bluuebunny/crossref_metadata_2025 huggingface dataset:
Non‐Pharmacological Sleep Interventions after Cardiac Surgery: A Systematic Review and Meta‐Analysis of Randomised Controlled Trials
Authors: Lee Sueyeon , Chen Pei , Park Chang , Zhu Bingqian , Balserak Bilgay I.
Published: December 2024

Aim

To synthesise up‐to‐date research evidence for non‐pharmacological interventions to improve various sleep outcomes (e.g., sleep quality, duration) in postsurgical cardiac patients.

Background

Sleep disturbances are common amongst postsurgical cardiac patients, yet the effectiveness of non‐pharmacological interventions in improving various sleep outcomes has not been comprehensively reviewed.

Design

A systematic review and meta‐analysis guided by the PRISMA protocol.

Methods

CINAHL, PubMed, PsycINFO, Embase, Web of Science, and Cochrane Library were searched for relevant research in May 2023. Included studies used a randomised controlled trial design that applied a non‐pharmacological intervention for postsurgical cardiac patients and reported sleep as an outcome. For the meta‐analysis, mean effect sizes were separately calculated for studies with regular and reverse‐scored scales.

Results

Of 37 studies included, the most common cardiac surgery was coronary artery bypass graft. Most interventions were performed within the first postoperative week and assessed sleep quality outcomes using the Pittsburgh Sleep Quality Index. The interventions are categorised into five types. Human resource‐based strategies emerged as the most effective. The meta‐analysis of 27 eligible studies showed a mean effect size of 0.76 for studies with regular scoring scales and − 1.04 for those with reverse‐scored scales, indicating medium to large effect sizes.

Conclusion

Our findings provide strong evidence that non‐pharmacological interventions, particularly human resource‐based strategies, significantly improve sleep quality in postsurgical cardiac patients. The medium to large effect sizes underscore the clinical significance of these findings.

Implications

Healthcare professionals should consider incorporating non‐pharmacological interventions, especially human resource‐based strategies, in care plans for postsurgical cardiac patients to improve sleep outcomes and promote recovery. These interventions should be tailored to individual physical and cultural differences for maximum effectiveness. Future research should evaluate the long‐term effects of these interventions on various sleep outcomes, using both objective and subjective measures to provide a comprehensive assessment of their efficacy.

Reporting Method

This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) protocol.

No patient or public contribution

Patient and public contributions were not required for this review.
Diet Quality Among Older Adolescent Boys and Girls in the Southeast Asia Region
Authors: Pries Alissa M. , Feeley Alison , Kupka Roland
Published: December 2024

Adolescence is a period of tremendous physical and neurophysiological change, and today's rapidly changing food system has implications for adolescent nutritional and health outcomes. Ensuring nutritious diets during adolescence requires evidence on what is being consumed by adolescent boys and girls, however, little is known about the dietary patterns among this age group. This study assessed the prevalence of food group consumption and indicators of diet quality among adolescents in the Southeast Asia region and compared these results to the adult population. Secondary analysis of the Gallup World Poll, a population‐based survey, was performed using datasets from Cambodia, Indonesia, Laos PDR, the Philippines and Vietnam. Pooled analysis of nine diet quality indicators was conducted among all adolescents 15–19 years of age (n = 479), with comparison to the adult population (n = 4589). Various unhealthy food groups were consumed by one‐quarter to one‐half of adolescents, with a greater proportion of adolescents consuming instant noodles, sweets, processed meats and salty snacks, as compared to adults. Just over one‐third of adolescents (37.4%) consumed all five recommended food groups to meet dietary guidelines, almost two‐thirds (62.6%) consumed sweet beverages and over three‐quarters consumed unhealthy/ultra‐processed foods (76.8%). Overall indicators of diet quality showed that Southeast Asian adolescents' diets were less healthy than adults. This is one of the first studies to explore the healthy and unhealthy aspects of diets among both adolescent boys and girls across the Southeast Asia region, with results indicating that diets are not nutritionally adequate.
War abolition and the whole war critique
Authors: Fiala Andrew
Published: December 2024

War is an absurd social practice. It ought to be abolished. Indeed, as I show in the paper, a number of prominent pacifists have argued in support of war abolition. War abolitionism is connected to what I call “the whole war critique.” The whole war critique has been explored by Robert Holmes. But war abolition and the whole war critique have been under‐thematized in the philosophical literature on pacifism and just war theory. This paper seeks to remedy that neglect. Holmes distinguishes between just war theory and the broader critique of war as a whole, what he calls “whole war.” Holmes concludes that “No actual, probable or possible whole wars in the modern world are morally permissible.” He argues that the entire social, cultural, economic, and political practice of war is immoral. This claim and the comprehensive critical project of war abolition is much broader than the narrow set of judgments found in just war theory. The just war theory does not ask about the morality of war as a whole—as a social, cultural, economic, and political practice. Nor does it focus on suggestions for how we might prevent or abolish war. This paper will explain and elucidate the whole war critique and how it contributes to war abolitionist pacifism. It will also clarify how this critical standpoint is an ideal theory that is nonetheless not utopian.
Understanding the Interaction Between Family Dynamics and Childhood Obesity in the Middle Eastern Population: A Qualitative Study
Authors: Yazeedi Basma Al , Al‐Adawi Samir , Waly Mostafa , Qassabi Fathiya Al , Al‐Azkawi Hanan , Khalaf Atika
Published: December 2024

Objective(s)

We aim to understand the interaction between family dynamics and lifestyle behaviors of school‐age children with overweight or obesity in Oman. The outcomes would clarify the mediating familial determinants that contribute to childhood obesity in the Middle East population.

