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Yanan Yang,1,* Shuoye Yang,1,2,* Beibei Zhang,1 Jinpeng Wang,1 Di Meng,1 Lan Cui,1,2 Lu Zhang1,2 1School of Biological Engineering, Henan University of Technology, Zhengzhou, People’s Republic of China; 2Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuoye Yang, School of Biological Engineering, Henan University of Technology, Lianhua Street, Gaoxin District, Zhengzhou, 450001, People’s Republic of China, Tel/Fax: +86-371-67756513, Email yangshuoyehaut@163.comIntroduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer.Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects.Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance.Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.Keywords: mesoporous silica nanoparticles, multidrug resistance, small interfering RNA, doxorubicin, hybrid nanoparticles

Abstract This study aims to explore the efficacy of a hybrid deep learning and radiomics approach, supplemented with patient metadata, in the noninvasive dermoscopic imaging-based diagnosis of skin lesions. We analyzed dermoscopic images from the International Skin Imaging Collaboration (ISIC) dataset, spanning 2016–2020, encompassing a variety of skin lesions. Our approach integrates deep learning with a comprehensive radiomics analysis, utilizing a vast array of quantitative image features to precisely quantify skin lesion patterns. The dataset includes cases of three, four, and eight different skin lesion types. Our methodology was benchmarked against seven classification methods from the ISIC 2020 challenge and prior research using a binary decision framework. The proposed hybrid model demonstrated superior performance in distinguishing benign from malignant lesions, achieving area under the receiver operating characteristic curve (AUROC) scores of 99%, 95%, and 96%, and multiclass decoding AUROCs of 98.5%, 94.9%, and 96.4%, with sensitivities of 97.6%, 93.9%, and 96.0% and specificities of 98.4%, 96.7%, and 96.9% in the internal ISIC 2018 challenge, as well as in the external Jinan and Longhua datasets, respectively. Our findings suggest that the integration of radiomics and deep learning, utilizing dermoscopic images, effectively captures the heterogeneity and pattern expression of skin lesions.

Abstract Background Human aging and white blood cell (WBC) count are complex traits influenced by multiple genetic factors. Predictors of chronological age have been developed using epigenetic clocks. However, the bidirectional causal effects between epigenetic clocks and WBC count have not been fully examined. Methods This study employed Mendelian randomization (MR) to analyze summary statistics from four epigenetic clocks involving 34,710 participants, alongside data from the Blood Cell Consortium encompassing 563,946 individuals. We primarily explored bidirectional causal relationships using the random-effects inverse-variance weighted method, supplemented by additional MR methods for comprehensive analysis. Additionally, multivariate MR was applied to investigate independent effects of WBC count on epigenetic age acceleration. Results In the two-sample univariate MR (UVMR) analysis, we observed that a decrease in lymphocyte count markedly accelerated aging according to the PhenoAge, GrimAge, and HannumAge metrics (all P

Mingyan Wang,1– 3,&ast; Siyuan Yang,1– 3,&ast; Linxin Yang,1– 3 Ning Lin1– 3 1Ultrasound Department of Shengli Clinical Medical College of Fujian Medical University, Fuzhou City, Fujian Province, 350001, People’s Republic of China; 2Ultrasound Department of Fujian Provincial Hospital, Fuzhou City, Fujian Province, 350001, People’s Republic of China; 3Ultrasound Department of Fuzhou University Affiliated Provincial Hospital, Fuzhou City, Fujian Province, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Lin, Ultrasound Department of Fujian Provincial Hospital, 134 East Street, Fuzhou City, 350001, Fujian Province, People’s Republic of China, Tel +86 0591-87557768, Email NingLin2413@163.comAim: The study aimed to compare the diagnostic performance of AI-SONICTM Thyroid System (AI-SONICTM) with six thyroid nodule ultrasound risk stratification systems, as well as the interobserver agreement among different-year ultrasound examiners using the same diagnostic approach.Methods: This retrospective study included patients who underwent thyroid ultrasound examination and surgery between 2010 and 2022. Three ultrasound examiners with 2, 5, and 10 years of experience, respectively, used AI-SONICTM and six guidelines to risk-stratify the nodules. The diagnostic performance and interobserver agreement were assessed.Results: A total of 370 thyroid nodules were included, including 195 papillary thyroid carcinomas (PTC) and 175 benign nodules. For physicians of varying seniority from low to high, AI-SONICTM had a moderate sensitivities of 82.56%, 83.08%, 84.62%, respectively, while AACE/ACE/AME had the highest diagnostic sensitivities (96.41%, 95.38%, 96.41%, respectively); And relatively higher specificities were 85.14%, 85.71%, 85.71% for KSThR, while moderate specificities with values of 84.0%, 85.14%, and 85.71%, respectively were found for AI-SONICTM; The accuracy was highest for ATA (excluding non-classifiable nodules), with values of 87.26%, 87.93%, and 88.82%, respectively, while the accuracy for AI-SONICTM were 83.24%, 84.05%, and 85.14%, respectively. The Kendall’s tau coefficient indicated strong or moderate interobserver agreement among all examiners using different diagnostic methods (Kendall’s tau coefficient > 0.6, P< 0.001). AI-SONICTM showed the highest interobserver agreement (Kendall’s tau coefficient=0.995, P< 0.001). A binary probit regression analysis showed that nodules with cystic components had a significantly higher regression coefficient value of 0.983 (P=0.002), indicating that AI-SONICTM may have higher accuracy for nodules with cystic components.Conclusion: AI-SONICTM and the six thyroid nodule ultrasound risk stratification systems showed high diagnostic performance for papillary thyroid carcinoma. All examiners showed strong or moderate interobserver agreement when using different diagnostic methods. AI-SONICTM may have higher accuracy for nodules with cystic components.Keywords: AI-SONICTM thyroid system, six thyroid risk stratification guidelines, papillary thyroid cancer

