bluuebunny/crossref_metadata_2025 huggingface dataset:
Kin-State Intervention and the Securitization-Minority Policy Nexus: Hungarians and Russian-Speakers in Central and Eastern Europe
Authors: Csergő Zsuzsa , Kallas Kristina , Kiss Tamás
Published: October 2024

Russia’s full-scale invasion of Ukraine in 2022, launched under the pretext of protecting the rights of Russian kin populations outside of Russia, had a massive impact on security concerns beyond Ukraine. An important consequence was the intensification of insecurities about the presence of large Russian-speaking minorities in Russia’s neighboring states. Scholars have long emphasized that kin-state involvement can lead to the securitization of minority issues, harming the willingness of governments to support collective claims by minorities associated with that kin-state. Yet there is scarce empirical knowledge about whether and under what conditions an assertive kin-state triggers securitization resulting in restrictive minority policy. We assessed this securitization-minority policy nexus comparatively, focusing on the impact of intensifying Hungarian and Russian kin-state activism on policies toward Hungarian and Russophone minorities in five states in Central and Eastern Europe. Our main finding is that intensified kin-state activism does not significantly disrupt previously established paths in minority policy-making, unless a kin-state turns to territorial revisionism. We also found that titular ontological insecurity (faced by actors belonging to a state’s dominant ethnic group) is a helpful heuristic for explaining instances when securitization results in policy restrictions, and we offer conceptual tools for analyzing the salience of both internal and external sources of titular insecurity. Ultimately, our findings highlight the necessity for scholars to distinguish between nonterritorial and territorial types of kin-state intervention in studies about the security dimension of kin-state involvement.
Energy attenuation of seismic metamaterials composed of a periodic array of coated elliptical cylinders
Authors: Huang Wei-Hsiang , Lin Zong-Ying , Chen Tungyang
Published: October 2024

We present a numerical study on energy attenuation of seismic metamaterials consisting of a periodic array of coated elliptical cylinders. The aim is to perceive the effect of aspect ratio for different wave modes so that the metamaterials can interact with the incoming wave causing them to interfere with each other destructively, especially for low-frequency seismic waves with relatively wide bandgap. Previous studies mainly focused on the configuration of coated circular cylinders or spheres, in which the metamaterial is composed of a hard inclusion surrounded by a soft coating layer and dispersed within a hard matrix. Here we utilize numerical simulations based on finite element calculation to analyze the local fields within the unit cell. Effective mass density, mass moment of inertia and shear modulus are analyzed through a homogenization procedure to characterize the macroscopic behavior of the effective medium. The effective behavior will be dependent for different aspect ratios and for different types of wave motions. To verify the effectiveness of energy attenuation, a full-scale model is adopted. Specifically, to identify optimal energy attenuation configurations, we illustrate the attenuation effects of elliptical metamaterials under longitudinal and shear horizontal types of waves. The present study demonstrates that elliptical metamaterials will have more reflexibilities to tune with the aspect ratio of the elliptical geometry as well as the directionality of incidence waves. Based on our simulations, we show the ability of the designed configuration in tuning local resonance frequencies and bandwidths for real implementations and applications of seismic metamaterials.
Education beyond the limits: addressing violence against women and girls
Authors: Skilbeck Adrian
Published: October 2024

This article is a contribution to a suite of articles on violence against women and girls. It sets out the context in which this issue is currently discussed, how it might be understood and how it can be addressed. Education is seen as a key mechanism for the prevention of gender-based violence through the transformation of the attitudes and beliefs that boys and young men hold about women and girls and what it means to be a man. This article considers the challenges of achieving this in the face of online influencers like Andrew Tate with their appeal to masculine entitlement and supremacy, often expressed in terms of misogynistic violence and coercion. Drawing on the work of Jacqueline Rose, Judith Butler, and others, the article argues that this is a task that involves creative and affective pedagogy as well as sustained critical engagement. There is, therefore, an important role for the arts and humanities in providing spaces for exploration, conversation, and reflection about the embodied experience of violence and abuse. Through difficult educational encounters it may be possible to initiate a change in boys and young men from impervious thoughtlessness to a greater recognition and understanding of the impact of harassment and violence, both within the educational setting and beyond.
Beat-to-beat analysis of hemodynamic response to mental and psychological stress in sickle cell anemia
Authors: Abiri Arash , Marmarchinia Sara , Shah Payal , Thuptimdang Wanwara , Coates Thomas D , Khoo Michael C K , Khine Michelle
Published: October 2024

Objectives

Vaso-occlusive crises are a hallmark symptom of SCD. Physical stressors can trigger decreased microvascular blood flow and increase the risk for vaso-occlusive crises. However, the effect of mental and psychological stressors on vascular physiology in SCD is not well-established. We hereby examined fluctuations in continuous blood pressure to evaluate hemodynamic changes in SCD patients during mental and psychological stress.

Methods

Thirteen SCD subjects from the Children’s Hospital Los Angeles and 11 healthy volunteers were recruited. Continuous blood pressure was recorded during 2 mental tasks and 1 psychological stress task. Systolic beat-to-beat blood pressure variability measurements were calculated for each subject. Three very short-term blood pressure variability metrics served as outcome measures: SD, coefficient of variation, and average real variability. Peripheral augmentation index was calculated from arterial waveforms. Linear mixed effects models evaluated associations between patient factors and outcome measures.

