functional outcome of the allosteric modulator.

Graphical abstract
Novel Evidence Showing the Possible Effect of Environmental Variables on COVID‐19 Spread
Authors: Zhang Sixuan , Wang Bingyun , Yin Li , Wang Shigong , Hu Wendong , Song Xueqian , Feng Hongmei
Published: January 2022

Coronavirus disease (COVID‐19) remains a serious issue, and the role played by meteorological indicators in the process of virus spread has been a topic of academic discussion. Previous studies reached different conclusions due to inconsistent methods, disparate meteorological indicators, and specific time periods or regions. This manuscript is based on seven daily meteorological indicators in the NCEP reanalysis data set and COVID‐19 data repository of Johns Hopkins University from 22 January 2020 to 1 June 2021. Results showed that worldwide average temperature and precipitable water (PW) had the strongest correlation (ρ > 0.9, p < 0.001) with the confirmed COVID‐19 cases per day from 22 January to 31 August 2020. From 22 January to 31 August 2020, positive correlations were observed between the temperature/PW and confirmed COVID‐19 cases/deaths in the northern hemisphere, whereas negative correlations were recorded in the southern hemisphere. From 1 September to 31 December 2020, the opposite results were observed. Correlations were weak throughout the near full year, and weak negative correlations were detected worldwide (|ρ| < 0.4, p ≤ 0.05); the lag time had no obvious effect. As the latitude increased, the temperature and PW of the maximum confirmed COVID‐19 cases/deaths per day generally showed a decreasing trend; the 2020‐year fitting functions of the response latitude pattern were verified by the 2021 data. Meteorological indicators, although not a decisive factor, may influence the virus spread by affecting the virus survival rates and enthusiasm of human activities. The temperature or PW threshold suitable for the spread of COVID‐19 may increase as the latitude decreases.
Data science appositeness in diabetes mellitus diagnosis for healthcare systems of developing nations
Authors: Gourisaria Mahendra Kumar , Jee Gaurav , Harshvardhan G. M. , Singh Vijander , Singh Pradeep Kumar , Workneh Tewabe Chekole
Published: January 2022

One of the capacious applications of data science could be its use in bioinformatics. With its proper implementation, chronic diseases like diabetes mellitus, responsible for millions of deaths worldwide, could be diagnosed and predicted with high efficacy. But if not attended, could lead to fatal issues such as kidney failures, heart diseases, and even limb amputation. Diabetic cases have only elevated in numbers in the recent past. The authors use various machine learning, deep learning, and data dimensionality reduction techniques to detect diabetes mellitus. The research is principally conducted on two datasets, first from the Frankfurt Hospital, Germany, second from the University of California, Irvine repository. Models such as support vector machines, Naïve Bayes, and Random Forests were implemented to classify diabetic patients from non‐diabetic ones. Subsequently, after hyperparameter tuning, a comparative study on the results was done and the most prominent model was promoted. This process was repeated for the datasets with reduced dimensionality using linear discriminant analysis and principal component analysis. For the Frankfurt, Germany, dataset, K‐nearest neighbours showed the best accuracy of 98.2%, and the Random Forest classifier for the University of California, Irvine, repository showed 99.2%. With such proficiency, the authors thereby propose a statistical approach for the prediction of diabetes in its early stages. They hope to counter the concern of undiagnosed diabetic cases in developing nations where there is a lack of a basic healthcare system.
Process intensification for generating and decomposing formic acid, a liquid hydrogen carrier
Authors: Egbert Jonathan D. , Grubel Katarzyna , Howe Daniel T. , Weber Robert S. , Agarwal Arun S. , Brix Todd
Published: January 2022