Design

A qualitative phenomenological approach.

Sample

Mothers of school‐age children with overweight or obesity.

Measurements

Semi‐structured interviews were conducted following an interview guide, and thematic analysis was used to identify key themes and subthemes.

Results

The study identified three main themes based on data collected from 12 participants. The first theme, “Children's Lifestyle Behaviors,” highlighted the need to address unhealthy food consumption, low physical activity, and inconsistent sleeping habits. The second theme, “Parenting Lifestyle behaviors,” underscored the importance of regaining control over children's eating behaviors, fostering shared interest in outdoor activities, and establishing a consistent sleep routine. Lastly, the third theme, “Determinants of Parenting Lifestyle Behaviors,” identified factors such as parental stress, the high cost of healthy options, cultural influence on healthy eating, limited outdoor activity options, and the availability of unhealthy snacks in schools.

Conclusion

Our study underscores the need for family‐centered obesity programs that address several determinants of parenting lifestyle behaviors, including psychological, financial, social, and environmental challenges.
DesignQA: A Multimodal Benchmark for Evaluating Large Language Models’ Understanding of Engineering Documentation
Authors: Doris Anna C. , Grandi Daniele , Tomich Ryan , Alam Md Ferdous , Ataei Mohammadmehdi , Cheong Hyunmin , Ahmed Faez
Published: December 2024

This research introduces DesignQA, a novel benchmark aimed at evaluating the proficiency of multimodal large language models (MLLMs) in comprehending and applying engineering requirements in technical documentation. Developed with a focus on real-world engineering challenges, DesignQA uniquely combines multimodal data—including textual design requirements, CAD images, and engineering drawings—derived from the Formula SAE student competition. Unlike many existing MLLM benchmarks, DesignQA contains document-grounded visual questions where the input image and the input document come from different sources. The benchmark features automatic evaluation metrics and is divided into segments—Rule Comprehension, Rule Compliance, and Rule Extraction—based on tasks that engineers perform when designing according to requirements. We evaluate state-of-the-art models (at the time of writing) like GPT-4o, GPT-4, Claude-Opus, Gemini-1.0, and LLaVA-1.5 against the benchmark, and our study uncovers the existing gaps in MLLMs’ abilities to interpret complex engineering documentation. The MLLMs tested, while promising, struggle to reliably retrieve relevant rules from the Formula SAE documentation, face challenges in recognizing technical components in CAD images and encounter difficulty in analyzing engineering drawings. These findings underscore the need for multimodal models that can better handle the multifaceted questions characteristic of design according to technical documentation. This benchmark sets a foundation for future advancements in AI-supported engineering design processes. DesignQA is publicly available at online.
La inseguridad habitacional en palma de mallorca como efecto de la gentrificación y turistificación
Authors:   UNED, Rodriguez Nuñez Juan Alonso
Published: December 2024

Esta ponencia muestra el estudio etnográfico que explora los efectos de la gentrificación y turistificación en los residentes del barrio del Casc Antic de Palma de Mallorca. Se analizan los desplazamientos, la transformación del espacio urbano y las percepciones de los vecinos ante el cambio. Los objetivos son comprender cómo afectan estos procesos a la vivienda y la inclusión social de los residentes, y evaluar las propuestas para mitigar sus efectos negativos desde una perspectiva antropológica.La investigación combina un marco teórico sobre globalización, gentrificación, turistificación y exclusión social con una metodología cualitativa basada en entrevistas y observación participante. Refleja, cómo la presión inmobiliaria y el incremento de alojamientos turísticos generan desplazamientos, encarecimiento de la vivienda, y amenazas a la identidad del barrio, y analiza las intervenciones necesarias desde políticas públicas y comunidad local.El turismo ha sido un acelerante para la transformación del barrio que ha modificado tanto su configuración y las estructuras socioculturales. Como resultado, procede un necesario enfoque integral que conjugue la regulación, la protección de la vivienda, y preservación de la identidad cultural para abordar estos cambios urbanos desde la equidad y la sostenibilidad social. El estudio aporta nuevas perspectivas antropológicas sobre cómo los procesos de globalización afectan al bienestar de los residentes a nivel local, y sugiere formas de aplicar estos conocimientos para mitigar los efectos negativos. Por este motivo, este trabajo pretende analizar estos procesos, las causas y consecuencias que se generan sobre la vida de los habitantes de la ciudad.
International Delphi consensus on bone stress injuries in athletes
Authors: Hoenig Tim , Hollander Karsten , Popp Kristin L , Fredericson Michael , Kraus Emily A , Warden Stuart J , Tenforde Adam S
Published: December 2024

