bluuebunny/crossref_metadata_2025 huggingface dataset:
Barriers and enablers to the management of osteoarthritis in primary care in Ireland from the perspective of healthcare professionals and individuals with osteoarthritis: a qualitative study using the Theoretical Domains Framework
Authors: Cunningham Joice , Doyle Frank , Cadogan Cathal , Clyne Barbara , Ryan Jennifer , Smith Susan M , French Helen P
Published: December 2024

Objectives

To explore the barriers and enablers to providing and receiving primary care for osteoarthritis (OA) in Ireland from the perspectives of primary care healthcare professionals (HCPs) and individuals with OA.

Design

Descriptive qualitative study incorporating an inductive thematic analysis to identify key barrier and enabler themes and subsequent deductive mapping to the Theoretical Domains Framework (TDF).

Setting

Primary care in Ireland.

Participants

HCPs, including 6 general practitioners, 5 physiotherapists, 1 occupational therapist and 1 practice nurse, and 13 individuals with OA were interviewed.

Results

Identified barriers and enablers related to nine domains of the TDF. Key barriers identified by HCPs included limited and delayed access to multidisciplinary primary care services, lack of integrated care pathways specific to OA and insufficient training in musculoskeletal conditions including OA. Individuals with OA also reported poor access to health services due to long waiting lists, lack of education on OA and feelings of not being taken seriously by HCPs. There is a need for targeted HCP education and training to address the identified knowledge, skills and confidence gaps in communication, diagnosis and evidence-based management of OA. Improved management of OA through system-level changes, including integrated care pathways with multidisciplinary services to better support individuals with OA in the community, is required.

Conclusions

This study identified several barriers and enablers to the management of OA. These findings highlight areas to be targeted by future interventions aimed at improving the management of OA in primary care.
Dexamethasone alleviates acute lung injury in a rat model with venovenous extracorporeal membrane oxygenation support
Authors: Wei Shi-Lin , Du Jun-Zhe , Zhai Ke-Rong , Yang Jian-Bao , Zhang Ran , Wu Xiang-Yang , Li Yongnan , Li Bin
Published: December 2024

Background

In recent years, dexamethasone (Dex) has been used to treat acute respiratory distress syndrome (ARDS) in patients with COVID-19 and achieved promising outcomes. Venovenous extracorporeal membrane oxygenation (VV ECMO) support for patients with ARDS has increased significantly worldwide. However, it remains unknown whether Dex could improve the efficiency of VV ECMO to reduce lung injury. Here, we investigate the combined efficiency of VV ECMO and Dex in rats with acute lung injury (ALI).

Methods

We established VV ECMO in oleic acid (OA)-treated ALI rats and administered Dex. We conducted HE staining and evaluated lung and bronchoalveolar lavage (BAL) fluid cytokines to assess lung injury and inflammation. Furthermore, we investigated the activation of Hippo/YAP signalling in alveolar epithelial type II cell (AT2)-mediated alveolar epithelial repair using quantitative PCR, Western blotting and immunofluorescence. In vitro, the human alveolar epithelial cell line A549 was used to investigate the key role of YAP in alveolar epithelial cell differentiation.

Results

VV ECMO combined with Dex alleviated OA-induced lung injury and pulmonary inflammation. Pulmonary oedema and exudation were significantly alleviated, and the lung and BAL levels of IL-6, IL-8 and TNF-α were significantly reduced compared with those observed with ECMO alone. In addition, VV ECMO combined with Dex treatment protected alveolar epithelial cells by activating Hippo/YAP signalling. In vitro, Dex promoted YAP expression and alveolar epithelial cell differentiation, whereas YAP knockdown inhibited YAP-mediated differentiation.

Conclusions

Our findings suggest that adjuvant Dex treatment during VV ECMO could alleviate ALI and pulmonary inflammation by activating the Hippo/YAP signalling pathway, which promoted alveolar regeneration and AT2 differentiation.
Creep behavior of ice-rich warm peaty soils along the Trans Alaska Pipeline system at Lost Creek, Alaska
Authors: Bray Matthew , Darrow Margaret
Published: December 2024

In Interior Alaska, a slope underlying the Trans Alaska Pipeline System has recently experienced downslope movement, which is attributed to a buried frozen, ice-rich peat layer. We performed a field investigation of the site, including coring and sampling, and conducted a suite of laboratory tests, including mechanical tests at temperatures between −0.56 and −5 °C to quantify the secondary creep behavior and to estimate the impact of soil cooling on the creep deformation. We tested a variety of soils, including ice-rich silt, silty peat, and peat with the majority having an organic content of 10% or greater. The results indicated that temperature has a strong control on the resulting time-dependent mechanical properties. Here we provide secondary creep power law relationships for these soils. The analysis indicates that cooling the soils can be effective in reducing creep movement; for example, cooling by 1.1 °C from −0.56 to −1.67 °C results in an order of magnitude reduction in the shear deformation rates. These results are significant as they add to the limited amount of work done on the time-dependent mechanical behavior of ice-rich peat and organic soils at warm sub-freezing temperatures.
Quantum information of a relativistic particle with position-dependent mass under the Aharonov–Casher effect
Authors: Moreira A.R.P. , Amadi P.O. , Ikot A.N. , Horchani R. , Ali Norshamsuri
Published: December 2024