Results

SCD patients exhibit increased systolic blood pressure variability in response to psychological stress. All subjects exhibited a decrease in systolic blood pressure variability in response to mental stress tasks. During mental stress, both groups displayed increased augmentation index, reflective of stress-induced vasoconstriction, while psychological stress in SCD patients led to both decreased mean arterial pressure and increased augmentation index, suggestive of uncompensated vasoconstriction.

Conclusion

These findings emphasize the impact of mental and psychological stressors on vascular function in SCD and the potential for monitoring physiological signals to predict vaso-occlusive crisis events.
The LncNAT11–MYB11–F3'H/FLS module mediates flavonol biosynthesis to regulate salt stress tolerance in Ginkgo biloba
Authors: Liu Sian , Zhang Hanyue , Meng Zhaolong , Jia Zhichao , Fu Fangfang , Jin Biao , Cao Fuliang , Wang Li
Published: October 2024

Flavonols are important secondary metabolites that enable plants to resist environmental stresses. Although MYB regulation of flavonol biosynthesis has been well studied, the long non-coding RNA (lncRNA)–MYB networks involved in regulating flavonol biosynthesis remain unknown. Ginkgo biloba is rich in flavonols, which are the most important medicinal components. Based on multi-omics data and phylogenetic trees, we identified GbMYB11 as a potential key transcription factor regulating flavonol biosynthesis. Overexpression and virus-induced gene silencing (VIGS) experiments confirmed that GbMYB11 acts as a pivotal positive regulator in flavonol biosynthesis. In the transcriptome of calli overexpressing GbMYB11, we identified significant up-regulation of GbF3'H and GbFLS in the flavonol biosynthetic pathway. Yeast one-hybrid and dual-luciferase assays demonstrated that GbMYB11 enhances the expression of GbF3'H and GbFLS by binding to their promoters. Interestingly, we identified LncNAT11, an antisense lncRNA complement to GbMYB11, which negatively regulates flavonol biosynthesis by repressing the expression of GbMYB11. Consequently, we established the LncNAT11–GbMYB11–GbF3'H/GbFLS module as a critical regulator of flavonol biosynthesis in G. biloba, and further elucidated that this module can mitigate the accumulation of reactive oxygen species by modulating flavonol biosynthesis during salt stress. These findings unveil a novel mechanism underlying flavonol biosynthesis and an lncRNA–MYB-mediated salt stress tolerance strategy in plants.
ncPlantDB: a plant ncRNA database with potential ncPEP information and cell type-specific interaction
Authors: Liu Liya , Liu Enyan , Hu Yueming , Li Sida , Zhang Shilong , Chao Haoyu , Hu Yanshi , Zhu Yanyan , Chen Yifan , Xie Luyao , Shen Yi , Wu Liangwei , Chen Ming
Published: October 2024

The field of plant non-coding RNAs (ncRNAs) has seen significant advancements in recent years, with many ncRNAs recognized as important regulators of gene expression during plant development and stress responses. Moreover, the coding potential of these ncRNAs, giving rise to ncRNA-encoded peptides (ncPEPs), has emerged as an essential area of study. However, existing plant ncRNA databases lack comprehensive information on ncRNA-encoded peptides (ncPEPs) and cell type-specific interactions. To address this gap, we present ncPlantDB (https://bis.zju.edu.cn/ncPlantDB), a comprehensive database integrating ncRNA and ncPEP data across 43 plant species. ncPlantDB encompasses 353 140 ncRNAs, 3799 ncPEPs and 4 647 071 interactions, sourced from established databases and literature mining. The database offers unique features including translational potential data, cell-specific interaction networks derived from single-cell RNA sequencing and Ribo-seq analyses, and interactive visualization tools. ncPlantDB provides a user-friendly interface for exploring ncRNA expression patterns at the single-cell level, facilitating the discovery of tissue-specific ncRNAs and potential ncPEPs. By integrating diverse data types and offering advanced analytical tools, ncPlantDB serves as a valuable resource for researchers investigating plant ncRNA functions, interactions, and their potential coding capacity. This database significantly enhances our understanding of plant ncRNA biology and opens new avenues for exploring the complex regulatory networks in plant genomics.
ScRAPdb: an integrated pan-omics database for the Saccharomyces cerevisiae reference assembly panel
Authors: Miao Zepu , Ren Yifan , Tarabini Andrea , Yang Ludong , Li Huihui , Ye Chang , Liti Gianni , Fischer Gilles , Li Jing , Yue Jia-Xing
Published: October 2024

As a unicellular eukaryote, the budding yeast Saccharomyces cerevisiae strikes a unique balance between biological complexity and experimental tractability, serving as a long-standing classic model for both basic and applied studies. Recently, S. cerevisiae further emerged as a leading system for studying natural diversity of genome evolution and its associated functional implication at population scales. Having high-quality comparative and functional genomics data are critical for such efforts. Here, we exhaustively expanded the telomere-to-telomere (T2T) S. cerevisiae reference assembly panel (ScRAP) that we previously constructed for 142 strains to cover high-quality genome assemblies and annotations of 264 S. cerevisiae strains from diverse geographical and ecological niches and also 33 outgroup strains from all the other Saccharomyces species complex. We created a dedicated online database, ScRAPdb (https://www.evomicslab.org/db/ScRAPdb/), to host this expanded pangenome collection. Furthermore, ScRAPdb also integrates an array of population-scale pan-omics atlases (pantranscriptome, panproteome and panphenome) and extensive data exploration toolkits for intuitive genomics analyses. All curated data and downstream analysis results can be easily downloaded from ScRAPdb. We expect ScRAPdb to become a highly valuable platform for the yeast community and beyond, leading to a pan-omics understanding of the global genetic and phenotypic diversity.
VFDB 2025: an integrated resource for exploring anti-virulence compounds
Authors: Zhou Siyu , Liu Bo , Zheng Dandan , Chen Lihong , Yang Jian
Published: October 2024