The global wind energy industry is expected to expand in the context of carbon neutralization. Meanwhile, with the continuous improvement in carbon reduction tools such as carbon market and carbon tariffs, the carbon footprint of renewable energy may impact the cost and development of wind power in the future. Taking China, Europe, and the United States as the research object, this study constructs the lifecycle evaluation process and list of onshore wind power systems, conducts parameter comparison regarding the carbon footprint of onshore wind power in relevant regions, and summarizes the change trends. Moreover, it analyzes the cause of the trend and clarifies the influencing factors. The results indicate that the carbon footprint of onshore wind power shows a downward trend in the aforementioned regions from 2011 to 2022 owing to the large-scale wind turbines, improved generation efficiency, and cleanliness of industrial production. Specifically, the average decrease in China, Europe, and the United States was 49.2%, 46.2%, and 20.8%, respectively, and the decrease was concentrated in the equipment production stage. China has reduced its carbon footprint to a level close to Europe, and its gap with the United States has been reduced to 3.63 g/kW·h. However, China still lags behind Europe and the United States in terms of industrial production cleanliness and fan capacity factor, respectively. In the process of promoting industrial development, China should further promote the power generation efficiency of its wind power system, improve the cleanliness of industrial production, and support the recycling of decommissioned wind power systems, so as to steadily reduce the carbon footprints within the lifecycle of onshore wind power systems.

In response to the global climate crisis, some countries and regions have established green trade “carbon barriers” that leverage their advantages in carbon emissions accounting and certification to curtail exports of Chinese products. Facing these emerging challenges, China needs to refine its carbon accounting system to contribute to an equitable and cooperative global climate governance and trade system. This study aims to improve China’s carbon accounting system. It summarizes the essence and construction progress of the carbon accounting system, introduces the accounting and reporting requirements of international green trade mechanisms, and employs comparative analysis to examine the differences between China’s carbon market, the European Union’s Carbon Border Adjustment Mechanism, and the “Regulation (EU) 2023/1542 concerning batteries and waste batteries” in terms of accounting boundaries, methodologies, and data support and quality assurance systems. The findings indicate that while China’s carbon market aligns with international green trade mechanisms in terms of accounting methodologies, it lags significantly in its carbon footprint system as well as data support and quality assurance systems. These gaps mean that Chinese export-oriented enterprises struggle to overcome these carbon barriers with the current accounting system, potentially hindering the development of emerging industries. The study suggests that China should adhere to its fundamental stance of opposing unfair green trade barriers and take specific measures to improve the carbon accounting system: (1) enhancing the product-level carbon accounting system, (2) establishing a credible platform for emission factor data, (3) bolstering research support from academic institutions, (4) reinforcing data security management, and (5) improving the carbon accounting and reporting capabilities of affected enterprises.