In this work, the influence of the Aharonov–Casher (AC) effect is investigated for a relativistic particle with position-dependent mass through Shannon quantum information. Shannon’s formalism is appropriate because its results suggest explanations for the measurement uncertainties of a quantum system. To calculate Shannon’s entropy, it is necessary to obtain the description of quantum eigenstates. Using the eigenstates obtained, we analyzed the system quantum information in position and momentum space. Considering the results of Shannon’s entropy, it is possible to understand the influence of the AC effect and the position-dependent mass on the quantum information. It was possible to notice that the informational content decreases in the position space when we increase the value of the parameter that controls the mass profile. This result is strong, as it indicates a decrease in uncertainties related to particle position measurements. The opposite happens when we increase the quantum phase ΦAC.
Enhanced Data-Driven Framework for Anomaly Detection in Smart Grid IEDs
Authors: Khanh Son Nguyen , Sangaiah Arun Kumar , Medhane Darshan Vishwasrao , Alenazi Mohammed J. F. , AlQahtani Salman A. , Aborokbah Majed
Published: December 2024

The incorporation of Information and Communication Technologies (ICT) into traditional power grids has transformed them into smart grids, revolutionizing energy management systems. At the core of this transformation are Intelligent Electronic Devices (IEDs), which provide essential data for key Energy Management System (EMS) applications, such as state estimation and optimal power flow. IEDs are critical for ensuring the stability and security of smart grid operations, but they are also vulnerable to various anomalies, including infrastructure faults, equipment malfunctions, energy theft, and cyberattacks. Detecting these anomalies is vital to maintaining the reliability of smart grid systems and preventing potential threats to national security. This study introduces a statistical data-driven framework designed to detect and explain anomalies in IED-based smart grid systems. The framework includes a preprocessing module for ensuring high-quality input data and an anomaly detection module that prioritizes interpretability and explainability. Using methods like the Gaussian Mixture Model (GMM), Kalman Filter (KF), and ExtraTree Classifier, the framework achieves 99% accuracy in anomaly detection and 88% accuracy in classifying events as either natural occurrences or cyberattacks.
Out-of-Plane Crashworthiness of Buckling-Induced Hierarchical Quasi-Honeycomb
Authors: Li Xiang , Gu Hao , Zhao Lei , Xiang Feng , Wu Haihua , Fu Junjian , Li Ningchuang
Published: December 2024

A novel quasi-honeycomb (buckling-induced hierarchical quasi-honeycomb, BIHQ) with buckling-induced features and hierarchical structure has been designed to improve the crashworthiness of honeycomb structures. Its crashworthiness and deformation patterns are investigated by finite element simulation. The crashworthiness of BIHQ is compared with that of other conventional honeycomb structures, as well as the crashworthiness of different hierarchical BIHQs. It was found that the crashworthiness of BIHQ was improved by introducing geometrical defects in BIHQ, which greatly reduced the initial peak force (IPF) of the structure and increased the specific energy absorption (SEA). In addition, hierarchical structures have significant potential to improve crashworthiness by improving the SEA of honeycomb structures, especially, the second-order BIHQ in particular shows substantial advantages for energy absorption efficiency. Finally, the effects of relevant parameters on their crashworthiness were investigated by parametric analysis. It was found that the crashworthiness could be improved by changing the parameters of BIHQ. In particular, by decreasing the size ratio parameter k or increasing the number of induced layers N, the IPF and increasing the crushing force efficiency (CFE) of BIHQ can be effectively reduced, thus improving the crashworthiness of the structure.
Thermodynamics of Charged Acoustic Black Hole: Heat Engine
Authors: Mondal Debojyoti , Debnath Ujjal , Pradhan Anirudh
Published: December 2024

In this paper, the charged acoustic black hole with a cosmological constant has been assumed. We have taken into account the negative cosmological constant as thermodynamic pressure in the extended phase space. Then we derived the thermodynamic quantities and investigated their behavior. We have studied the critical values of temperature and pressure. By calculating the specific heat capacity, we have analyzed the thermal stability of the charged acoustic black hole. Then we studied the heat engine phenomena of the black hole. We discovered the Carnot engine’s efficiency and the brand-new engine phenomenon of the black hole.
Impact of curvature-matter coupling on charged spherical polytropes
Authors: Sadiq Sobia , Abbas Ertaza
Published: December 2024