With the escalating crisis of bacterial multidrug resistance, anti-virulence therapeutic strategies have emerged as a highly promising alternative to conventional antibiotic treatments. Anti-virulence compounds are specifically designed to target virulence factors (VFs), disarming pathogens without affecting bacterial growth and thus reduce the selective pressure for resistance development. However, due to the complexity of bacterial pathogenesis, no anti-virulence small molecules have been approved for clinical use thus far, despite the documentation of hundreds of potential candidates. To provide valuable reference resources for drug design, repurposing, and target selection, the virulence factor database (VFDB, http://www.mgc.ac.cn/VFs/) has systematically collected public data on anti-virulence compounds through extensive literature mining, and further integrated this information with its existing knowledge of bacterial VFs. To date, the VFDB has curated a comprehensive dataset of 902 anti-virulence compounds across 17 superclasses reported by 262 studies worldwide. By cross-linking the current knowledge of bacterial VFs with information on relevant compounds (e.g. classification, chemical structure, molecular targets and mechanisms of action), the VFDB aims to bridge the gap between chemists and microbiologists, providing crucial insights for the development of innovative and effective antibacterial therapies to combat bacterial infections and address antibiotic resistance.
Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics
Authors: Jiang Shuai , Li Huiqin , Zhang Luowanyue , Mu Weiping , Zhang Ya , Chen Tianjian , Wu Jingxing , Tang Haoyun , Zheng Shuxin , Liu Yifei , Wu Yaxuan , Luo Xiaotong , Xie Yubin , Ren Jian
Published: October 2024

High-quality schematic illustrations are fundamental to the publication of scientific achievements in biomedical research, which are crucial for effectively conveying complex biomedical concepts. However, creating such illustrations remains challenging for many researchers due to the need to devote a significant amount of time and effort to accomplish it. To address this need, we present the Generic Diagramming Platform (GDP, https://BioGDP.com), a comprehensive database of professionally crafted biomedical graphics (bio-graphics). Currently, GDP houses 7 562 high-quality bio-graphics, meticulously categorized into 10 major and 77 minor categories. To increase the design efficiency, GDP provides 204 customizable templates derived from an extensive review of over 2000 literature and 7 textbooks. With the interactive drawing platform and user-friendly web interface implemented in GDP, these resources can facilitate the efficient generation of publication-ready illustrations for the biomedical community. Additionally, GDP incorporates a collaborative submission system, allowing researchers to contribute their artwork, fostering a growing diagramming ecosystem, and ensuring continuous database expansion. Overall, we believe that GDP will serve as an invaluable platform, significantly enhancing the efficiency and quality of scientific illustration for biomedical researchers.
Activatable red/near-infrared aqueous organic phosphorescence probes for improved time-resolved bioimaging
Authors: Li Yang , Wu Zhiqin , Huang Zizhao , Yin Chenjia , Tian He , Ma Xiang
Published: October 2024

Organic red/near-infrared (NIR) room-temperature phosphorescence (RTP) holds significant potential for autofluorescence-free bioimaging and biosensing due to its prolonged persistent luminescence and exceptional penetrability. However, achieving activatable red/NIR organic RTP probes with tunable emission in aqueous solution remains a formidable challenge. Here we report on aqueous organic RTP probes with red/NIR phosphorescence intensity and lifetime amplification. These probes consist of supramolecular assemblies comprising macrocyclic cucurbit[8]uril and amine-containing alkyl-bridged pyridiniums, exhibiting viscosity-activatable phosphorescence with enhanced quantum yield (≤20%) and lifetime. Notably, by utilizing this activatable organic RTP probe, we successfully achieve two-photon imaging of lysosomal viscosity and millisecond-scale time-resolved cell imaging. Moreover, intravital phosphorescence imaging by using an RTP probe enables the monitoring of viscosity variations in inflammatory mice, demonstrating a significantly improved signal-to-background ratio compared with fluorescence imaging. This activatable red/NIR supramolecular platform facilitates versatile high-resolution phosphorescence imaging for in vivo tracking of specific biomarkers and physiological events.
The acceptability and feasibility of a mobile phone delivered brief intervention for hazardous drinking in India
Authors: Nadkarni Abhijit , Fernandes Danielle , Velleman Richard , Onyango Anastasia , Sambari Seema , D’Souza Ethel
Published: October 2024