Ying Yang,1– 3,&ast; Bixia Zhou,1,2,&ast; Min Li,4 Yishuai Sun,1,2 Xulei Jiang,1,2 Xinxin Zhou,1,2 Chengjun Hu,1,2 Dou Zhang,3 Hang Luo,3 Wuyuan Tan,1,2 Xinghua Yang,1,2 Shaorong Lei1,2 1Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, People’s Republic of China; 3State Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Oncology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaorong Lei, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email leishaorong@csu.edu.cn Xinghua Yang, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email yxhua8805@sina.comPurpose: The treatment of craniofacial bone defects caused by trauma, tumors, and infectious and degenerative diseases is a significant issue in current clinical practice. Following the rapid development of bone tissue engineering (BTE) in the last decade, bioactive scaffolds coupled with multifunctional properties are in high demand with regard to effective therapy for bone defects. Herein, an innovative bone scaffold consisting of GO/Cu nanoderivatives and GelMA-based organic-inorganic hybrids was reported for repairing full-thickness calvarial bone defect.Methods: In this study, motivated by the versatile biological functions of nanomaterials and synthetic hydrogels, copper nanoparticle (CuNP)-decorated graphene oxide (GO) nanosheets (GO/Cu) were combined with methacrylated gelatin (GelMA)-based organic-inorganic hybrids to construct porous bone scaffolds that mimic the extracellular matrix (ECM) of bone tissues by photocrosslinking. The material characterizations, in vitro cytocompatibility, macrophage polarization and osteogenesis of the biohybrid hydrogel scaffolds were investigated, and two different animal models (BALB/c mice and SD rats) were established to further confirm the in vivo neovascularization, macrophage recruitment, biocompatibility, biosafety and bone regenerative potential.Results: We found that GO/Cu-functionalized GelMA/β-TCP hydrogel scaffolds exhibited evidently promoted osteogenic activities, M2 type macrophage polarization, increased secretion of anti-inflammatory factors and excellent cytocompatibility, with favorable surface characteristics and sustainable release of Cu2+. Additionally, improved neovascularization, macrophage recruitment and tissue integration were found in mice implanted with the bioactive hydrogels. More importantly, the observations of microCT reconstruction and histological analysis in a calvarial bone defect model in rats treated with GO/Cu-incorporated hydrogel scaffolds demonstrated significantly increased bone morphometric values and newly formed bone tissues, indicating accelerated bone healing.Conclusion: Taken together, this BTE-based bone repair strategy provides a promising and feasible method for constructing multifunctional GO/Cu nanocomposite-incorporated biohybrid hydrogel scaffolds with facilitated osteogenesis, angiogenesis and immunoregulation in one system, with the optimization of material properties and biosafety, it thereby demonstrates great application potential for correcting craniofacial bone defects in future clinical scenarios. Keywords: nanomaterials, hybrid hydrogel, bone scaffolds, craniofacial bone defects, bone regeneration

Mengjie Xie,1,&ast; Fansu Meng,2,&ast; Panpan Wang,3,&ast; Alicia Marcelina Díaz-García,4 Marina Parkhats,5 Ralph Santos-Oliveira,6 Mulazim Hussain Asim,7 Nazish Bostan,8 Honghui Gu,9 Lina Yang,9 Qi Li,9 Zhenjiang Yang,9 Haibiao Lai,2 Yu Cai1 1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China / Guangdong Key Laboratory of Traditional Chinese Medicine Informatization / International Science and Technology Cooperation Base of Guangdong Province/School of Pharmacy, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 2Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong, 528400, People’s Republic of China; 3The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 4Bioinorganic Laboratory, Faculty of Chemistry, University of Havana, Havana, 1400, Cuba; 5B. I. Stepanov Institute of Physics, National Academy of Sciences of Belarus, Minsk, 220072, Belarus; 6Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Rio de Janeiro, RJ, 21941906, Brazil; 7College of Pharmacy, University of Sargodha, Punjab, 40100, Pakistan; 8Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan; 9Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, 518033, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Cai; Haibiao Lai, Email caiyu8@sohu.com; lhb8829@163.comAbstract: Data published in 2020 by the International Agency for Research on Cancer (IARC) of the World Health Organization show that breast cancer (BC) has become the most common cancer globally, affecting more than 2 million women each year. The complex tumor microenvironment, drug resistance, metastasis, and poor prognosis constitute the primary challenges in the current diagnosis and treatment of BC. Magnetic iron oxide nanoparticles (MIONPs) have emerged as a promising nanoplatform for diagnostic tumor imaging as well as therapeutic drug-targeted delivery due to their unique physicochemical properties. The extensive surface engineering has given rise to multifunctionalized MIONPs. In this review, the latest advancements in surface modification strategies of MIONPs over the past five years are summarized and categorized as constrast agents and drug delivery platforms. Additionally, the remaining challenges and future prospects of MIONPs-based targeted delivery are discussed. Keywords: Nanopreparations, Organic Nanomaterials, Inorganic Nanomaterials, Surface Engineering, Targeted Delivery