This study employs [Formula: see text] gravity, where [Formula: see text] is the Ricci scalar, and [Formula: see text] is the trace of energy–momentum tensor, to analyze charged spherically symmetric fluid distributions governed by a polytropic equation of state, thereby exploring the impact of direct coupling between matter fields and the curvature of spacetime on stellar configurations. We present two families of relativistic polytropes for both anisotropic and isotropic matter sources in the presence of electromagnetic field and derive the structural equations (mass conservation and modified Tolman–Oppenheimer–Volkoff equations). The numerical method is utilized to solve structural equations by varying the values of arbitrary parameters and polytropic constants. Using energy constraints, the physical feasibility of polytropes is examined. In addition to this, some other stellar properties such as compactness, redshift and adiabatic index are found to be well-behaved as they fulfill the required criteria. Also, the speed of sound parameter fulfills the stability criterion of the stellar body. For both isotropic and anisotropic stellar configurations, the effects of charge and the curvature-matter coupling parameter are important since they highly affect how compact these structures are.
The impact of f(Q,T) gravity on Barrow holographic dark energy: A cosmological analysis
Authors: Myrzakulov N. , Shekh S. H. , Pradhan Anirudh , Ghaderi K.
Published: December 2024

In this paper, we explore a new version of dark energy called Barrow holographic dark energy within the framework modified gravity called [Formula: see text] gravity by adopting the simple homogeneous, isotropic, and spatially flat Friedmann–Robertson–Walker (FRW) model of the universe. Our goal is to understand how the universe evolved over time. To do this, we use parameterizetion of Hubble’s parameter method. We then use a powerful tool called Monte-Carlo Markov Chain to find the best values for the constants in our formula. We do this by comparing our formula to actual data from observations of the universe. Once we have the best values for the constants, we calculate other important parameters that describe the universe’s evolution. These include: Deceleration parameter which measures how quickly the expansion is slowing down. We found [Formula: see text]. Equation of state parameter measures the properties of dark energy. We find [Formula: see text]. We also study the stability and energy conditions along with the state-finder and [Formula: see text]-parameter of our model to ensure it is consistent with our understanding of the universe.
An Ontology Network for Citizen Curation
Authors: Asprino Luigi , Damiano Rossana , Daquino Marilena , De Giorgis Stefano , Gangemi Aldo , Lieto Antonio , Sartini Bruno , Striani Manuel
Published: December 2024

Citizen curation is gaining momentum as a new form of engagement with cultural heritage. Citizen curatorial activities require and produce a wealth of information, ranging from descriptions of the artefacts to visitor experience feedback. Although formalising and integrating such various data is of paramount importance, the domain lacks comprehensive ontologies to enable querying, interpreting and reasoning over the collected data. Social Participation, Cohesion and Inclusion through Cultural Engagement (SPICE) is an EU project dedicated to experimenting with citizen curation activities to foster cultural engagement. SPICE develops technologies that help communities to create and share their own interpretation of cultural artefacts, hence developing a better understanding of, and empathy for, themselves and other communities. Part of the SPICE ecosystem of technologies is the SPICE Ontology Network (SON), which empowers applications with knowledge-level reasoning abilities and supports both applications and users interacting with data involved in citizen curation activities. This article provides an overview of the SON and outlines its main use cases.
Gradual C0: Symbolic Execution for Gradual Verification
Authors: DiVincenzo Jenna , McCormack Ian , Zimmerman Conrad , Gouni Hemant , Gorenburg Jacob , Ramos-Dávila Jan-Paul , Zhang Mona , Sunshine Joshua , Tanter Éric , Aldrich Jonathan
Published: December 2024

Current static verification techniques such as separation logic support a wide range of programs. However, such techniques only support complete and detailed specifications, which places an undue burden on users. To solve this problem, prior work proposed gradual verification, which handles complete, partial, or missing specifications by soundly combining static and dynamic checking. Gradual verification has also been extended to programs that manipulate recursive, mutable data structures on the heap. Unfortunately, this extension does not reward users with decreased dynamic checking as more specifications are written and more static guarantees are made. In fact, all properties are checked dynamically regardless of any static guarantees. Additionally, no full-fledged implementation of gradual verification exists so far, which prevents studying its performance and applicability in practice.

We present Gradual C0, the first practicable gradual verifier for recursive heap data structures, which targets C0, a safe subset of C designed for education. Static verifiers supporting separation logic or implicit dynamic frames use symbolic execution for reasoning; so Gradual C0, which extends one such verifier, adopts symbolic execution at its core instead of the weakest liberal precondition approach used in prior work. Our approach addresses technical challenges related to symbolic execution with imprecise specifications, heap ownership, and branching in both program statements and specification formulas. We also deal with challenges related to minimizing insertion of dynamic checks and extensibility to other programming languages beyond C0. Finally, we provide the first empirical performance evaluation of a gradual verifier, and found that on average, Gradual C0 decreases run-time overhead between 7.1 and 40.2% compared to the fully dynamic approach used in prior work (for context, the worst cases for the approach by Wise et al. [
2020
] range from 0.1 to 4.5 seconds depending on the benchmark). Further, the worst-case scenarios for performance are predictable and avoidable. This work paves the way towards evaluating gradual verification at scale.
Faster Matroid Partition Algorithms
Authors: Terao Tatsuya
Published: December 2024