Bone stress injuries, commonly referred to as stress reactions and stress fractures, represent overuse injuries to bone. These injuries result in physical limitations in activity and can be career-ending for high-level athletes. While bone stress injuries have received increased attention in recent years, international consensus is lacking on definitions, risk factors and strategies for management and prevention. This study aimed to ascertain and improve the level of agreement on bone stress injuries by utilising a three-part modified Delphi approach on (1) pathophysiology, diagnosis, terminology and classification systems; (2) risk factors, screening and prevention; and (3) management and return to sport. A multidisciplinary steering committee initiated the consensus process. A panel of 41 members from six continents was formed to complete three rounds of voting, including experts (scientists and clinicians) and representatives (athletes and coaches). Thirty-three, 28 and 28 panel members completed Delphi rounds 1, 2 and 3, respectively. Consensus was reached on 41 out of 58 statements. Findings from this Delphi study outline a multifactorial approach to identify and manage bone stress injuries and to promote bone health in athletes. This includes recommendations for diagnostic workup and treatment to assist clinicians in caring for patients with bone stress injuries. Finally, this consensus process identifies knowledge gaps and provides a framework for future research to advance the clinical care and prevention of bone stress injuries.
Differences in uni-dimensional breathlessness measures and thresholds for clinical response in a randomised controlled trial in people with chronic breathlessness: an exploratory study
Authors: Ferreira Diana , Ekström Magnus , Louw Sandra , McCloud Philip , Johnson Miriam , Clark Katherine , Currow David
Published: December 2024

Introduction

Optimally measuring improvements in chronic breathlessness in clinical practice and research continues to evolve. The aim of this study was to consider the performance of uni-dimensional measures inchronic breathlessness limiting exertion.

Methods

We report five measures of breathlessness (intensity:worst, bestandaveragein the previous 24 hours;breathlessness now; and an affective componentunpleasantness now) and two clinical thresholds over baseline on their 0–100 mm visual analogue scale (8.9 mm absolute improvement; and 15% relative improvement) collected in a multi-site, randomised, double-blind, parallel-arm, placebo-controlled trial of regular, low-dose, sustained-release morphine for people withchronic breathlessnesswith optimally treated underlying causes.

Results

Participants (n=284) were mostly elderly men with severe, chronic breathlessness.Worst breathlessness in the previous 24 hoursshowed improvement in people with more severe breathlessness and chronic obstructive pulmonary disease. By contrast,breathlessness nowandaverage breathlessness in the previous 24 hoursgenerated similar patterns of response, as didunpleasantness nowandbreathlessness now. Best breathlessness added little value. The two clinical thresholds showed differing patterns of significance.

Discussion

Consistent with other recent work, worst breathlessness may be an important uni-dimensional outcome in evaluating chronic breathlessness clinically and in research. This study does not support a differential between unpleasantness now and breathlessness now, previously observed in laboratory-generated, acute-on-chronic breathlessness. Timeframe for recall (now or the last 24 hours) and the threshold for a clinical meaningful improvement (absolute (8.9 mm) or relative (15%)) affect assessment performance.
Variation in ambulance pre-alert process and practice: cross-sectional survey of ambulance clinicians
Authors: Coster Joanne E , Sampson Fiona C , O'Hara Rachel , Long Jaqui , Bell Fiona , Goodacre Steve
Published: December 2024

Background

Ambulance clinicians use pre-alert calls to inform emergency departments (EDs) about the arrival of critically ill patients. However, there is variation in guidance between local ambulance service policies in terms of what should be pre-alerted and how pre-alerts should happen. We conducted a national online survey to understand the use of ambulance pre-alerts and to inform recommendations for practice and guidance.

Methods

Ambulance clinicians in England involved in pre-alert decision-making were recruited via ambulance trusts and social media to complete an anonymous online survey conducted during May–July 2023. Quantitative data was analysed descriptively using SPSS (version 28) and free-text responses are reported to illustrate the quantitative findings.

Results

We included 1298 valid responses from 10 English ambulance services. There was variation in practice at all stages of the pre-alert process, including the reported frequency of pre-alert (7.1% several times a shift, 14.9% once/two times per month). Most respondents reported that pre-alerts were delivered directly to the ED, but 32.8% reported pre-alerting via an ambulance control room. A third of respondents always used mnemonics to guide a pre-alert (eg, ATMIST (Age, Time of Incident, Mechanism of injury, Injuries, Signs, Treatments)), but 10.2% reported not using any fixed format.

The type of guidance used to identify patients for pre-alert varied between clinicians and ambulance services, with local ambulance service guidance being most commonly used, and 20% stating they never use national guidelines. Respondents reported variable understanding of appropriate conditions for pre-alert, with paramedic students particularly wanted further guidance on trauma in older patients and medical pre-alerts. 29% of respondents reported receiving specific pre-alert training, while 50% reported never receiving feedback.