Abstract Background Anxiety and depression are prevalent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, existing research has yielded conflicting findings regarding the effects of social frailty on anxiety and depression. The primary aim of this study is to validate the relationship between social frailty and social support with anxiety and depression in patients with acute exacerbations of COPD (AECOPD) and to investigate whether social support could explain the variations in prior study outcomes for patients with AECOPD. Methods Of the 315 patients hospitalized with AECOPD at the respiratory intensive care unit of a large tertiary care institution in Sichuan Province of China, between August 2022 and June 2023 who were surveyed, 306 were included in the analysis after excluding missing data. We conducted a logistic regression analysis to examine the associations of social frailty and social support with anxiety and depression and performed mediation analyses to examine whether social support mediates the relationship of social frailty with anxiety and depression. Results The logistic regression analysis revealed that social frailty did not associate anxiety or depression in patients with AECOPD. The mediation analysis supported this idea and indicated that while social frailty does not directly influence anxiety or depression, it can through social support. Conclusions The findings suggest that while social frailty may not directly impact anxiety or depression in patients with AECOPD, social support plays a crucial mediating role. Enhancing social support can indirectly alleviate anxiety and depression among these patients. Enhancing social support networks should thus be prioritized by healthcare providers and family members to improve mental health outcomes in this patient population.

Abstract Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.

Abstract Background Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. Methods This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. Results Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). Conclusions Sirolimus’s long-term administration is not associated with adverse effects on children’s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. Trial registration Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Min Qiu,1,2,&ast; Jinru Zou,2,&ast; Zheng Yang,3 Dan Yang,2 Rui Wang,1 Haie Guo1,4 1College of Veterinary Medicine, Inner Mongolia Agricultural University, Inner Mongolia, People’s Republic of China; 2College of Pharmacy, Baotou Medical College, Baotou, People’s Republic of China; 3The First Affiliated Hospital, Baotou Medical College, Baotou, People’s Republic of China; 4Agriculture, Animal Husbandry and Science and Technology Bureau of Liangcheng County, Ulanqab, Inner Mongolia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Wang; Haie Guo, Email wr2006@163.com; 153713887@qq.comAbstract: Exosomes belong to a subgroup of extracellular vesicles secreted by various cells and are involved in intercellular communication and material transfer. In recent years, exosomes have been used as drug delivery carriers because of their natural origin, high stability, low immunogenicity and high engineering ability. However, achieving targeted drug delivery with exosomes remains challenging. In this paper, a phage display technology was used to screen targeted peptides, and different surface modification strategies of targeted peptide exosomes were reviewed. In addition, the application of peptide-targeted exosomes in pulmonary diseases was also summarised.Keywords: exosome, targeted peptide modification, targeted delivery, lung

Wei Zhang,1,&ast; Jiayu Zhang,2,&ast; Dian Jiao,1,&ast; Qisheng Tang,1 Xiaoping Gao,1 Zhenyu Li,1 Fa Yang,3 Zhiguang Zhao,1 Longfei Yang4 1Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China; 2Department of Urology, Air Force Hospital of Southern Theater Command, Guangzhou, Guangdong, 510062, People’s Republic of China; 3Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China; 4Department of Transfusion Medicine, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longfei Yang; Zhiguang Zhao, Email y68lf@163.com; zzg13991809889@163.comPurpose: Lichen sclerosus urethral stricture disease (LS USD) is a refractory and progressive disease primarily affecting the anterior urethra in males. Various potential etiological factors, such as genetics, autoimmunity, infection, and exposure to infectious urine, have been suggested. However, the accurate etiology of LS in the male urethra remains unclear.Patients and Methods: In this study, we conducted single-cell RNA sequencing to identify the transcriptional profiles of three patients with LS USD and three patients with non-LS USD. Immunofluorescence was used to confirm the single-cell sequence results.Results: Our study revealed distinct subsets of vein endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) with high proportions in LS USD, contributing to the tissue microenvironment primarily involved in proinflammatory and immune responses. In particular, FBs displayed a unique subset, Fib7, which is exclusively present in LS USD, and exhibited high expression levels of SAA1 and SAA2. The accumulation of macrophages, along with the dysregulated ratios of M1/M2-like phenotype macrophages, may be engaged in the pathogenesis of LS USD. Through cell–cell communication analysis, we identified significant interactions involving CXCL8/ACKR1 and CCR7/CCL19 in LS USD. Remarkably, Fib7 exhibited exclusive communication with IL-1B macrophages through the SAA1/FPR2 receptor–ligand pair.Conclusion: Our study provides a profound understanding of the tissue microenvironment in LS USD, which may be valuable for understanding the pathogenesis of LS USD. Keywords: lichen sclerosus, urethral stricture disease, single-cell RNA sequencing, heterogeneity, fibroblasts, macrophages