In the matroid partitioning problem, we are given

\(k\)

matroids

\(\mathcal{M}_{1}=(V,\mathcal{I}_{1}),\dots,\mathcal{M}_{k}=(V,\mathcal{I}_{k})\)

defined over a common ground set

\(V\)

of

\(n\)

elements, and we need to find a partitionable set

\(S\subseteq V\)

of largest possible cardinality, denoted by

\(p\)

. Here, a set

\(S\subseteq V\)

is called partitionable if there exists a partition

\((S_{1},\dots,S_{k})\)

of

\(S\)

with

\(S_{i}\in\mathcal{I}_{i}\)

for

\(i=1,\ldots,k\)

. In 1986, Cunningham presented a matroid partition algorithm that uses

\(O(np^{3/2}+kn)\)

independence oracle queries, which was the previously known best algorithm. This query complexity is

\(O(n^{5/2})\)

when

\(k\leq n\)

.

Our main result is to present a matroid partition algorithm that uses

\(\tilde{O}(k^{\prime 1/3}np + kn)\)

independence oracle queries, where

\(k^{\prime}=\min\{k,p\}\)

. This query complexity is

\(\tilde{O}(n^{7/3})\)

when

\(k\leq n\)

, which improves upon that of Cunningham’s algorithm. To obtain our algorithm, we present a new approach
edge recycling augmentation
, which can be attained through new ideas: an efficient utilization of the binary search technique by Nguy

\(\tilde{{\hat{\text{e}}}}\)

n and Chakrabarty et al. and a careful analysis of the independence oracle query complexity. Our analysis differs significantly from the one for matroid intersection algorithms, because of the parameter

\(k\)

. We also present a matroid partition algorithm that uses

\(\tilde{O}((n+k)\sqrt{p})\)

rank oracle queries.
Structure-Adaptive and Power-Aware Broadcast Scheduling for Multihop Wireless-Powered IoT Networks
Authors: Chen Quan , Cai Zhipeng , Li Jing , Li Ning , Cheng Lianglun , Gao Hong , Guo Song
Published: December 2024

Wireless Power Transfer technology, which can charge IoT devices over the air, has become a promising technology for IoT networks. In wireless-powered IoT networks, broadcasting is a fundamental networking service for disseminating messages to the whole network. To seek a fast and collision-free broadcast schedule, the problem of Minimum Latency Broadcast Scheduling (MLBS) has been well studied when nodes are energy-abundant. However, in wireless-powered networks, a node can only receive or transmit packets after it has harvested enough energy. In such networks, it is of great importance to exploit the divergent harvested energy to reduce the broadcast latency. Unfortunately, existing works always assume a predetermined tree and a fixed transmission power for broadcast scheduling, which greatly limits their performance. Thus, in this article, we investigate the first work for the MLBS problem in wireless-powered networks without relying on predetermined trees. First, the problem is formulated and proved to be NP-hard. Then, two structure-adaptive scheduling algorithms are proposed with a theoretical bound, which can intertwine the construction of broadcast tree with the computation of an energy-aware schedule simultaneously. Furthermore, a power-aware scheduling method is also proposed to take the structure of the broadcast tree, the adjustment of nodes’ transmission powers, and the interference during transmissions into account simultaneously. Additionally, the algorithm for the MLBS problem under the physical interference model is also studied. Finally, the theoretical analysis and simulation results verify that the proposed algorithms have high performance in terms of latency.
Cultural Adaptation and Psychometric Validation of the Simplified Chinese Version of the Fear Avoidance Component Scale (FACS)
Authors: Tu Zhongyi , Miao Junfang , Zhang Yanzhao , Yang Zhaohui , Xu Rui , Neblett Randy
Published: December 2024

Background: Strong associations have been demonstrated between chronic musculoskeletal pain, pain‐related fear‐avoidance (FA) of activities of daily living, and functional disability. The Fear Avoidance Components Scale (FACS) is a patient‐reported outcome (PRO) measure, which was designed to evaluate cognitive, emotional, and behavioural dimensions of FA.

Objective: The study aims were to translate the English version of the FACS into Simplified Chinese and then to examine its psychometric properties.

Methods: The translation and cross‐cultural adaptation of the FACS from English to Chinese was performed with standard methodology. A group of 330 subjects with chronic musculoskeletal pain completed the FACS‐Chi and additional FA‐related PRO measures. The FACS‐Chi was then completed a second time, 1 week later.

Results: The FACS‐Chi showed excellent internal consistency (Cronbach’s alpha = 0.920) and test‐retest reliability (ICC = 0.918). A confirmatory factor analysis of the 2‐factor model determined in the original English version of FACS revealed an acceptable fit. Strong correlations were found between FACS‐Chi scores and other PRO measures of perceived level of disability, pain catastrophizing, and pain‐related anxiety (p < 0.001 for all analyses).