The effectiveness of Brief Interventions (BIs) for hazardous drinking is well established. However, the implementation of BIs at scale in low- and middle-income countries such as India is rare, primarily due to human resource related barriers. This paper describes the testing of acceptability and feasibility, and the preliminary impact, of a mobile phone delivered BI in an uncontrolled treatment cohort and nested qualitative study. Consenting adult (≥18 years) participants with an Alcohol Use Disorder Identification Test score between 8 to 15 were recruited from educational institutions, workplaces and primary care settings. The TLFB (Time-Line Follow Back) was administered to participants at baseline and 3 months post recruitment. All participants received the BI through text messages or IVR (Interactive Voice Response) over eight weeks; and in-depth interviews were conducted with some participants. The mean pre and post outcomes were compared using paired t-test. Qualitative data was analysed using thematic analyses. 29 participants received the intervention and 16 (55%) completed the outcome assessments. Some key qualitative findings indicated the desire from participants for fewer messages and messages that did not require interaction; and more messages with motivational content and information on practical skills to reduce drinking. The percentage days abstinent was significantly higher at follow up than baseline in all those who had completed the TLFB at baseline and follow up. Feasibility and acceptability testing is an important component of the intervention development process to ensure that the resulting intervention is suitable for the context.
The kinase ATR controls meiotic crossover distribution at the genome scale in Arabidopsis
Authors: Zhu Longfei , Dluzewska Julia , Fernández-Jiménez Nadia , Ranjan Rajeev , Pelé Alexandre , Dziegielewski Wojciech , Szymanska-Lejman Maja , Hus Karolina , Górna Julia , Pradillo Mónica , Ziolkowski Piotr A
Published: October 2024

Meiotic crossover, i.e. the reciprocal exchange of chromosome fragments during meiosis, is a key driver of genetic diversity. Crossover is initiated by the formation of programmed DNA double-strand breaks (DSBs). While the role of ATAXIA-TELANGIECTASIA AND RAD3-RELATED (ATR) kinase in DNA damage signaling is well-known, its impact on crossover formation remains understudied. Here, using measurements of recombination at chromosomal intervals and genome-wide crossover mapping, we showed that ATR inactivation in Arabidopsis (Arabidopsis thaliana) leads to dramatic crossover redistribution, with an increase in crossover frequency in chromosome arms and a decrease in pericentromeres. These global changes in crossover placement were not caused by alterations in DSB numbers, which we demonstrated by analyzing phosphorylated H2A.X foci in zygonema. Using the seed-typing technique, we found that hotspot usage remains mainly unchanged in atr mutants compared with wild-type individuals. Moreover, atr showed no change in the number of crossovers caused by two independent pathways, which implies no effect on crossover pathway choice. Analyses of genetic interaction indicate that while the effects of atr are independent of MMS AND UV SENSITIVE81 (MUS81), ZIPPER1 (ZYP1), FANCONI ANEMIA COMPLEMENTATION GROUP M (FANCM), and D2 (FANCD2), the underlying mechanism may be similar between ATR and FANCD2. This study extends our understanding of ATR's role in meiosis, uncovering functions in regulating crossover distribution.
Chemical-sensitized MITOGEN-ACTIVATED PROTEIN KINASE 4 provides insights into its functions in plant growth and immunity
Authors: Zhang Yan , Ge Shating , Dong Lele , Liu Niu , Shao Yiming , Fan Zong , Yang La , Si Qi , Ye Yajin , Ren Dongtao , Zhang Shuqun , Xu Juan
Published: October 2024

Two mitogen-activated protein kinase (MAPK) cascades with MPK4 and MPK3/MPK6 as the bottommost kinases are key to plant growth/development and immune signaling. Disruption of the MPK4 cascade leads to severe dwarfism and autoimmunity, complicating the study of MPK4 in plant growth/development and immunity. In this study, we successfully rescued the Arabidopsis (Arabidopsis thaliana) mpk4 mutant using a chemical-sensitized MPK4 variant, MPK4YG, creating a conditional activity-null mpk4 mutant named MPK4SR (genotype: PMPK4:MPK4YG mpk4) that could be used to examine the functions of MPK4 in plant growth/development and immunity. We discovered that the duration of the loss of MPK4 activity is important to plant immune responses. Short-term loss of MPK4 activity did not impact flg22-induced ROS burst or resistance against Pseudomonas syringae (Pst). Enhanced Pst resistance was only observed in the MPK4SR plants with stunted growth following prolonged inhibition of MPK4 activity. Transcriptome analyses in plants with short-term loss of MPK4 activity revealed a vital role of MPK4 in regulating several housekeeping processes, including mitosis, transcription initiation, and cell wall macromolecule catabolism. Furthermore, the constitutive weak activation of MPK4GA in the MPK4CA plants (genotype: PMPK4:MPK4GA mpk4) led to early flowering and premature senescence, which was associated with its compromised resistance against Pst. These findings suggest that MPK4 plays important roles in plant growth and development and in maintaining the delicate balance between growth/development and immune adaptation in plants.
How to induce honesty: results from a large-scale experiment
Authors: Ho Teck-Hua , Hsu Su-Chin , Jin Lawrence , Kim Dayoung , Kim Jeongbin , Leong Ching
Published: October 2024