We preview two processes that facilitate using formic acid (HCOOH) as a liquid hydrogen carrier to store renewably‐generated electrical energy and then release it to generate electrical power cleanly for backup or emergency applications. First, we show that simultaneously oxidizing an organic solute (typically a waste stream) can assist the electrochemical synthesis of formic acid by lowering the cell potential. The electrolyser comprises a hybrid 3‐chamber PEM stack that reduces CO₂ via a gas‐diffusion cathode boosted by the oxidation of aqueous methanol. However, the extent of the boosting needs to be optimized across the whole operation of the cell. Next, we present results from an intensified reactor for decomposing formic acid back into H₂ and CO₂ at elevated pressure so that the H₂ can be used in a fuel cell. The reactor combines three operations: Vaporization of the formic acid, its decomposition, and separation of the product stream. Their close coupling affords energy savings and a compact design that could be mounted on a mobile skid. We briefly discuss the electrode catalyst that facilitates the first process and two thermally activated catalysts (Ir supported on covalent triazine framework and Pd supported on carbon) that enable the second process.
Biomimetic Diels–Alder Reactions in Natural Product Synthesis: A Personal Retrospect
Authors: Tang Yefeng , Liu Jingchun , Xi Shuang
Published: January 2022

Nature has been recognized for her super capability of constructing complex molecules with remarkable efficiency and elegancy. Among nature’s versatile synthetic toolkits, Diels–Alder reaction is particularly attractive since it allows for rapid generation of molecular complexity from simple precursors. For natural products biosynthetically formed through Diels–Alder reactions, the most straightforward way to access them should build on biomimetic Diels–Alder reactions. However, the implementation of biomimetic Diels–Alder reactions in a laboratory setting may encounter considerable challenges, particularly for those suffering from complicated reactivity and selectivity issues. Indeed, the translation of a biosynthetic hypothesis into a real biomimetic synthesis entails the orchestrated combination of nature’s inspiration and chemist’s rational design. In this Account, we will briefly summarize our recent progress on the application of biomimetic Diels–Alder reactions in natural product synthesis. As shown in the discussed stories, rational manipulation of the structures of biosynthetic precursors plays a crucial role for the successful implementation of biomimetic Diels–Alder reactions.

1 Introduction

2 Biomimetic Synthesis of Rossinone B

3 Biomimetic Synthesis of Homodimericin A

4 Biomimetic Synthesis of Polycyclic and Dimeric Xanthanolides

5 Biomimetic Synthesis of Periconiasins and Pericoannosins

6 Biomimetic Synthesis of Merocyctochalasans

7 Conclusion and Outlook
Investigation into the thermal effect of the LIPS-200 ion thruster plume
Authors: CHEN Xinwei , HE Bijiao , GU Zuo , GENG Hai , GUO Ning , ZHAO Yong , SHI Kai , TIAN Kai , CHEN Tao , MA Yifan
Published: January 2022

The distribution of the thermal effects of the ion thruster plume are essential for estimating the influence of the thruster plume, improving the layout of the spacecraft, and for the thermal shielding of critical sensitive components. In order to obtain the heat flow distribution in the plume of the LIPS-200 xenon ion thruster, an experimental study of the thermal effects of the plume has been conducted in this work, with a total heat flow sensor and a radiant heat flow sensor over an axial distance of 0.5–0.9 m and a thruster angle of 0°–60°. Combined with a Faraday probe and a retarding potential analyzer, the thermal accommodation coefficient of the sensor surface in the plume is available. The results of the experiment show that the xenon ion thruster plume heat flow is mainly concentrated within a range of 15°. The total and radial heat flow of the plume downstream of the thruster gradually decreases along the axial and radial directions, with the corresponding values of 11.78 kW m−2 and 0.3 kW m−2 for the axial 0.5 m position, respectively. At the same position, the radiation heat flow accounts for a very small part of the total heat flow, approximately 3%–5%. The thermal accommodation factor is 0.72–0.99 over the measured region. Furthermore, the PIC and DSMC methods based on the Maxwell thermal accommodation coefficient model (EX-PWS) show a maximum error of 28.6% between simulation and experiment for LIPS-200 ion thruster plume heat flow, which, on the one hand, provides an experimental basis for studying the interaction between the ion thruster and the spacecraft, and on the other hand provides optimization of the ion thruster plume simulation model.
DISCOVERY OF IBD3540: A NOVEL GUT-RESTRICTED GLUTAMATE CARBOXYPEPTIDASE II INHIBITOR WITH ORAL ACTIVITY IN MOUSE COLITIS MODELS
Authors: Peters Diane , Norris Lauren , Tenora Lukas , Snajdr Ivan , Zhu Xiaolei , Sakamoto Shinji , Thomas Ajit , Majer Pavel , Rais Rana , Slusher Barbara
Published: January 2022

BACKGROUND & AIMS

Glutamate carboxypeptidase II (GCPII) is robustly overexpressed in both Crohn’s disease and ulcerative colitis and is a promising therapeutic target for IBD. We have previously published that systemically or enema administered small molecule GCPII inhibitors have efficacy in multiple mouse colitis models. While this is a highly encouraging activity profile for a candidate IBD drug, an oral dose route would be strongly preferred. Thus, here we develop and characterize a new class of GCPII inhibitors designed to be gut-restricted for oral administration, with the intention of selecting a lead inhibitor for further clinical development.