Conclusions: The FACS‐Chi demonstrated good psychometric properties, including excellent test‐retest reliability and internal consistency and satisfactory construct validity. The FACS‐Chi may be a useful measure of pain‐related FA in Chinese‐speaking patients with chronic musculoskeletal pain.
Fowl Cholera in Chickens: Current Trends in Diagnosis and Phenotypic Drug Resistance in Gondar City, Ethiopia
Authors: Geda Abdo Megra
Published: December 2024

Ethiopia, with an estimated chicken population of 17 million, serves as a source of high‐quality animal protein, helping to reduce malnutrition, improve nutritional status, and provide food and food products. However, Ethiopia has not fully leveraged the value of chicken production due to various bacterial diseases, with fowl cholera (FC) being the most common. Therefore, the objective of this review is to highlight the current trends in the diagnosis of FC in chickens and asses its phenotypic drug resistance patterns in Gondar City. FC is an infectious disease caused by Pasteurella multocida (P. multocida), which poses significant health and financial losses to the poultry industry. Culturally, the bacterium P. multocida can be isolated using bacteriological and biochemical tests from chicken infected with FC. Molecular‐based techniques such as capsular and lipopolysaccharide genotyping, as well as nucleic acid amplification tests through PCR assays, are also among the best methods used to detect P. multocida. In conclusion, understanding the current trends in diagnosing FC and assessing its phenotyping drug resistance, which helps in choosing effective antibiotics in Gondar City, is essential. It is also important to assess the disease‐associated factors that enhance the occurrence of the disease, in addition to providing the disease preventive and control measures and vaccination programs based on the diagnosis of its causative agent.
spatialGE Is a User-Friendly Web Application That Facilitates Spatial Transcriptomics Data Analysis
Authors: Ospina Oscar E. , Manjarres-Betancur Roberto , Gonzalez-Calderon Guillermo , Soupir Alex C. , Smalley Inna , Tsai Kenneth Y. , Markowitz Joseph , Khaled Mariam L. , Vallebuona Ethan , Berglund Anders E. , Eschrich Steven A. , Yu Xiaoqing , Fridley Brooke L.
Published: December 2024

Spatial transcriptomics (ST) is a powerful tool for understanding tissue biology and disease mechanisms. However, the advanced data analysis and programming skills required can hinder researchers from realizing the full potential of ST. To address this, we developed spatialGE, a web application that simplifies the analysis of ST data. The application spatialGE provided a user-friendly interface that guides users without programming expertise through various analysis pipelines, including quality control, normalization, domain detection, phenotyping, and multiple spatial analyses. It also enabled comparative analysis among samples and supported various ST technologies. The utility of spatialGE was demonstrated through its application in studying the tumor microenvironment of two data sets: 10× Visium samples from a cohort of melanoma metastasis and NanoString CosMx fields of vision from a cohort of Merkel cell carcinoma samples. These results support the ability of spatialGE to identify spatial gene expression patterns that provide valuable insights into the tumor microenvironment and highlight its utility in democratizing ST data analysis for the wider scientific community.

Significance: The spatialGE web application enables user-friendly exploratory analysis of spatial transcriptomics data by using a point-and-click interface to guide users from data input to discovery of spatial patterns, facilitating hypothesis generation.
First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors
Authors: Johnson Melissa L. , Wolf Beni B. , Wang Judy S. , Philipovskiy Alexander , Shapiro Geoffrey I. , Bockorny Bruno , Guo Wei , Shen Jinshan , Jen Kai Yu , LeRose MaryBeth , Hunter Tamieka Lauz , Padval Mahesh , Schmidt-Kittler Oleg , Bhatia Namrata , Dubey Sarita , Suchomel Julia , Bendell Johanna C. , Jauhari Shekeab , Eng-Wong Jennifer , Lin Jessica J.
Published: December 2024

Src homology-2 domain–containing phosphatase 2 promotes rat sarcoma viral oncogene homolog–MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective Src homology-2 domain–containing phosphatase 2 inhibitor designed for the treatment of rat sarcoma viral oncogene homolog–MAPK–driven cancers, particularly in combination with other targeted agents. Here, we report first-in-human study results of single-agent migoprotafib in patients with advanced solid tumor. We conducted a phase Ia, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics (PK), pharmacodynamics (peripheral blood phosphorylated ERK), and preliminary antitumor activity. Fifty-six heavily pretreated patients were treated with migoprotafib (10–150 mg once daily). Migoprotafib had a rapid absorption rate (∼0.5–2 hours) with dose-dependent increases in exposure and pathway modulation (phosphorylated ERK changes). The maximum tolerated dose was 100 mg, and the recommended phase II dose was 60 mg daily (once daily) based on safety, PK, pharmacodynamics, and antitumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, aspartate aminotransferase increase, and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports once-daily dosing and demonstrated promising safety, tolerability, and clinical activity at the recommended phase II dose. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.
Denfivontinib Activates Effector T Cells Through the NLRP3 Inflammasome, Yielding Potent Anticancer Effects by Combination with Pembrolizumab
Authors: Kim Dong Kwon , Synn Chun-Bong , Lee Wongeun , Jo Ha-Ni , Lee Chai Young , Lee Seul , Hwang Joon Yeon , Kim Youngtaek , Kang Seong-san , Baek Sujeong , Na Kwangmin , Yang Seung Min , Kim Mi Hyun , Han Heekyung , Han Yu Jin , Kim Jae Hwan , Park So Young , Park Young Joon , Lee Gang-Taik , Choi Su-Jin , Sohn Jie-Ohn , Ye Sang-Kyu , Lee Jii Bum , Lim Sun Min , Hong Min Hee , Pyo Kyoung-Ho , Cho Byoung Chul
Published: December 2024

Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutic limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances antitumor effects when combined with anti–PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γexpression in the YHIM-2004 xenograft model derived from patients with non–small cell lung cancer. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating NLRP3 inflammasome formation. This leads to macrophage activation via NF-κB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knockout mice confirmed that AXL inhibition by denfivontinib enhances the antitumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk RNA sequencing data from 21 patients with non–small cell lung cancer undergoing anti–PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti–PD-1 immunotherapy, suggesting a role for the NLRP3 inflammasome in activating immune responses during treatment.
Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease
Authors: Zhu (朱培) Pei , Chao Calvin L. , Steffeck Adam W.T. , Dang Caitlyn , Hamlish Noah X. , Pfrender Eric M. , Jiang Bin , Peek Clara B.
Published: December 2024

BACKGROUND:

Peripheral artery disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia.

METHODS:

We performed secondary analysis of publicly available RNA-sequencing data sets derived from patients with PAD to identify the differential expression of circadian-related genes in endothelial cells and ischemic limb skeletal muscles. We used mice with specific genetic loss of the circadian clock activator, BMAL1 (brain and muscle ARNT-like 1), in adult skeletal muscle tissues (
Bmal1

muscle

).
Bmal1

muscle

mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser Doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and assay for transposase-accessible chromatin with sequencing analyses in primary myotube culture model.

RESULTS:

Disrupted expression of circadian rhythm–related genes was observed in existing RNA-sequencing data sets from endothelial cells and ischemic limb skeletal muscles derived from patients with PAD. Genetic loss of
Bmal1
specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in
Bmal1

muscle

mouse muscles in the ischemic limbs but not in their contralateral nonischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia adaptation in
Bmal1

muscle

mouse muscles. These changes were corroborated in
Bmal1
-deficient cultured primary myotubes cultured under hypoxic conditions.

CONCLUSIONS:

Circadian clock in skeletal muscle is crucial for the muscle’s response to hypoxia during hindlimb ischemia. Targeting the muscle circadian clock may have therapeutic potential for enhancing muscle response to reduced blood flow and promoting recovery in conditions such as PAD.
Human Genetic Evidence to Inform Clinical Development of IL-6 Signaling Inhibition for Abdominal Aortic Aneurysm
Authors: Burgess Stephen , Cronjé Héléne T. , deGoma Emil , Chyung Yung , Gill Dipender
Published: December 2024

BACKGROUND:

Abdominal aortic aneurysm (AAA) represents a significant cause of mortality, yet no medical therapies have proven efficacious. The aim of the current study was to leverage human genetic evidence to inform clinical development of IL-6 (interleukin-6) signaling inhibition for the treatment of AAA.

METHODS:

Associations of rs2228145, a missense variant in the
IL6R
gene region, are expressed per additional copy of the C allele, corresponding to the genetically predicted effect of IL-6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39 221 cases and 1 086 107 controls) and UK Biobank (1963 cases and 365 680 controls). To validate against known effects of IL-6 signaling inhibition, we present associations with rheumatoid arthritis, polymyalgia rheumatica, and severe COVID-19. To explore mechanism specificity, we present associations with thoracic aortic aneurysm, intracranial aneurysm, and coronary artery disease. We further explored genetic associations in clinically relevant subgroups of the population.

RESULTS:

We observed strong genetic associations with AAA risk in the AAAgen consortium, UK Biobank, and FinnGen (odds ratios: 0.91 [95% CI, 0.90–0.92],
P
=4×10
−30
; 0.90 [95% CI, 0.84–0.96],
P
=0.001; and 0.86 [95% CI, 0.82–0.91],
P
=7×10
−9
, respectively). The association was similar for fatal AAA but with greater uncertainty due to the lower number of events. The association with AAA was of greater magnitude than associations with coronary artery disease and even rheumatological disorders for which IL-6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm or intracranial aneurysm. Associations attenuated toward the null in populations with concomitant rheumatological or connective tissue disease.