Liu Yang,1 Kaijie Gao,1 Weihua Gong,1 Ci Li,1 Nan Chen,1 Tiewei Li,1 Shan Wang,1 Jiajia Ni,2,3 Junmei Yang1 1Department of Clinical Laboratory, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou Key Laboratory of Children’s Infection and Immunity, Zhengzhou, Henan, People’s Republic of China; 2Research and Development Center, Guangdong Meilikang Bio-Science Ltd, Foshan, Guangdong People’s Republic of China; 3Department of Detection and Diagnosis Technology Research, Guangzhou National Laboratory, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Junmei Yang, Email yangjunmei7683@163.comPurpose: Although allergic diseases in children are on the rise, there has been no comprehensive investigation of the allergens affecting children with allergic diseases in central China. Therefore, we aimed to analyze the distribution of serum allergen species among children with allergic conditions in central China to inform the prevention, diagnosis, and treatment of childhood allergies.Patients and Methods: A total of 9213 children (5543 males with 2.88 ± 0.04 years old and 3670 females with 2.91 ± 0.05 years old) underwent allergen screening, and serum allergen-specific IgE (sIgE) antibodies were detected using an automated fluorescent enzyme immunoassay system.Results: Our findings revealed a total sIgE-positive rate (sIgE-PR) of 57.83%, with mixed food (42.10%), egg whites (30.83%), milk (28.97%), mixed dust mites (24.57%), and mixed molds (23.20%) being the most prevalent source of allergens. The sIgE-PR for common sources of allergens exhibited significant sex-based differences, with males having greater susceptibility than females (p< 0.05). Dust mites were the primary source of inhaled allergens, whereas egg white was the predominant source of food allergens. Sources of food allergens were most dominant among infants (0– 3 years old); sIgE-PRs for most source of food allergens decreased with age, whereas those for most source of inhaled allergens increased. The autumn sIgE-PRs for mixed molds, weed pollen combinations, and tree pollen combinations were significantly higher than those found in other seasons (p< 0.05).Conclusion: Our findings suggest that sources of allergens profiles in children with allergies vary across age groups and seasons. Understanding these patterns can improve the effective prevention of childhood allergies.Keywords: allergen, childhood allergies, IgE antibodies, source of food allergens, allergy prevention

【Objective】In order to solve the problem that it is difficult to make the temperature sensor of the Photonic Crystal Fiber (PCF) with Surface Plasma Resonance (SPR), a D-structure PCF temperature sensor is proposed. The micro-structure and arrangement of the air hole are also designed. The method of coating the polishing surface of the optical fiber with gold layer is used to stimulate the SPR of the optical fiber.【Methods】Ethanol is used as a temperature-sensitive material, and the temperature-sensitive effect is used as the temperature sensing mechanism to achieve the effect of temperature sensing. The finite element analysis method is used to simulate the thickness of the gold layer and the size of the elliptical air hole of the fiber respectively. The coupling characteristics between the core mode and the surface plasma mode are analyzed under different conditions, and the structure of the sensor is optimized.【Results】The temperature characteristics of the sensor are simulated. In the range of -80~80 ℃, the sensitivity of the sensor is 3.4 nm /℃, and the linearity is better than 0.969 63.【Conclusion】The temperature sensor designed in this paper has a wide temperature detection range, satisfactory sensitivity, and linearity, which can be used for real-time temperature monitoring in industrial, agricultural, and medical fields.

Abstract Hierarchical compartmentalization responding to changes in intracellular and extracellular environments is ubiquitous in living eukaryotic cells but remains a formidable task in synthetic systems. Here we report a two-level compartmentalization approach based on a thermo-responsive aqueous two-phase system (TR-ATPS) comprising poly(N-isopropylacrylamide) (PNIPAM) and dextran (DEX). Liquid membraneless compartments enriched in PNIPAM are phase-separated from the continuous DEX solution via liquid-liquid phase separation at 25 °C and shrink dramatically with small second-level compartments generated at the interface, resembling the structure of colloidosome, by increasing the temperature to 35 °C. The TR-ATPS can store biomolecules, program the spatial distribution of enzymes, and accelerate the overall biochemical reaction efficiency by nearly 7-fold. The TR-ATPS inspires on-demand, stimulus-triggered spatiotemporal enrichment of biomolecules via two-level compartmentalization, creating opportunities in synthetic biology and biochemical engineering.