Everyday public behavior is premised on honesty. But the imperative to be honest can conflict with self-interest. This conflict between public good and private gain is one of the largest sources of malignity in policymaking, often resulting in noncompliance, inaction, or outright sabotage. This empirical paper examines whether giving the option to be seen as honest helps to reduce malignity in public behavior. We conduct a large field experiment involving 34,543 adults in nine countries to study what drives people to behave more honestly. In a three-arm randomized control trial, subjects reported the outcome from a single roll of an unbiased, six-sided die. The higher the reported value, the more they earned. In two of the arms (“private cash” and “private lottery”), the roll was observed only by the subject. In the third arm (“public cash”), subjects could opt to have their roll observed by the experimenter. A truthful report will yield an average value of 3.5. In the two “private” arms, we found significant overreporting (from 3.76 in China to 4.43 in Mexico). In the “public cash” arm, 85% of subjects opted to be observed, with zero or minimum overreporting (3.46 in Germany, to 3.61 in Indonesia). We develop and estimate a model of honesty that can account for behavioral regularities across the nine countries well. Our study shows that most people want to be seen as honest and a simple policy of providing the additional option of being observed is sufficient to induce them to behave honestly.
A unified theory of risk
Authors: Hirvelä Jaakko , Paterson Niall J
Published: October 2024

A novel theory of comparative risk is developed and defended. Extant theories are criticized for failing the tests of extensional and formal adequacy. A unified diagnosis is proposed: extant theories consider risk to be a univariable function, but risk is a multivariate function. According to the theory proposed, which we call the unified theory of risk, the riskiness of a proposition is a function of both the proportion and the modal closeness of the possible worlds at which the proposition holds. It is argued the theory passes the tests of extensional and formal adequacy.
Lymphadenopathy in systemic lupus erythematosus: no microbial trigger found by shotgun metagenomics in a retrospective study on 38 patients
Authors: Papo Matthias , Cappy Pierre , Degachi Alexandre , Woerther Paul-Louis , Saal Caroline , Charlotte Frédéric , Brocheriou Isabelle , Lhote Raphaël , Trefond Ludovic , Hié Miguel , Haroche Julien , Pha Micheline , Cohen-Aubart Fleur , Mathian Alexis , Rodriguez Christophe , Amoura Zahir
Published: October 2024

Objectives

Lymphadenopathy is a classical manifestation of SLE flare, occurring in approximately half of patients during the course of the disease. Lymphadenopathy in SLE is frequently associated with fever. Microbial infection may play a role in SLE onset and flares. The objectives of this study were to describe lymphadenopathy in the course of SLE and identify potential infectious triggers using microbial metagenomic analysis.

Methods

We performed a retrospective monocentric study of 38 patients with SLE who had lymph node biopsy at baseline or during follow-up. Shotgun metagenomics were performed in the patient’s lymph node biopsy to look for microbial RNA and/or DNA.

Results

Lymph node pathological analyses revealed follicular and/or paracortical hyperplasia in 73.7% of patients and histiocytic necrotizing lymphadenitis in 23.7%. At the time of biopsy, SLE patients exhibited fever in 29%, splenomegaly in 10%, cutaneous manifestations in 47%, polyarthritis in 32%, seritis in 13% and LN in 18%. Half of the patients (50%) had an increased CRP level, 35% had low C3, 65% had hypergammaglobulinemia. Microbial metagenomic analysis of lymph node biopsy revealed an absence of microbial DNA in 92% of patients, the presence of CMV in very small quantities in 2 patients, and the presence of HHV-7 in low quantities in a single patient.

Conclusion

Despite suggestion that certain microorganisms may play a role in the pathogenesis and flares of SLE, our microbial metagenomic analysis study did not highlight possible infectious triggering factors. Further and better-designed studies are needed to confirm these results.
High serum levels of CXCL13 predict lower response to csDMARDs in both ACPA-positive and ACPA-negative early rheumatoid arthritis
Authors: De Stefano Ludovico , Bozzalla Cassione Emanuele , Sammali Ylenia , Luvaro Terenzj , Montecucco Carlomaurizio , Manzo Antonio , Bugatti Serena
Published: October 2024

Objectives

Increased circulating levels of CXCL13 reflect synovial production and indicate immune dysregulation in patients with RA. Here we tested whether CXCL13 predicts response to first-line treatment with MTX in patients with early RA, independently and in association with ACPA and IgM-RF.

Methods

A prospective cohort of 243 early RA patients undergoing treat-to-target with MTX was evaluated. CXCL13, ACPA and IgM-RF were determined on baseline sera. Short-term variations of CXCL13 were measured after 2 months. The association of high CXCL13 (≥100 pg/ml) with disease remission after 6 months and escalation to second-line therapies within year 2 was evaluated in the total population and in ACPA subgroups separately.

Results

High levels of CXCL13 were found in 53.6% of ACPA-positive and 31.5% of ACPA-negative patients, with minimal association with disease activity and RF. Serum CXCL13 remained stable after 2 months. High baseline CXCL13 independently predicted failure to achieve remission and more frequent requirement of second-line treatment in ACPA-positive patients, with adjusted odds ratios (ORs) in the range of 0.17–0.49 for remission and 6.75 for second-line treatment. In ACPA-negative patients with high CXCL13, remission occurred at the expense of higher doses of MTX, and levels of CXCL13 predicted MTX escalations with an adjusted OR (95% CI) of 2.69 (1.35–5.34).

Conclusions

High serum levels of CXCL13 identify a subgroup of RA patients who are more refractory to first-line treatment with MTX. CXCL13 appears a promising biomarker of response to MTX in both ACPA-positive and -negative early RA.
Enhancing the in vivo bioavailability and absorption of Niclosamide with amorphous solid dispersion via solvent method
Authors: Li Jing , Chang Yu , Zou Zhiyang Zack
Published: October 2024

Objectives

This research aims to prepare a superior amorphous solid dispersion (ASD) formulation via solvent method for the oral delivery of Niclosamide to enhance oral bioavailability and absorption.