CONCLUSIONS:

Inhibition of IL-6 signaling is a promising strategy for treating AAA but not other types of aneurysmal disease. These findings serve to help inform clinical development of IL-6 signaling inhibition for AAA treatment.
Cross-Sex Hormone Therapy Is Associated With Loss of Circadian Rhythm in the Male Rat
Authors: Mallette Jordan H. , Crudup Breland F. , Oudomrath Speyrer Adrian , Rawls Adam Z. , Cockrell Kathy , Willis Alex T. , Davenport Kacey , Yanes Cardozo Licy L. , Shawky Noha M. , Alexander Barbara T.
Published: December 2024

BACKGROUND:

Transgender women are individuals born male but identify as female. Many transgender women undergo gender-affirming hormone therapy to alleviate the distress that can occur due to gender incongruence. For transgender women, gender-affirming hormone therapy includes 17β-estradiol (E2) combined with an antiandrogen therapy (AA) or surgical intervention. Numerous studies suggest that the risk of cardiovascular disease is elevated in transgender women; yet, the biological effects of gender-affirming hormone therapy on cardiovascular health are unknown. We hypothesize that a shift in the hormonal milieu versus natal sex in the male rat is associated with an increase in blood pressure at baseline and an enhanced responsiveness to a hypertensive challenge.

METHODS:

We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women.

RESULTS:

Chronic E2 plus castration or the E2+antiandrogen spironolactone was associated with a significant reduction in lean mass and testosterone. At baseline, 24-hour mean arterial pressure did not differ in E2+castration or E2+antiandrogen therapy versus control, but circadian rhythm was disrupted. In response to chronic Ang II (angiotensin II; 200 ng/kg per minute), the Ang II-induced increase in blood pressure was attenuated in E2+castration compared with control, but the blood pressure response to Ang II was similar in E2+antiandrogen therapy versus control.

CONCLUSIONS:

Thus, these data indicate that the type of combination therapy utilized may exert differential effects on blood pressure and that disruption of circadian rhythm may be a contributory factor to the increased risk of adverse cardiovascular outcomes in transgender women exposed to high 17β-estradiol coupled to androgen suppression.
Malevolent Creativity of Adolescents in Different Socio-political Contexts
Authors: Meshkova Natalya V. , Bochkova Margarita N. , Dmitrieva Elena A. , Enikolopov Sergey N. , Meshkov Ivan A.
Published: December 2024

Background. Malevolent creativity is realized in interpersonal interaction in the form of bullying and unethical behavior, harming the psychological health of the victim. The relevance of studying antisocial creativity is due to the optimization of interpersonal relationships and interactions among adolescents.
Objectives. The aim is to study the links between antisocial creativity, hostility, consent, conscientiousness and values in adolescents in different socio-political conditions.
Study Participants. The study is a cross-sectional one and was conducted in 2018 and 2024. The study sample in 2018 was made up of cadets (N=52, Mage = 15.8 SD=0.425; 6 of them were girls). In 2024, high school students from one of the schools in Moscow took part in the study (N=46, Mage = 16.0 SD=0.390; 28 of them were girls).
Methods. Participants filled out forms with questionnaires in person: "NEO-FFI" (adapted by V. Orla, I. Senin), BPAQ-24 (adapted by S.N. Enikolopov, N.P Tzibulskiy), "Behavioral features of antisocial creativity" (adapted by N.V. Meshkova, etc.), Schwartz's portrait value questionnaire — revised PVQ-R. To process quantitative data, Spearman's correlation analysis, nonparametric comparisons using the Mann-Whitney criterion are used.
Results. It was found that the levels of malevolent creativity are higher, and the values of the highest order and the traits of the "Big Five" are lower in adolescents of the 2024 sample. Another peculiarity of the last sample is the absence of a correlation between malevolent creativity and the “Agreeableness” trait and a significant positive correlation between hostility and the “Conscientiousness” trait.
Conclusions. Modern teenagers are less inclined to think over their actions before committing them, are less demanding of observing moral norms, are more concerned about their own interests, are less ready for new ideas and transformative actions, they have reduced values of personal and social focus. Adolescents with such a psychological profile may be at risk for implementing antisocial creativity in deviant behavior. The practice-oriented recommendation is to pay special attention to the formation of values of the younger person.
Development of a Sense of Humor in Preschoolers and Younger Schoolchildren: a Review of Diagnostic Tools
Authors: Shatskaya Arina N. , Oshchepkova Ekaterina S. , Veraksa Nikolay E. , Bayanova Larisa F. , Kovyazina Maria S.
Published: December 2024