Objective Most urban rail transit trains use PWM (pulse width modulation) variable frequency drive system, which often leads to bearing corrosion problems due to the excessive bearing voltage and bearing current during operation. Therefore, it is necessary to conduct in-depth research on the problem of excessive traction motor bearing voltage and bearing current considering whole-train grounding conditions. Method The formation mechanism of traction motor bearing voltage and bearing current is briefly analyzed. The bearing current paths of two typical vehicle models adopting different grounding schemes are analyzed separately. Based on this, a high-frequency equivalent circuit model containing vehicle grounding loop and traction system is established. The characteristics of bearing voltage and bearing current under two grounding schemes are simulated and analyzed. The effectiveness of different measures to suppress bearing voltage and bearing current is compared, and a circuit optimization design scheme is proposed from the perspective of whole-train grounding. Result & Conclusion The grounding system optimization scheme effectively reduces the grounding cable lengths, thereby diminishing the cable inductance. This optimization scheme can not only avoid the impact of electrostatic shielding method on traction motor efficiency and the impact of carbon brush grounding method on protective grounding, but also be compatible with the internal optimization schemes for these two traction drive systems. Simulation results verify that this optimization scheme can effectively reduce bearing voltage and bearing current while improving the return flow and potential of carbody.

Dan-Dan Li,1,&ast; Xue Yang,1,&ast; Yang Yang,2,&ast; Li-Hua Zhao,1 Tian-Tian Zhang,3 Yi-Nan Wang,1 Jian-Bin Su,1 Li-Hua Wang,4 Hai-Yan Shi3 1Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 2Department of General Practice, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 3Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 4Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Hua Wang, Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email wlh512512@163.com Hai-Yan Shi, Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email 1198827119@qq.comBackground: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied.Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level.Results: One-way analysis of variance showed that β-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p< 0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p< 0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-β (p> 0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes.Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.Keywords: type 2 diabetes, physical activity, body composition, correlation

Jianming Yang,1,&ast; Yu Zhang,2,&ast; Yewu Chen,1,&ast; Yang Yang,1,3 Yinan Deng1 1Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Breast Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Yang; Yinan Deng, Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, People’s Republic of China, Tel +86 20 85253106, Fax +86 20 85252276, Email yysysu@163.com; dengyinan2010@163.comBackgrounds and Aims: Multiple regimens of immune checkpoint inhibitors (ICIs) plus targeted therapies are commonly prescribed as first-line treatments for unresectable hepatocellular carcinoma (uHCC). Here, we aimed to investigate the correlation between dynamic changes of neutrophil-to-lymphocyte ratio (NLR) and tumor response to the combination of ICIs and targeted therapies for uHCC.Methods: Sixty-one patients who received ICIs plus targeted therapies for uHCC were enrolled in this retrospective study. The NLR before and at 3– 6 weeks after treatments were assessed to calculate the dynamic NLR changes (ΔNLR). Multivariate logistic regression and Cox regression models were used to explore the relationship between dynamic NLR changes and tumor response or progression-free survival (PFS), respectively. Furthermore, we assessed the predictive effect of alpha-fetoprotein (AFP) changes in combination with dynamic NLR changes compared to AFP changes alone.Results: The NLR at 3– 6 weeks and ΔNLR after treatments significantly increased in patients who underwent progressive disease (PD), while the baseline NLR showed no significant difference between different tumor responses. Increased NLR and AFP after treatments were both independent predictors of PD (For NLR increase: OR, 2.28; 95% CI, 1.47– 3.88, P < 0.001; For AFP increase: OR, 1.46; 95% CI, 1.03– 2.17, P = 0.043), and correlated with worse PFS (for NLR increase: HR, 4.08; 95% CI, 1.99– 8.36, P < 0.001; for AFP increase: HR, 2.10; 95% CI, 1.04– 4.24, P = 0.039). The receiver operating characteristic (ROC) curve and net reclassification index (NRI) showed that the combination of dynamic NLR and AFP changes was better than AFP changes alone on predicting PD (AUC: 0.83 vs 0.68, P = 0.034; NRI: 0.340, P = 0.048) and PFS (AUC: 0.80 vs 0.70, P = 0.166; NRI: 0.431, P = 0.042).Conclusion: Dynamic changes of NLR might be an effective predictor of the therapeutic response to ICIs plus targeted therapies for uHCC.Keywords: hepatocellular carcinoma, neutrophil-to-lymphocyte ratio, immune checkpoint inhibitors, targeted therapies