METHODS

Anti-inflammatory secondary bile acids lithocholic acid, deoxycholic acid and ursodeoxycholic acid were conjugated to GCPII inhibitor, 2-PMPA, yielding three novel constructs. These conjugates were screened for oral activity in murine dextran sulfate sodium (DSS) colitis, followed by detailed characterization of the most active inhibitor to: measure GCPII inhibition (IC50), confirm colon target engagement, evaluate plasma and colon pharmacokinetic profiles, compare efficacy versus standard-of-care agents, evaluate mechanisms of anti-inflammatory activity in vivo, confirm efficacy in a second colitis model (IL10-/-), and assess safety in standard preclinical assays.

RESULTS

The deoxycholic acid 2-PMPA conjugate, IBD3540, was identified as the lead inhibitor (IC50 = 4nM). Oral IBD3540 was robustly efficacious in acute DSS colitis, where it dose-dependently inhibited colon GCPII, attenuated both gross disease activity index and blinded colon histopathology scores, and exhibited improved efficacy relative to both sulfasalazine and tofacitinib when compared head-to-head. Mechanistically, we determined that IBD3540 attenuated pathogenic monocytic inflammation in the colon, as measured by flow cytometry, and also decreased colon pro-inflammatory cytokine content. We confirmed efficacy of IBD3540 in spontaneously occurring, chronic, IL10-/- colitis, where treatment initiated 4 weeks after the onset of colon inflammation improved multiple disease endpoints. Further, in preclinical safety screens, inclusive of CYP inhibition/induction assays, Eurofins SafetyScreen44, and AMES/hERG mutagenicity testing, no concerns were identified.

CONCLUSION

IBD3540 is a novel, gut-restricted, GCPII inhibitor with potent oral anti-colitis efficacy in both acute (DSS) and chronic (IL10-/-) mouse colitis models and a promising preclinical safety profile. Further development of this mechanistically unique candidate IBD drug is warranted.
POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF OZANIMOD IN ULCERATIVE COLITIS
Authors: Tatosian Daniel , Shen Jun , Chen Lu , Lavigne Jean , Teuscher Nathan , Harris Sarah , Chitkara Denesh , Tirucherai Giridhar , Marta Cecilia
Published: January 2022

BACKGROUND

Ozanimod is an oral small molecule sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis (RMS) and moderately to severely active ulcerative colitis (UC) and under development for Crohn’s disease. Ozanimod and its major active metabolites CC112273 and CC1084037 block lymphocyte egress from lymphoid tissues, reducing the absolute lymphocyte count (ALC) in blood. To characterise the influence of patient characteristics on ALC response, a population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted.

METHODS

A nonlinear mixed-effects Emax model described the ALC time course and relationship to CC112273 concentrations in healthy subjects and patients with UC or RMS. The analysed data included 34,449 ALC values obtained from 4122 subjects enrolled in 11 Phase 1, 2, and 3 clinical studies. The effect of age, sex, smoking status, disease type, body weight, total bilirubin, and baseline ALC on the maximum ALC reduction (Emax) and half-maximal concentration (EC50) were investigated. Simulations of typical ALC reductions for healthy subjects and patients with UC or RMS receiving 0.5 or 1 mg ozanimod were conducted to explore the influence of smoking and assess the time for ALC recovery.