Methods

Phase solubility tests were conducted to select an optimal carrier combination for Niclosamide solid dispersion (SD). The Niclosamide ASD was synthesized using a solvent rotary evaporation method and characterized through in vitro dissolution tests, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction, and scanning electron microscopy. In vivo oral pharmacokinetic studies were conducted in Sprague Dawley rats at a dose of 50 mg/kg.

Key findings

PEG6000 and poloxamer 188 combination was selected as an optimal carrier. ASD named ASD-5 was successfully prepared, encompassing a 25% drug loading, Niclosamide within ASD-5 remains amorphous and stable. 75% of Niclosamide in ASD-5 rapidly dissolved in 5 min, while below 5% of pure Niclosamide and physical mixture dissolved in a longer time. Amorphization of Niclosamide in ASD-5 notably contributes to its dissolution rate and extent. Furthermore, among reported Niclosamide SD formulations with drug loading above 25%, ASD-5 demonstrated the highest bioavailability, showing a 2.33-fold increase in plasma exposure and bioavailability compared to pure Niclosamide.

Conclusions

Amorphous ASD-5 prepared by the solvent method has higher drug loading and is scalable in pre-clinical stage preparation. Due to using PEG6000 and poloxamer 188 combination, ASD-5 had the highest bioavailability among reported Niclosamide SDs with a drug load exceeding 25%. Also, ASD-5 presented a simplified preparation procedure compared to other reported Niclosamide SD.
The development of attitudes toward science and technology: a longitudinal analysis of Generation X
Authors: Miller Jon D , Laspra Belén , Polino Carmelo , Branch Glenn , Ackerman Mark S , Pennock Robert T
Published: October 2024

Research on public attitudes toward science and technology policy has relied on surveys taken at single points in time. These surveys fail to indicate how these attitudes develop or change. In this study, we use data from the Longitudinal Study of American Life that has followed a national sample of Generation X for 33 years—from middle school to midlife. We demonstrate that the critical period for the formation of attitudes toward science and technology is the 15–18 years after high school—college, work, family, and career. The attitudes formed in this period remain stable for most individuals during midlife. This work provides an important perspective for scientists, engineers, and the leadership of the scientific community in their efforts to foster positive attitudes toward science and technology and to understand the roots of concerns and reservations about science.
Isolation and characterisation of novel lytic bacteriophages for therapeutic applications in biofilm-associated prosthetic joint infections
Authors: Burton Nathan J , Melo Luís D R , Tadesse Michaël F D , Pearce Bethany , Vryonis Evangelos , Sagona Antonia P
Published: October 2024

Prosthetic joint infections are devastating complications of joint arthroplasties. Without effective management, they can lead to limb amputation and even death. A significant proportion of these infections is caused by the primarily commensal Coagulase-negative Staphylococci pathogens, which form thick, antibiotic-resistant biofilms at the site of infection. Combinatorial therapy involving antibiotics and bacteriophages may represent a strategy to overcome resistance. Previous research indicates that as bacteria develop resistance to antibiotics, they often become more susceptible to bacteriophages. In this study, we produced a cocktail of novel bacteriophages and assessed their viability to eradicate nosocomial staphylococcal biofilms. Here, we used clinical isolates from prosthetic joint infections to isolate and identify four new bacteriophages from sewage effluent. These novel phages were characterized through electron microscopy and full genome sequencing. Subsequently, we combined them into a phage cocktail, which effectively re-sensitized biofilms to vancomycin and flucloxacillin. Notably, this phage cocktail demonstrated low cytotoxicity in vitro to human epithelial cells, even when used alongside antibiotic treatments. These findings highlight the potential of the phage cocktail as a tool to increase antibiotic treatment success in prosthetic joint infections.
Effects of Buprenorphine, Methadone, and Substance-Use on COVID-19 Morbidity and Mortality
Authors: Christian Nicholaus J. , Zhou Xin , Radhakrishnan Rajiv
Published: October 2024

Objectives

Substance use disorder has been associated with increased morbidity in COVID-19 infection. However, less is known about the impact of active substance use and medications for opioid use disorder (MOUD) on COVID-19 outcomes. We conducted a retrospective cohort study to evaluate the impact of substance use, namely, cannabis, cocaine, alcohol, sedative and opioid use; and buprenorphine or methadone on COVID-19 morbidity and mortality.

Methods

Using electronic health record data at a large urban hospital system, patients who tested positive for COVID-19 between January 1, 2020, and December 31, 2021, were included. Substance use was identified from urine toxicology and MOUD prescriptions within 90 days prior to admission. COVID-19 outcomes included mortality, ICU admission, need for intubation, and number and duration of hospitalizations. Multivariable logistic regression was performed controlling for variables such as age, sex, medical comorbidity, tobacco use, and social disadvantage.

Results

Among COVID-19–positive patients (n = 17,423), sedative, cannabis, cocaine, and opioid use was associated with statistically significant increases in need for ICU care, need for ventilatory support, number of hospitalizations, and duration of hospitalization. Substance use was not associated with an increase in all-cause mortality. There were no statistically significant differences between methadone, buprenorphine, and other opioids on COVID-19 outcomes.