Xiang Wen,1,&ast; Xiaohui Wu,1,&ast; Zhishan Deng,1,&ast; Fan Wu,1,2 Huajing Yang,1 Shan Xiao,1 Cuiqiong Dai,1 Changli Yang,3 Shuqing Yu,4 Ruiting Sun,1 Pixin Ran,1,2 Yumin Zhou1 1State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease & National Center for Respiratory Medicine & Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou National Laboratory, Guangzhou, Guangdong, People’s Republic of China; 3Wengyuan County People’s Hospital, Shaoguan, People’s Republic of China; 4Lianping County People’s Hospital, Heyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yumin Zhou; Pixin Ran, Email zhouyumin410@126.com; pxran@gzhmu.edu.cnBackground: The previous findings on the correlation between spirometry and high-density lipoprotein (HDL) cholesterol are intriguing yet conflicting. The aim of this research is to evaluate the relationship between HDL levels and spirometry as well as imaging parameters in patients with chronic obstructive pulmonary disease (COPD) in China.Methods: This study encompasses a total of 907 COPD patients. Participants with complete data from questionnaire interviews, lipid profile examinations, spirometry testing, and computed tomography (CT) scans were included in the analysis. A generalized additive model was employed to identify the non-linear relationship between HDL levels and both spirometry and imaging parameters. In the presence of non-linear correlations, segmented linear regression model was applied to ascertain threshold effects.Results: After adjusting for various factors, we found a non-linear correlation between HDL levels and spirometry/imaging parameters, with an inflection point at 4.2 (66 mg/dL). When Ln (HDL) was below 4.2, each unit increase correlated significantly with reduced post-bronchodilator FEV1 (0.32L, 95% CI: 0.09– 0.55), decreased predicted FEV1% (11.0%, 95% CI: 2.7– 19.3), and lowered FEV1/FVC (8.0%, 95% CI: 4.0– 12.0), along with notable increases in Ln (LAA− 950) by 1.20 (95% CI: 0.60– 1.79) and Ln (LAA− 856) by 0.77 (95% CI: 0.37– 1.17). However, no significant associations were observed when Ln (HDL) was greater than or equal to 4.2.Conclusion: A non-linear correlation existed between HDL levels with lung function and CT imaging in COPD patients. Prior to reaching 66 mg/dL, an elevation in HDL was significantly associated with impaired lung function, more severe gas trapping and emphysema.Keywords: COPD, high-density lipoprotein, lung function, computed tomography imaging

Abstract Objective To evaluate whether and how the radiological journals present their policies on the use of large language models (LLMs), and identify the journal characteristic variables that are associated with the presence. Methods In this meta-research study, we screened Journals from the Radiology, Nuclear Medicine and Medical Imaging Category, 2022 Journal Citation Reports, excluding journals in non-English languages and relevant documents unavailable. We assessed their LLM use policies: (1) whether the policy is present; (2) whether the policy for the authors, the reviewers, and the editors is present; and (3) whether the policy asks the author to report the usage of LLMs, the name of LLMs, the section that used LLMs, the role of LLMs, the verification of LLMs, and the potential influence of LLMs. The association between the presence of policies and journal characteristic variables was evaluated. Results The LLM use policies were presented in 43.9% (83/189) of journals, and those for the authors, the reviewers, and the editor were presented in 43.4% (82/189), 29.6% (56/189) and 25.9% (49/189) of journals, respectively. Many journals mentioned the aspects of the usage (43.4%, 82/189), the name (34.9%, 66/189), the verification (33.3%, 63/189), and the role (31.7%, 60/189) of LLMs, while the potential influence of LLMs (4.2%, 8/189), and the section that used LLMs (1.6%, 3/189) were seldomly touched. The publisher is related to the presence of LLM use policies (p

The metamaterial with artificial synthetic gauge field has been proved as an excellent platform to manipulate the transport of the electromagnetic wave. Here we propose an inhomogeneous spoof surface plasmonic metasurface to construct an in-plane pseudo-magnetic field, which is generated by engineering the gradient variation of the opened Dirac cone corresponding to spatially varying mass term. The chiral zeroth-order Landau level is induced by the strong pseudo-magnetic field. Based on the bulk state propagation of the chiral Landau level, the photonic Dirac waveguide is designed and demonstrated in the experimental measurement, in which the unidirectionally guided electromagnetic mode supports the high-capacity of energy transport. Without breaking the time-reversal symmetry, our proposal structure paves a new way for realizing the artificial in-plane magnetic field and photonic Dirac waveguide in metamaterial, and have potential for designing integrated photonic devices in practical applications.