RESULTS

Increasing CC112273 concentrations were associated with reductions in ALC to a maximum of 74% from baseline, with an estimated EC50 of 2.8 nM CC112273. Healthy subjects, females, and higher body weights were associated with larger ALC Emax (Figure 1), while healthy subjects, increased age, nonsmokers and higher baseline ALC were associated with an increased EC50 (Figure 2). UC patients receiving 0.5 mg and 1 mg ozanimod HCl are predicted to have mean ALC reductions of 46.1% and 57.2%, respectively, with similar reductions for RMS patients of 48.0% and 57.4%. Smoking was associated with a 27.2% reduction in the ALC EC50, which partially offsets the reduced plasma CC112273 concentrations in smokers. Simulations show that 1 mg ozanimod has comparable ALC reductions of 57.4% in nonsmokers and 52.7% in smokers. Upon discontinuing ozanimod 1 mg in UC patients, a mean recovery time to normal (1 x 109/L ALC count) of 32.8 days was predicted, with 90% of the population recovering in 3 months. Overall results were consistent with findings from clinical trials.

CONCLUSION

Population analysis demonstrated a similar PK/PD relationship for ALC reductions in patients with RMS and UC. Smoking was not associated with substantial difference in ALC, consistent with no loss of efficacy in smokers. Upon discontinuation of ozanimod treatment, the majority of UC and RMS patients will recover lymphocyte counts to normal within 3 months.
NOVEL INSIGHTS INTO THE MECHANISM OF ACTION OF EXCLUSIVE ENTERAL NUTRITION IN CROHN’S DISEASE: PRE-CLINICAL STUDY IN A RODENT MODEL OF CROHN’S-LIKE COLITIS
Authors: Geesala Ramasatyaveni , Lin You-Min , Zhang Ke , M’Koma Amosy , Cohn Steven , Shi Xuan-Zheng
Published: January 2022

BACKGROUND AND AIMS

Exclusive enteral nutrition (EEN) is the only established dietary therapy for Crohn’s disease (CD). However, mechanisms of action of EEN in CD are not clear. CD is characterized by recurrent transmural inflammation in the gut. Mechanical stress, associated with inflammatory cell infiltration, edema, fibrosis, and obstruction, is inevitably present in CD tissue. We hypothesized that transmural inflammation causes mechanical stress, which induces expression of mechanosensitive genes such as IL-6 and COX-2 in the gut, and that EEN treatment attenuates inflammation by alleviating the effect of mechanical stress-induced expression of proinflammatory genes in CD.

METHODS

CD-like colitis was induced by intracolonic instillation of TNBS (65 mg/kg in 250 μL of 40% ethanol) into the distal colon of 8∼10 weeks old SD rats. Control rats were treated with intracolonic saline instillation. We fed the control and colitis rats with either normal pellet food or EEN with Ensure liquid diet ad lib. Rats were euthanized 7 days after treatments.

RESULTS

(1) TNBS colitis rats presented decreased body weight, increased disease activity and inflammation index of the colon in pellet food treated rats, which were dramatically improved by EEN treatment. (2) EEN did not significantly affect body weight in control rats, though it dramatically reduced fecal weight by 84.5(±4.3)%, and increased fecal water content by 29.8(±1.3)%. (3) In the solid food fed rats, TNBS treatment induced a localized transmural inflammation with narrowed lumen in the site of instillation (site I) (Figure 1). This led to a distended colon segment (site P) prior to site I, and a non-distended segment (site D) distal to site I. Expression of IL-6 and COX-2 mRNAs was increased significantly (p<0.01) by 111(±44) and 13.1(±2.5)-fold in site I of CD rats, compared to controls. Importantly, the IL-6 and COX-2 mRNA expression was also significantly increased in the distended site P [228(±72) and 16.6(±4.3)-fold], but not in site D (Figure 2). The increased expression of IL-6 and COX-2 occurred mainly in the colonic smooth muscle cells (SMC). (4) However, EEN treatment with Ensure Regular prevented lumen distention in colitis rats. The increase of IL-6 and COX-2 expression in colitis was attenuated drastically in sites I and P (Figure 2). Treatment with other types of liquid diet (Ensure Clear or rodent liquid diet) had similar effects. (5) Expression of IL-6 and COX-2 was highly inducible by mechanical stretch in cultured colonic SMC in vitro and by lumen distention in colon obstruction.