Conclusion

We identified variation in pre-alert processes and practices that may result in uncertainty and challenges for ambulance clinicians providing time-critical care. Guidance and training on the use of pre-alerts may promote more consistent processes and practices.
The Internet of Bio-Nano Things with Insulin-Glucose, Security and Research Challenges: A Survey
Authors: Bulasara Phani Krishna , Sahoo Somya , Gupta Nitin , Han Zhu , Kumar Neeraj
Published: December 2024

The Internet of Bio-Nano Things (IoBNT) is collaborative cell biology and nanodevice technology interacting through Molecular Communication (MC). The IoBNT can be accomplished by using the Information and Communication Theory (ICT) study of biological networks. Various technologies such as the Internet of Nano Things (IoNT), the Internet of Bio-degradable Things (IoBDT), and the Internet of Ingestible Things (IoIT) contribute to the development of IoBNT. Our survey discussed the Bio-Nano network and the role of IoT-based technologies along with a comparative study from various literature. We surveyed the various applications of IoNT in which the drug delivery for Insulin-Glucose system is prominent. Our survey aims to provide information about the Insulin-Glucose system involving the IoBNT and MC. We described the details of various factors for a diabetes analysis. We surveyed the diffusion coefficients of Insulin, Glucose, and the various parameters that influence insulin production in the body. Our survey identifies the security aspects of IoBNT such as attacks in nanonetworks, bio-cyber interface, Insulin-Glucose system, and their possible mitigation techniques. Our survey also provides a hierarchical model of the Bio-Nano network collaborating all the related technologies. Finally, our survey includes the research challenges involved in the proper handling of the IoBNT.
Denoising Heterogeneous Graph Pre-training Framework for Recommendation
Authors: Sang Lei , Wang Yu , Zhang Yiwen , Wu Xindong
Published: December 2024

Heterogeneous graph neural networks (HGNN) have exhibited significant performance gains by modeling the information propagation process in graph-structured data for recommender systems. However, existing HGNN-based Recommendation still face two challenges: 1) They overlook the rich semantics brought by the combination of different meta-paths, making it difficult to capture the importance of various meta-paths; 2) when HGNN use meta-paths to capture high-order information, they are susceptible to noise data, as noise from connected nodes can create cumulative effects on a target node in the graph. To tackle these issues, we propose a new model called the Denoising Heterogeneous Graph Pre-training Framework (
DHGPF
) to enhance recommendation tasks. This framework has two stages: pre-training and training. In the pre-training stage, we assign learnable weights to different meta-paths and use a simplified multi-layer graph convolution network to automatically aggregate semantic information from different meta-path combinations. This approach can capture the importance of these paths. The training stage focuses on reducing noise using gating mechanism and denoising structure learning methods. These methods accomplish the denoising process through information filtering. Our model was evaluated on three real-world datasets, demonstrating that DHGPF outperforms other state-of-the-art recommendation methods. We have further organized the source code of the paper at
https://github.com/wangyu0627/DHGPF
.
Efficacy of Local N‐Acetylcysteine Administration in Mitigating OHSS Parameters: A Comparative Analysis With Dopaminergic Agonist in the OHSS Model
Authors: Letras-Luna Dulce Elena , Rosas-Murrieta Nora Hilda , Pazos-Salazar Nidia Gary , Flores-Hernández Jorge , Castelán Francisco , Venegas Berenice , Díaz Alfonso , Treviño Samuel , Juárez-Serrano Daniel , García-Suastegui Wendy Argelia , Handal-Silva Anabella , Morán-Perales José Luis
Published: December 2024

In this study, we evaluated the effects of intrabursal administration of cabergoline and N‐acetylcysteine on ovarian hyperstimulation syndrome (OHSS) in an immature rat model. The study assessed body, ovarian, and uterine weights, as well as the concentrations of vascular endothelial growth factor A (VEGF‐A). Moreover, levels of MDA, 4‐HDA, and nitrites were assessed in ovarian homogenates, and vascular permeability was quantified in the peritoneal cavity. Ovarian morphology was characterized using histology and hematoxylin–eosin staining, determining the count of ovarian follicles and corpus luteum. Our results demonstrated a significant increase in lipoperoxidation, nitrite levels, and VEGF‐A concentrations in the OHSS group compared to the control group. These biochemical alterations corroborate the successful induction of OHSS in the experimental model. Direct injection into the ovarian bursa resulted in reduced vascular permeability and VEGF‐A levels, suggesting that the effects of cabergoline are predominantly ovarian. Particularly, cabergoline did not significantly alter other parameters such as ovarian weight, lipoperoxidation, nitrite levels, or morphology. Conversely, low concentrations of N‐acetylcysteine (25–50 µg/kg) significantly reduced ovarian and uterine weights, VEGF‐A levels, and vascular permeability. Interestingly, this dose–response relationship was not observed at higher NAC concentrations (100–200 μg/kg), suggesting a potential threshold beyond which NAC loses efficacy in these specific parameters. Our results suggest that the localized administration of N‐acetylcysteine shows promise as a therapeutic strategy for OHSS by modulating key parameters associated with the syndrome. These promising results warrant further investigation into its mechanisms and efficacy, potentially expanding therapeutic options for OHSS management.
Peptide BG From Bitter Gourd (Momordica Charantia) Improves Adjuvant‐Induced Arthritis by Modulating the Necroptosis/Neutrophil Extracellular Traps/Inflammation Axis and the Gut Microbiota
Authors: Han Wenyan , Xu Yanan , Qimuge Suyila , Wang Changshan , Su Xiulan
Published: December 2024

Background: BG is a novel bioactive peptide derived from bitter gourd (Momordica charantia), known for its anti‐inflammatory and immunomodulatory properties. In the present study, our objective is to investigate the functional roles and mechanisms of BG in the context of rheumatoid arthritis (RA).