Background. A sense of humor is one of the most productive coping strategies that allow both adults and children to effectively cope with stress, regulate emotions, and establish positive social interactions with others. The study of adaptive capabilities of a developed sense of humor, as well as its relationship with various aspects of mental development is limited due to various methodological limitations of existing methods of diagnosing the sense of humor and related constructs (irony, sarcasm, sense of the comic).
Objectives. The purpose of the current paper is to present the results of a review of the main types of diagnostic tools for assessing the development of a sense of humor in preschoolers and younger schoolchildren 4–10 years old in Russian and foreign studies over the last thirty years.
Study Materials. A literature search retrieved 966 publications (626 English-language publications and 340 Russian-language ones). After applying study selection criteria, 66 publications were included in the final qualitative analysis.
Methods. The diagnostic tools used in the reviewed publications were divided into six types according to the main content of the used method of diagnosing the sense of humor. A description of the procedures of the selected types of techniques, as well as the conditions of applicability of each of them, is given.
Results. The results of the conducted review allow us to divide the whole diagnostic toolkit for assessing the sense of humor of preschoolers and younger schoolchildren into techniques for assessing understanding and creation of humor. The most important limitations of each type of methods and recommendations for their use are given. The materials of this review may be useful in selecting diagnostic tools in studies of the sense of humor in children aged 4–10, as well as in developing new diagnostic methods, taking into account the limitations of currently available tools.
Conclusions. When planning future studies, it is important to determine whether children's understanding or production of humor will be assessed in order to select diagnostic instruments, given the complex structure of the children's humor construct and its age-specific characteristics, as well as the limitations of the methods used.
Existential Isolation Scale: Russian Adaptation of the EIS
Authors: Averina Polina A. , Lebedeva Anna A.
Published: December 2024

Background. The Existential Isolation Scale (EIS) appears to be the most successful psychometrically valid instrument for the study of existential isolation. Since the scale's development, the number of existential isolation studies worldwide has increased significantly.
Objective. The purpose of this study was to adapt the Russian-language version of the EIS.
Study Participants. The number of participants of the study amounted to 300 people aged 18 to 72 years, including 200 women and 100 men.
Methods. The study participants filled out the Russian-language version of the EIS and instruments assessing the expression of different aspects of loneliness, self-esteem, Big Five traits, and life satisfaction.
Results. The reliability of the Russian-language version of the EIS, measured using the Cronbach's α coefficient, demonstrated a high degree of internal consistency and amounted to 0.816. Factor validity was checked by confirmatory factor analysis. As a result, the one-factor structure of the questionnaire was confirmed to be consistent with the original version. Convergent validity of the scale was determined using correlation analysis, which demonstrated relationships between existential isolation scores and theoretically similar constructs such as isolation, alienation, and loneliness. At the same time, existential isolation differs from the named constructs in its correlations with such phenomena as dysphoria, dependence on communication, life satisfaction, self-esteem, and extraversion, which allowed us to conclude that the scale has sufficient discriminant validity.
Conclusions. The Russian-language version of the EIS measures the degree of expression of the phenomenon of existential isolation, different from those measured by loneliness questionnaires in Russian. The adapted EIS scale is a reliable and valid instrument that can be recommended for assessing existential isolation among Russian-speaking research participants.
Aggressiveness Traits as Predictive Factors for the Components of the Wellbeing of Young People
Authors: Rean Artur A. , Shevchenko Andrey O. , Stavtsev Alexey A. , Konovalov Ivan A. , Kuzmin Roman G.
Published: December 2024

Background. Aggression and aggressiveness as properties of personality are certainly among the most destructive phenomena. As young people are an important social group in the structure of society, the direction of development greatly depends on them. It becomes topical to study the relationship between the parameters of psychological well-being and aggression in the personality structure of student youth.
Objective. The goal is to study the relationship of aggression with life satisfaction, self-esteem and self-efficacy of student youth in the Russian Federation.
Methods. Bass-Perry aggression questionnaire, E. Diener’s Life Satisfaction questionnaire, Self-esteem questionnaire — Self-esteem. Rosenberg Self-esteem Scale (RSE). Correlation analysis and linear regression were used in the processing of the obtained results.
Study Participants. 1398 respondents participated, mean subject age 20.2 (min. — 17, max. — 30): 1033 female subjects and 365 male subjects.
Results. Upon analyzing the general patterns of linear regression and correlation, it was found that not all scales have similar trends: in some cases the relationships between “Life Satisfaction”, “Self-Esteem” and “Self-Efficacy” and aggressiveness scales are non-linear. It was found that the influence of aggressiveness scales on level-groups — “Life Satisfaction”, “Self-esteem” and “Self-efficacy”, are not equivalent to the results of general trends. Thus, the general pattern was that “Hostility” was a negative predictor of all three criteria of personality well-being: self-esteem, self-efficacy and life satisfaction. Regression analysis showed a U-shaped relationship between the scale “Physical Aggression” and Self-Efficacy. “Verbal aggression” is a significant predictor for low scores of Self-esteem and Self-efficacy.
Conclusions. “Hostility” is a universal predictor (negative), in almost all cases and level-groups of well-being. “Verbal aggression” can be a positive predictor of “Self-Esteem” growth, only in the group of subjects with low self-efficacy, also it can act as a predictor of self-efficacy growth in the group of subjects with low self-efficacy values. “Physical aggression” is a significant predictor in the groups with high and low values of self-efficacy. The revealed patterns demonstrate the complexity of aggression. In addition, in certain cases, manifestations of aggression can be an effective mechanism of imaginary adaptation of the personality, however, in the long term, this overlaps the possibility of full systemic adaptation for the subject.