Conclusions

Active substance use was associated with increased morbidity in COVID-19 infection. MOUD was not associated with worse COVID-19 outcomes compared to other opioids. Future studies focused on MOUD treatments that reduce morbidity may help improve clinical outcomes in COVID-19.
A Qualitative Assessment of Adolescent Symptom Report and Caregiver Concordance Following Outpatient Surgery
Authors: Brown Sydney E.S. , Costa Camila , Kelly Alyssa , Oh Sarah , Waitzman Gillian , Dinh Dan , Clauw Daniel , Waljee Jennifer F. , Carlozzi Noelle E.
Published: October 2024

Objectives:

Limited data exist regarding recovery from surgery from the adolescent’s perspective, or data regarding concordance between adolescent and caregiver symptom reports preventing appreciation of adolescent needs and hindering the provision of appropriate care.

Methods:

We conducted semi-structured interviews with adolescents ages 12 to 17 and a parent caregiver 2 weeks following a variety of outpatient elective surgeries about recovery symptoms. We used latent manifest content analysis to analyze interview data. Caregiver-adolescent response concordance was assessed using Cohen κ.

Results:

Interviews were conducted with 31 adolescent-caregiver pairs (median age: 15 y). Fifty-eight percent of adolescents and 84% of caregivers were female; 71% of adolescents were White. Twenty-three percent of children reported severe pain, some of which was not expected given the surgery. Severe pain was associated with nausea (71%, P=0.002), pain-related sleep disturbance (86%, P=0.007), and severe anxiety (43%, P=0.008). Fatigue was also common (58%), but not associated with severe pain (P=0.484) or sleep disturbance (P=0.577). Thirty-nine percent reported anxiety; 32% experienced anger/frustration. Caregiver-adolescent concordance was only substantial for severe pain (κ=0.71) and anger/frustration (κ=0.67). Caregiver reports also often included psychological symptoms not reported by their children, with qualitative evidence supporting caregiver accuracy.

Discussion:

Adolescents may experience significant physical symptoms, such as pain and fatigue, even after minor surgeries. Fatigue symptoms may be unrelated to pain or sleep. Caregiver report of adolescent psychological symptoms may be necessary to gain a complete understanding of those symptoms in this population.
The Kinetic and Kinematic Efficacy of Posterior Leaf Spring Ankle-foot Orthosis in Patients with Drop foot
Authors: Rahbar Soulmaz , Pourhoseingholi Ensieh , Hoseini Parinaz , Asgharian Seyedeh Fatemeh , Nouri Mohamad Javad , Mohamadi Somayeh , Piri Mohamed Mahdi
Published: October 2024

Background:

Dorsi flexor weakness is one of the common consequences of stroke with a negative impact on normal walking. Posterior leaf spring (PLS) Ankle Foot Orthosis (AFO) is the most frequent prescription to assist foot clearance and leg propulsion in these patients. However, the real efficacy of this AFO needs more attention. This study aimed to investigate the efficacy of PLS AFO on gait outcomes as the most common AFO in drop foot post-stroke patients.

Methods:

The study design was a pre–post-test experiments in which twenty drop foot patients with a mean age of 65 years with a mean age of 58.45 (±5.23) years who were 4/5 years post-stroke. They walked at self-selected walking speed on a 10 meters walk away in two conditions of with their own shoes and PLS AFO. The 3D motion capture gait analysis system including 6 vicon cameras and a Kistler force plate were used in order to measure gait kinetic and kinematic variables. For each trial, each joints (ankle, knee and hip) angle, moment and power were averaged over one-minute walking.

Results:

Walking with PLS showed a statistically significant improve kinetic and kinematic variables in hip, knee and ankle joints included power, moments and angles at entire gait cycle. P<0.05.

Conclusions:

In our study of stroke patients who were fitted with a PLS AFO, immediate significant improvements occurred in most kinetic and kinematic than shoes only in sacrifice some others.
Inclusion body myositis: an update
Authors: Anderson Nicolaas C. , Lloyd Thomas E.
Published: October 2024

Purpose of review

To review recent advances in our understanding of the epidemiology, pathophysiology, and management of inclusion body myositis (IBM).

Recent findings

Recent epidemiologic studies have highlighted the morbidity and mortality associated with IBM, including the impact of dysphagia. Multiomic analyses of IBM tissues have identified new pathogenic pathways and biomarkers for use in clinical trials. New diagnostic criteria and outcome measures have been proposed to improve clinical trial design. Ongoing clinical trials are targeting T cells and autophagy.

Improvements in our understanding of IBM pathogenesis are identifying new pathways and biomarkers that need validation in larger cohorts. Exercise remains the primary therapeutic modality available, and new treatment targets are needed.
Releasing our model T – chimeric antigen receptor (CAR) T-cells for autoimmune indications
Authors: Wobma Holly , Chang Joyce C. , Prockop Susan E.
Published: October 2024

Purpose of review

This review provides an update on the rapidly growing field of engineered cellular therapies for autoimmune disorders, primarily focusing on clinical experience and correlative studies with chimeric antigen receptor (CAR) T-cells.

Recent findings

To date, two case series describing treatment with CAR T-cell therapy for systemic lupus erythematosus (SLE) suggest that drug-free remission can be sustained in patients with previously treatment-refractory disease. The outcomes of these studies are similar, despite the use of different CAR constructs and lymphodepletion regimens. Although it is not yet clear whether the patients described have truly been cured, the majority of remissions have remained durable up to last follow-up at 1–2 years from treatment. Meanwhile, mechanistic studies are providing a window into how transient B-cell depletion mediates lasting benefit. With the encouraging data in SLE, CAR T-cells and other novel B-cell-depleting agents (e.g. bispecific T-cell engagers) are now being evaluated as treatment for other autoimmune conditions, with the goal of durable response.