Methods: A rat model of adjuvant‐induced arthritis (AIA) was established by administering complete Freund’s adjuvant (CFA). The viability of BG‐mediated AIA was evaluated by assessing changes in rat body weight, joint swelling, ankle joint pathology, inflammation, necroptosis, the formation of neutrophil extracellular traps (NETs), and gut microbiota.

Results: The results of the study showed that peptide BG was effective in improving weight loss, joint swelling, serum IgM‐rheumatoid factor (IgM‐RF) level, and pathological injury of ankle joint in rats with AIA. BG administration resulted in a decrease in erythrocyte sedimentation rate, serum C‐reactive protein (CRP), and inflammatory factor (interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α)) in AIA rats. Additionally, the administration of CFA resulted in an increase in the protein levels of myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (CitH3), peptidyl arginine deiminase 4 (PAD4), p‐mixed lineage kinase domain‐like (p‐MLKL), and cleaved caspase 8. However, this increase was found to be inhibited by BG treatment. Furthermore, it has been found that peptide BG possesses the capacity to regulate the species composition structure of the intestinal microbiota, thereby, facilitating the reestablishment of microbial diversity and equilibrium.

Conclusion: Peptide BG has demonstrated efficacy in ameliorating AIA through its regulation of the necroptosis/NETs/inflammation axis and the gut microbiota. This finding underscores the potential of BG as a promising therapeutic intervention for RA.
Perception of the World in a Time Perspective by Forced Migrants with Different Types of Dilemma Solutions
Authors: Almazova Olga V. , Dolgikh Alexandra G. , Molchanov Sergei V. , Shaigerova Ludmila A.
Published: December 2024

Background. The relevance of the study is due to the need for a better understanding of the individual characteristics of decision-making by forced migrants and the relationship of these features with a temporary perspective and long-term orientation.
Objective. The research is aimed at studying the perception of the surrounding world in a time perspective by forced migrants with different types of decision-making.
Study Participants. The study involved 36 respondents aged 32 to 73 years (Mage = 43; SD = 8.4; 2 men), forced migrants from the Donetsk People's Republic living with children or grandchildren in a temporary accommodation in the Moscow region.
Methods. We used “Dilemmas of choice in difficult life situations” and “Semantic differential” to assess respondents' perception of the world in a time perspective.
Results. Nine categories of decision-making analysis in a difficult situation were identified using the dilemma method based on the created scenarios, which made it possible to identify and characterize three types of decision-making among forced migrants — awaiting, active, and thinking, and to make comparisons between them. The application of the “Semantic differential” method made it possible to detect and characterize the differences and similarities between the types of decision-making in the perception of a time perspective in the present and the future and the absence of differences in the perception of the past.
Conclusions. The discovered categories of decision-making analysis in a difficult situation through the dilemma method allow us to identify individual features of decision-making. The representatives of the expectant type, whoare not ready for changes, control over the situation and responsibility for themselves and their close people can be considered as the most vulnerable group from the point of view of adaptation. The differences between the three types identified in relation to the perception of the present and the future can act as predictors of success in short-term and long-term adaptation.
Producing Ephemeral City during the Pandemic: Healthcare and Cultural Continuity at Data Saheb’s Urs in Lahore (Pakistan)
Authors: Hasnain Sajjad
Published: December 2024

This article explores frictions between state-led pandemic measures and public aspirations that sought religious-cultural continuity during covid-19 crisis. Through the case of annual festival at Data Saheb’s shrine (Lahore), it shows that devotees built an ephemeral city for three-day celebrations as a way of asserting their commitment to a centuries old tradition. It is argued that the cultural continuities of devotion to the city saint appeared to be flowing undeterred in the face of healthcare initiatives – making the shrine a microcosm that reflected flexibilities and lapses at the national level vis-à-vis pandemic governance. While elsewhere that might be seen as a case of (in)effective public health administration, at the shrine, it unearthed power equation between the religious actors and the state in Pakistan manifesting itself since Data Saheb’s demise in 12th century around political legitimation, public morality, patronage of shrines and control of religious actors in local politics.
AGRO-robotics: Problems and Prospects
Authors: Shavazov Kadirjon , Zhuravleva Larisa , Karpov Mihail
Published: December 2024