CONCLUSIONS

Mechanical stress plays a critical role in gut inflammation by inducing expression of mechanosensitive proinflammatory mediators in CD-like colitis. EEN treatment reduces inflammation in CD by alleviating the effects of mechanical stress on expression of genes such as IL-6 and COX-2.
CLINICAL FEATURES AND OUTCOMES OF PAEDIATRIC PATIENTS WITH ISOLATED COLONIC CROHN’S DISEASE: A MULTICENTRE STUDY FROM THE PAEDIATRIC IBD PORTO GROUP OF ESPGHAN
Authors: Berger Tal , Lee Huey Miin , Padmanaban Lavenya Ramasamy , Wine Eytan , Yerushalmy-Feler Anat , Hojsak Iva , Kazeka Denis , Serban Daniela Elena , Yogev Dotan , Ledder Oren , Lionetti Paolo , Scarallo Luca , Gasparetto Marco , Croft Nicholas M , Miele Erasmo , Staiano Annamaria , Meredith Joseph , Aloi Marina , Alvisi Patrizia , Urlep Darja , Weiss Batia , Malham Mikkel , Matar Manar , Navas-López Víctor , Romano Claudio , Dipasquale Valeria , Norsa Lorenzo , Kolho Kaija-Leena , Shamir Raanan , Shouval Dror
Published: January 2022

BACKGROUND

Adult studies suggest that patients with isolated colonic Crohn’s disease (L2 CD) exhibit unique characteristics differentiating them from patients with ileo-cecal (L1) CD and ulcerative colitis (UC). We aimed to characterize clinical features and outcomes of paediatric patients with L2.

METHODS

Retrospective data was collected through the Porto IBD group of ESPGHAN on paediatric patients with L2, L1 or UC at different time-points. Outcome measures included time to 1st flare, hospital admissions, initiation of anti-TNFa drug, stricture and surgery.

RESULTS

Three hundred patients were included: 102 L1, 94 L2 and 104 UC. Rates of hematochezia at presentation were 14.7%, 44.7% and 95.2%, while rates of fever were 12.7%, 26.6% and 2.9%, for patients with L1, L2 and UC, respectively (P<0.001 for all comparisons). Skip lesions were identified in 65% of patients with L2, and granulomas in 36%, similar to L1 patients. Rates of ASCA and pANCA positivity significantly differed between the groups: 25.4% and 16.7% for patients with L2, compared with 55.2% and 2.3%, and 1.8% and 52.9% for patients with L1 and UC, respectively. Response rates to exclusive enteral nutrition were comparable between L1 and L2 (78.3-82.4%), as was the response to oral steroids (70.4-76.5%) in the three groups. While times to 1st flare and admission were similar between groups, patients with L1 were commenced on anti-TNFa earlier. Moreover, stricturing phenotype and need for colectomy were very rare in patients with L2.

CONCLUSIONS

Significant differences are observed in the clinical presentation and outcomes of paediatric patients with L2, compared to patients with L1 and UC.
FEAR OF THE COVID-19 PANDEMIC IN ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE: RELATIONSHIP TO PSYCHOLOGICAL AND PHYSICAL OUTCOMES
Authors: Neiman Nicole , Anjur Kavya , Yeh Ann Ming , Bensen Rachel , Wren Anava
Published: January 2022

BACKGROUND

The fear of contracting COVID-19 has taken a significant toll on the psychological and physical health of adolescents and young adults (AYA), especially those with chronic health conditions. AYA with Inflammatory Bowel Disease (IBD) are at increased risk for poor psychological and physical well-being. However, to date, there is no published research examining the Fear of COVID-19 Scale (FCV-19S) in AYA with IBD.

AIMS

To assess: 1) the reliability of the Fear of COVID-19 Scale in AYA with IBD, and 2) how the fear of COVID-19 relates to key psychological (i.e., anxiety, depression) and physical (i.e., fatigue, pain, disease activity) outcomes in AYA with IBD.

METHODS

This ongoing study is a collaboration between Stanford University and ImproveCareNow. Participants included 64 AYA with IBD (M=18.7 years old; 52% Ulcerative Colitis; 60% female; 60% White). Participants completed a one-time online survey. Correlation analyses examined the association between fear of COVID-19, outcome variables (i.e., anxiety, depression, fatigue, pain, disease activity), and demographic variables. Multiple linear regression (MLR) analyses (using the F test) further examined the association between fear of COVID-19, outcome variables, and significant demographic variables (i.e., age, sex).