Recent reports highlight cellular therapies as a promising strategy for patients with treatment-refractory autoimmune conditions; however, there is still limited experience, and better insight into this therapeutic approach is expected to emerge rapidly.
A scoping review of the epidemiology of systemic sclerosis and its organ manifestations: 2018–2024
Authors: Good Samuel D. , Lee Ju Young , Johnson Robert E. , Volkmann Elizabeth R.
Published: October 2024

Purpose of review

Updates from large, observational cohorts and new statistical techniques have resulted in new data on the epidemiology of systemic sclerosis (SSc). This scoping review uses data from 2018 to 2024 to describe the current understanding of the epidemiology of SSc and several of its organ- manifestations.

Recent findings

Our review identified new estimates for the global incidence and prevalence of SSc (1.4–8.6 per 100 000 person-years and 17.6–18.9 per 100 000 individuals, respectively). Mortality rates remain high, though mortality at younger ages has decreased. interstitial lung disease and pulmonary arterial hypertension remain the most common causes of death for patients with SSc. Literature on gastrointestinal (GI) manifestations of SSc was scarce, and we identified significant heterogeneity in results. Furthermore, data on the epidemiology of racial, ethnic and sex-based disparities was lacking.

New techniques for the evaluation of the epidemiology of SSc highlight the high morbidity and mortality of SSc, and a growing prevalence rate compared with prior eras. Further research is needed to address notable heterogeneity in the reporting of epidemiological data and understudied disease manifestations, including GI disease and health disparities in disease outcomes.
Cast-OFF 2: One Week Versus 3–5 Weeks of Plaster Cast Immobilization for Non- or Minimally Displaced Distal Radius Fractures—A Stepped Wedge Cluster Randomized Controlled Trial
Authors: de Bruijn Marcel A. N. , Boersma Emily Z. , van Silfhout Lysanne , van Ginkel Laura A. , Tromp Tjarda N. , van de Krol Erik , Edwards Michael J. R. , Stirler Vincent M. A. , Hermans Erik ,   Cast-OFF 2 Study Group
Published: October 2024

OBJECTIVES:

Implementation of 1 week of cast immobilization followed by gradually increasing wrist mobilization for non- or minimally displaced distal radius fracture (DRF) and comparison of the functional outcomes and pain scores with the usual care (3–5 weeks of cast immobilization).

METHODS:

Design:

A randomized stepped wedge cluster design, prospective cohort.

Setting:

Academic and peripheral hospitals in levels 1, 2, and 3 trauma centers.

Patient Selection Criteria:

All patients between 18 and 85 years old with an isolated non- or minimally and nonreduced DRF were eligible for inclusion. Participating hospitals were randomized to transition from usual care (3–5 weeks of cast immobilization) to 1 week of cast immobilization, following the stepped wedge design.

Outcome Measures and Comparisons:

Patient characteristics, secondary dislocation, surgical treatment, visual analog scale, Patient Rated Wrist Evaluation (PRWE), Patient Reported Outcomes Measurement Information System Pain Interference, Pain Catastrophizing Scale 4, and patient satisfaction were compared between control and intervention group at weeks 1, 3–5, 6, months 3, 6, and 12. A difference around 11 points on the PRWE scale was considered clinically significant.

RESULTS:

Four hundred two patients were included (control n = 197 vs. intervention n = 205, 267/135, female/male). There were no differences in age (53.7 ± 18.6 vs. 53.3 ± 19.5, P = 0.27), sex (66% vs. 67% female, P = 0.44), dominant hand fractured (44% vs. 53%, P = 0.39), and type of fracture (39% vs. 41% extra-articular, P = 0.44). After 6 weeks, the PRWE score showed no clinically significant differences (−4.5 [confidence interval −12.9 to 4.02], P = 0.30). No significant differences were observed for function, pain scores, and patient satisfaction between groups (all P > 0.05). Furthermore, there was no significant difference in secondary dislocation rate (control 1.5% vs. intervention 1.0%, P = 0.32) and operation rate (control 1.5% vs. 1.5% intervention, P = 0.92).

CONCLUSIONS:

This study compared 1 week of cast immobilization followed by gradually increasing wrist mobilization to the usual care of 3–5 weeks for nonreduced DRF. No clinically significant differences in function, pain scores, patient satisfaction, secondary dislocation, and operations were observed. Therefore, 1 week of plaster immobilization can be safely recommended for the non- or minimally displaced and nonreduced DRF treatment.

LEVEL OF EVIDENCE:

Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Philadelphia chromosome-positive or Philadelphia chromosome-like B-cell precursor acute lymphoblastic leukemia with multilineage involvement in pediatric patients: a report of two cases and literature review
Authors: Lin Han , Chen Lu , Huang Ruoyao , Xue Shufang , Sun Gaoyuan , Wang Chengyi , Shen Shuhong , Zhang Hui , Zheng Yongzhi
Published: October 2024

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity ‘Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL)’ into two subtypes: lymphoid-only and multilineage involvement (Ph+ ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph
+
ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.