The article discusses innovative areas of development of forestry and agricultural machinery with intelligent control systems. Kinematics is considered using the example of a harvester with a multi-link manipulator and walking chassis. Systems of equations are presented that characterize the spatial position of the working and chassis equipment with a large number of degrees of freedom. For this purpose, many companies have set themselves the task of creating multifunctional robots that operate autonomously and are controlled remotely using cloud technologies with special software. Intelligent control systems currently being developed can significantly expand the technological capabilities of machines that were unavailable in the not so distant past. The use of robots allows the introduction of new highly efficient technologies in which a person will be relieved of heavy physical labor, work in hazardous conditions, aggressive environments, etc. As a result of using robots, significant savings in material and labor resources, increased labor productivity and reduced production costs can be achieved. Currently, the use of walking vehicles for cargo transportation, clearing rubble, conducting emergency rescue operations in undeveloped areas in off-road conditions, as well as military use is considered promising. An assessment of existing problems and development prospects is given.
Potent Effects of Lenalidomide-Conjugated Anti-CD38 Antibody-Drug Conjugate (TE-1146) on Multiple Myeloma Cells Isolated from Patients
Authors: Jiang Jing Gu , Lin Shih-Chiang , Cheng Shih-Syuan , Yu Yueh-Hsiang , Chang Tse Wen , Chu Hsing-Mao , Yu Yuan-Bin
Published: December 2024

Background: Despite available therapies such as proteasome inhibitors, antibodies, and immunomodulators, multiple myeloma (MM) remains incurable, with patients often experiencing relapses and severe side effects. To address this issue, we employed a proprietary HighDAR platform and developed TE-1146, which is a site-specific lenalidomide (Len)-conjugated antibody-drug conjugate (ADC) targeting CD38 on MM cells. TE-1146 utilizes cleavable linkers recognized by lysosomal cathepsin B and carries six Len molecules. Studies have shown that TE-1146 has stronger direct cytotoxicity than the combination of daratumumab (Dara) and Len, while maintaining similar Fc-mediated effects such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). Additionally, TE-1146 has a long half-life (t1/2: 11.1 days) in healthy mice and demonstrates superior anti-tumor efficacy in human MM cell line-derived xenograft mouse models compared to the Dara and Len combination.

Methods: This study evaluates the efficacy of TE-1146 using human MM cells isolated from bone marrow samples obtained from patients between July 2023 and May 2024. Fifteen samples were categorized into three subgroups (5 samples each): (1) from treatment-naïve patients, (2) from relapsed patients without prior Dara/Len treatments, and (3) from relapsed patients with prior Dara/Len treatments. Isolated MM cells were treated with TE-1146 or Dara/Len combination, and cytotoxicity was assessed.

Results: Of the 15 screened samples, 14 were eligible for the study, all expressing both CD138 and CD38. In subgroup 1 (treatment-naïve patients), among 5 eligible samples, TE-1146 achieved a 100% cytotoxic response with a mean IC50 value of 0.05 nM. In subgroup 2 (patients who relapsed after bortezomib, thalidomide, and dexamethasone [VTD] regimens, without prior Dara/Len treatment), all 4 eligible samples exhibited a 100% cytotoxic response with a mean IC50 value of 0.02 nM. In subgroup 3 (relapsed, with prior Dara/Len treatment, 5 eligible samples), one sample responded to TE-1146 treatment with an IC50 value of 1.96 nM. In subgroups 1 and 2, TE-1146 exhibited at least 100-fold greater MM cell lysis compared to Dara, Len, or their combination, based on IC50 values. Nevertheless, in subgroup 3, TE-1146 showed limited efficacy, likely due to developed resistance to Dara or Len.

Conclusion: This study demonstrates that TE-1146 enhanced direct cytotoxicity, significantly improving efficacy over the Dara/Len combination while potentially reducing the required dosage and associated side effects of Len. These results support further development and clinical evaluation of TE-1146 ADC as a promising treatment for MM.
UBE2E3 Supports Survival of Leukemia Stem Cells By Regulation of Polycomb Repression Complex (PRC) 1.1
Authors: Miller Vika , Hija Ayat , Abdal-Rhaman Mohamed , Gross Even-Zohar Noa , Saltsman Michal , Botham Aaron , Haran Arnon , Aumann Shlomzion , Vainstein Vladimir , Gatt Moshe E , Raught Brian , Schimmer Aaron D , Nachmias Boaz
Published: December 2024

AML cells are arranged in a hierarchy with leukemia stem cells giving rise to a more differentiated bulk leukemia cells. The determinants that support stemness are still not completely understood.

Recently, we identified importin 11 (IPO11), a nuclear transport receptor, as a regulator of stemness in AML. To identify cargo protein imported into the nucleus by IPO11, we conducted a BioID-mass spectrometry screen. Through this screen, we discovered that IPO11 interacts with the E2 ligase, UBE2E3 to regulate its nuclear localization. The importance of UBE2E3 in AML and its role in leukemia stemness is currently unknown. Therefore, we focused our investigation on UBE2E3.

To understand the role of UBE2E3 in AML and leukemia stem cells, we knocked down UBE2E3 in AML cell lines. Silencing of UBE2E3 shifted the transcriptomic signature away from leukemia stem cells and hematopoietic stem cell progenitors toward a more differentiated and mature signature: LSC+ vs. LSC- (FDR ≤0.01, GSE76008) and progenitor/stem vs. myeloid cluster (FDR ≤ 0.01, TCGA-AML). Moreover, knockdown of UBE2E3 in OCI-AML2, NB4 and K562 AML cells reduced growth and viability of by 60-70%, as well as reduced clonogenic growth, consistent with an effect on leukemia initiating cells.