RESULTS

The internal reliability of FCV-19S was measured using Crohnbach’s alpha (α=0.88), indicating high internal consistency. Correlation analyses demonstrated that fear of COVID-19 was significantly associated with anxiety, depression, and fatigue (Table 1). The overall MLR models were significant for anxiety (P<0.001), depression (P=0.002), and fatigue (P=0.031), but not for pain and disease activity. Fear of COVID-19, age, and sex accounted for 29% of the variance in anxiety, 27% of the variance in depression, and 17% of the variance in fatigue. Fear of COVID-19 was not a significant independent predictor of outcomes (Table 2). Female sex was a significant independent predictor for greater levels of anxiety (b=-0.31, P=0.016) and depression (b=-0.35, P=0.008). Older age was a significant independent predictor for greater levels of depression (b=0.29, P=0.031).

CONCLUSION

Preliminary results suggest that FCV-19S can be reliably assessed in AYA with IBD. Analyses indicate that fear of COVID-19 is associated with anxiety, depression, and fatigue in AYA with IBD. While COVID-19 fear may be important in explaining these outcomes, female sex independently predicted increased anxiety and depression, and older age independently predicted depression. This highlights the importance of assessing relevant demographic variables (e.g., female sex, young adults) when considering predictors of adjustment in AYA with IBD. Research should further investigate fear of COVID-19 in larger, more diverse IBD populations to better understand its relationship to key IBD outcomes.
BEZLOTOXUMAB THERAPY FOR RECURRENT CLOSTRIDIUM DIFFICILE INFECTION IN AN ULCERATIVE COLITIS PATIENT
Authors: Fein Aaron , Kern Cody , Mohamed Rana , Barrett Terrence , Perry Courtney
Published: January 2022

INTRODUCTION

Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea, comprising 10-20% of all cases. CDI is a significant complication for IBD patients. Not only can CDI induce IBD flare, IBD patients also experience significantly higher CDI recurrence when compared to the general population. New monoclonal antibody (mAB) therapies, such as bezlotoxumab, have improved management of recurrent CDI (rCDI). The MODIFY I/II trial included 44 patients with known IBD, 28 of which received bezlotoxumab. Among these 28 patients, there was a 27.2% absolute reduction in the incidence of rCDI. Encouraged by these results, we recently prescribed bezlotoxumab in a UC patient with rCDI and herein report our experience.

CASE REPORT

A 21-year-old female with a history of ulcerative colitis (UC) diagnosed in 2017 presented for treatment of rCDI. Her first episode of CDI occurred in 2019 during an active UC flare treated with steroids and infliximab induction. CDI was successfully treated with a four-week course of 125mg oral vancomycin twice daily followed by once daily for an additional four weeks. She had a recurrent episode of CDI one year after her initial infection while on vedolizumab for UC treatment. She was treated with 125mg oral vancomycin, four times daily, and tapered down by one dose over a four-month period. Two years after her initial CDI, she developed worsening non-bloody diarrhea, nausea, and anorexia with weight loss. She again tested positive for C. difficile via glutamate dehydrogenase antigen and PCR for toxin B. Fecal calprotectin was 2190 mg/g. She was treated with 14-day course fidaxomicin 200mg BID and a single infusion of bezlotoxumab 10mg/kg. Treatment for UC was not adjusted. At follow up one month later, her symptoms had resolved and fecal calprotectin normalized (17 mg/g). Six months later, she remains asymptomatic.

DISCUSSION

Recurrent CDI is a frequent culprit for inducing IBD flares, and is difficult to manage. Fecal transplant (FMT) is an option for rCDI, but often entails logistical challenges and risks cross-contamination of endoscopic facilities. Bezlotoxumab is an appealing option for rCDI as a single dose medication with few reported side effects in the MODIFY clinical trials. While the number of IBD patients in the MODIFY trial was small, results were promising. In our patient, bezlotoxumab quickly resolved her rCDI and IBD flare without need for alteration or escalation of her biologic therapy, and she has remained asymptomatic for six months. This case corroborates the prospect that bezlotoxumab positively affects the clinical outcomes of UC patients with rCDI compared to those on repetitive antimicrobial therapy and/or FMT without mAB therapy. Further investigation into the long-term efficacy of this therapy is merited for the IBD patient population in the real-world setting.