To investigate how UBE2E3 regulates leukemic stemness, we performed a BioID mass spectrometry screen for proteins that interact with UBE2E3. Through this screen, we discovered that UBE2E3 interacted with poly-comb repression complex (PRC) proteins, including four core components of a variant of PRC-1, designated PRC1.1, KDM2B, BCOR, RING1 and PCGF1. The PRC mediates epigenetic transcriptional repression, governing key cellular processes, including proliferation and differentiation. Previous work has shown that PRC1.1 control specific genes required for leukemic cell viability. Knockdown of UBE2E3 decreased expression of known PRC 1.1 target genes specific for AML (FDR ≤0.01, GSE54580), such as PKM, MAP3K6 and ERCC1, demonstrating that UBE2E3 positively regulates PRC1.1 activity.

In summary, we identified UBE2E3 as a novel regulator of non-canonical PRC 1.1 complex in AML and through that mechanism a positive regulator of leukemia stemness. Thus, we identified UBE2E3 as a possible novel target in AML.
Correlation between Familial Waldenström Macroglobulinemia Clusters Withclinical Features, Complications, and Outcomes in 1000 Patients: A Single-Center Retrospective Cohort Study
Authors: Ramirez Andres , Castillo Jorge J. , Tsakmaklis Nickolas , Hunter Zachary R , Guerrera Maria Luisa , Flynn Catherine A. , Sarosiek Shayna R , Treon Steven P.
Published: December 2024

Context: Waldenström macroglobulinemia (WM) is a rare type of B-cell lymphoma, with around 20% of patients having a family history of blood malignancies. However, most data about family history are derived from clinical databases with scarce information regarding clinical features, complications, and treatment outcomes among different family groups.

Objective: To determine the relationship between family history, presenting characteristics, complications, and treatment outcomes of patients with WM.

Design, Participants, and Setting: This retrospective study examines family history and clinical data from 1000 adult patients with a clinicopathological diagnosis of WM evaluated at our institution between 2000 and 2022. Patients were followed up until December 2023.

Main Outcome Measures: The primary outcome was to correlate clinical features at the time of diagnosis (sex, age, adenopathy, splenomegaly, hemoglobin, platelets, LDH, albumin, beta-2-microglobulin, IgM, light chain restriction, % bone marrow involvement, MYD88 and CXCR4 mutational status), complications at any time during the disease course (Bing-Neel syndrome, cryoglobulinemia, cold-agglutinin syndrome, malignant pleural effusions, renal involvement, DLBCL transformation, AL amyloidosis, and WM-attributed neuropathy), prevalence of family history (WM, other B-cell, non-B-cell, and sporadic) and treatment outcomes (treatment status, overall survival). Chi-square test and logistic regression models were fitted to evaluate between variables. Cox proportional-hazard regression models were fitted to evaluate survival prognostic factors.

Results: The median follow-up time from diagnosis was 13 years (95% CI, 9.66-16.59). We found that compared with sporadic WM, patients with a family history of WM were more likely women (34% vs 50%; P<0.01). Patients with familial WM showed increased odds of developing Bing-Neel syndrome (OR 5.6; 95% CI, 2.1-14.4; P<0.01) and cryoglobulinemia (OR 3.1; 95% CI, 1.4-7.0; P=0.01) but less likely to develop neuropathy (OR 0.38; 95% CI, 0.2-0.8; P=0.01). In multivariate Cox regression analyses, no significant difference in excess mortality was detected in patients with family history of WM (HR, 1.1; 95% CI, 0.92-1.31; P=0.3).

Conclusion: Our study suggests that patients with a family history of WM are more likely women, have higher odds of cryoglobulinemia and Bing-Neel syndrome, and lower odds of neuropathy. However, no excess mortality was observed.
Impact of Protein Energy Malnutrition on Hospitalized Patients with Amyloidosis: A United States Population-Based Cohort Study
Authors: Arya Yajur , Syal Arshi , Jones Colton Frisco , Byfield Karecia , Casipit Bruce Adrian , Dourado Claudia , Varadi Gabor
Published: December 2024

Background

Amyloidosis can affect virtually any organ system and lead to a multitude of clinical manifestations. Patients with amyloidosis tend to have varying degrees of protein energy malnutrition (PEM) due to multiple reasons, including cachexia, sarcopenia, and systemic involvement. End organ damage, including renal failure, heavy proteinuria, and malabsorption due to gastrointestinal involvement, further complicates the clinical picture. The impact of PEM on clinical outcomes in this subgroup needs further exploration.

Methods

We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with amyloidosis and PEM using appropriate ICD-10 diagnostic codes. We stratified patients with amyloidosis based on the presence or absence of PEM. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of <0.05 was considered statistically significant. The aim of this study was to investigate the impact of PEM on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charges among hospitalized patients with amyloidosis.

Results

We identified a total of 3525 hospitalized patients with amyloidosis, of which 12.48% (440/3525) had comorbid PEM. The overall in-hospital mortality among patients with amyloidosis was 5.39% (190/3525). Among those with concomitant PEM, the mortality rate was significantly higher at 12.50% (55/440, p=0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, PEM was found to be an independent predictor of increased in-hospital mortality (adjusted OR 2.69; 95% (confidence interval [CI] 1.23-5.85; p=0.013), longer LOS (coefficient 3.09; CI 0.12-6.06; p=0.041), higher total hospitalization charges ($59817; [CI] $8531-$111104; p=0.022), and increased need for mechanical ventilation (adjusted OR 2.21; CI 1.00-4.86; p=0.049).

Conclusion

Our analysis demonstrated that PEM was widely prevalent in hospitalized patients with amyloidosis. It was associated with significantly worsened in-hospital mortality, longer LOS, total cost of healthcare utilization, and increased need for mechanical ventilation. Efforts should be made to promote nutritional assessment and screening mechanisms with the aim to include early nutritional support as indicated. Further prospective studies with larger sample size are warranted to better understand these associations.
Transient Activation of PIEZO1 Mechanosensitive Channel Facilitates Ex Vivo expansion of Hematopoietic Stem Cells
Authors: Wang Qiwei , Zhao Weili , Huang He , Qian Pengxu
Published: December 2024

Achieving long-term ex vivo expansion of functional hematopoietic stem cells (HSCs) is critical for unlocking the potential of clinical applications based on HSC transplantation. Understanding the microenvironment in which HSCs maintain their functions is a prerequisite, with mechanical perception being one of the key factors. Studies have revealed mechanosensitive ion channels (MSICs) are vital in hematopoietic system, but their roles in the expansion and functional maintenance of ex vivo cultured HSCs remain largely elusive. Here, we show that PIEZO1 is the MSIC predominantly expressed in HSCs. Unexpectedly, both absence and sustained chemical activation of PIEZO1 are detrimental to cultured HSCs, suggesting that maintaining cultured HSCs required transient PIEZO1 activation. To identify conditions that lead to such activation, we screen different microspheres and demonstrate that stiff polymer microspheres with a diameter of 500 nm transiently activate PIEZO1. PS500 (polystyrene microsphere with diameter of 500 nm) markedly promotes ex vivo expansion of murine bone marrow (BM)-derived HSCs with long-term in vivo repopulating ability, and also showed expansion effect for human umbilical cord blood (hUCB)-derived HSCs with repopulating ability in primary immunodeficient mice. Mechanistically, the transiently-activated PIEZO1 channels trigger Ca2+-dependent transcription of proliferative cytokines, which ultimately lead to STAT3 activation to maintain self-renewal and promote cell proliferation and survival. Collectively, our results demonstrate that PS500 transiently activates PIEZO1 mechano-sensitive channel and efficiently expands functional HSCs without any toxicity, pointing towards a promising strategy to produce functional HSCs for clinical applications.
Targeting Druggabble Long Non-Coding RNA MALAT1: Epigenetic Regulation of CD38 and Energy Metabolism in Multiple Myeloma
Authors: Cho Shih-Feng , Chang Wen-Hsin , Liao Wei-Ting , Yeh Tsung-Jang , Wang Hui-Ching , Du Jeng-Shiun , Hsu Chin-Mu , Hsiao Hui-Hua , Liu YI-Chang
Published: December 2024

Multiple myeloma (MM), the second most common hematologic malignancy, exhibits complex genetic and epigenetic abnormalities in its pathogenesis. Long non-coding RNA (lncRNA), defined as non-coding transcripts of more than 200 nucleotides, has been shown to play a crucial role in various critical cellular functions, including those related to malignant diseases. The lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), was found to be upregulated in both newly diagnosed and relapsed MM, indicating its potential oncogenic role. Previous studies also revealed therapeutic targeting MALAT exhibited a significant anti-MM effect. However, the specific mechanisms by which MALAT1 contributes to MM pathogenesis remain to be elucidated.

This study aims to investigate the role of this druggable lncRNA, MALAT1, in the development of MM. Initially, MALAT1 was overexpressed in MM cells, and its expression, along with CD38, was further upregulated in lenalidomide-resistant MM cell lines. Knocking down MALAT1 using antisense oligonucleotides (ASO) significantly decreased MM cell proliferation/viability in both lenalidomide-sensitive and resistant cells. RNAseq-based transcriptome profiles showed that genes related to the oxidative phosphorylation (OXPHOS) pathway were significantly down-regulated following MALAT1 knockdown. Downregulation of MALAT1 further reduced adenosine triphosphate (ATP) levels and elevated the generation of reactive oxygen species (ROS), suggesting those alterations in energy metabolism and the oxidative stress response in MM cells resulted in decreased cell viability. Furthermore, using a ChIP-PCR assay, MALAT1 epigenetically modulated CD38 expression via H3K27me3 modification, involving the polycomb repressive complex 2 (PRC2) complexes with H3K27 methyltransferase EZH2 and EED. Taken together, targeting the druggable lncRNA MALAT1 suppresses MM cell growth, reduces CD38 expression through epigenetic regulation by the PRC2 complexes, and has potential applications in treating lenalidomide resistance in MM.