ObjectiveTo explore the application value of endoscopic ultrasound fine-needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis and treatment ofpatients with pancreatic cancer combined with obstructive jaundice.MethodsClinical data of patients hospitalized in the Department of Gastroenterology of Peking Union Medical College Hospital who underwent ERCP biliary stent drainage for pancreatic cancer combined with obstructive jaundice from January 1, 2023 to February 26, 2024 were retrospectively collected. They were categorized into the fusion technology group and the simple ERCP group according to whether EUS-FNA was performed in the same endoscopic unit. The differences in pathologic diagnosis rate, ERCP drainage success rate, postoperative complication rate and patients' single hospitalization time were compared between the two groups.ResultsA total of 161 patients with pancreatic cancer combined with obstructive jaundice who underwent ERCP biliary stent drainage meeting the inclusion and exclusion criteria were enrolled, of which 80 were in the fusion technique group and 81 were in the simple ERCP group. The pathological diagnosis rate in the fusion technique group was higher than that in the simple ERCP group[92.50%(74/80) vs. 46.15%(12/26), P < 0.001], and the ERCP drainage success rate[82.50%(66/80) vs. 86.42%(70/81), P=0.360], the overall postoperative complication rate[5.00%(4/80) vs. 2.47%(2/81), P=0.443], and single hospitalization time[4 (4, 7)d vs. 5 (3, 9)d, P=0.397] were not statistically different from simple ERCP groups.ConclusionThe fusion of EUS-FNA and ERCP enhances the efficiency of diagnosis and treatment for pancreatic carcinoma, warranting widespread adoption and further research.

Yuru He,1,2 Xing Wang,1,2 Zuowei Wang,3,4 Ping Zhang,5 Xiaojia Huang,3,4 Meihong Yu,5 Jill K Murphy,6 Erin E Michalak,6 Jing Liu,6 Tao Yang,1,2 Xiaorui Yang,7 Yiru Fang,1,8,9 Raymond W Lam,6 Jun Chen1,2 1Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China; 3Division of Mood Disorders, Shanghai Hongkou Mental Health Center, Shanghai, People’s Republic of China; 4Clinical Research Center for Mental Health, School of Medicine, Shanghai University, Shanghai, People’s Republic of China; 5Fengxian District Mental Health Center, Shanghai, People’s Republic of China; 6Department of Psychiatry, University of British Columbia, Vancouver, Canada; 7Department of Psychology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 8Department of Psychiatry & Affective Disorders Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 9CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, People’s Republic of ChinaCorrespondence: Jun Chen, Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People’s Republic of China, Tel +86 21-34773367, Email doctorcj2010@gmail.com Raymond W Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada, Tel +1 604-822-7325, Email r.lam@ubc.caPurpose: To validate the efficacy of enhanced measurement-based care against standard measurement-based care in patients with major depressive disorder.Patients and Methods: In this pilot study of an ongoing multicenter cluster randomized controlled trails, 160 patients diagnosed with major depressive disorder were enrolled from 2 mental health centers, with a plan to include 12 centers in total. One hundred patients engaged in a six-month evaluation using a technology-enhanced measurement-based care tool, including assessments of clinical symptoms, side effects, and functionality at baseline, two months, four months and six months. Simultaneously, the remaining 60 patients underwent standard paper-based measurement-based care, utilizing the same set of scales over the same six-month period, with assessments at the same time points.Results: Patients utilizing the enhanced measurement-based care tool demonstrated a significantly higher reduction rate in PHQ-9 scores compared to those using standard paper-based measurement-based care during the two-month follow-up. Additionally, a notable positive correlation was observed between the frequency of enhanced measurement-based care tool usage and the quality of life during the two-month follow-up.Conclusion: Enhanced measurement-based care has the effect of reducing depressive symptoms. Our study emphasized that using enhanced measurement-based care via smartphones is a feasible tool for patients with major depressive disorder. Our future study, including results from additional research centers, may further validate the effectiveness of enhanced measurement-based care.Keywords: major depressive disorder, measurement-based care, enhanced measurement-based care, smartphone-based intervention

Objective·To investigate the effects of the cancer-testis antigen 14 (CT14) on embryonic and larval development in nematodes by using the model organism Caenorhabditis elegans (C. elegans), aiming to uncover its potential functions and mechanisms during development.Methods·Transgenic C. elegans strains were constructed by using microinjection for the inducible expression of human CT14 (HsCT14), a truncated mutant of CT14 (HsCT14∆CIR) lacking CT14-specific intermediate region (CIR), and a green fluorescent protein (GFP) control. The impacts of full-length and truncated mutant CT14 on nematode embryonic and larval development were analyzed and compared. Additionally, transgenic C. elegans strains with inducible expression of CT14 from various primates, including the crab-eating macaque (Macaca fascicularis) and mouse lemur (Microcebus murinus), were also constructed to assess the effects on egg hatching and larval-to-adult transformation rates. The differential gene expression in nematode embryos induced by CT14 was analyzed by Smart-seq transcriptome sequencing, with further insights gained through KEGG (Kyoto Encyclopedia of Genes and Genomes) and GSEA (Gene Set Enrichment Analysis), to explore the involved biological processes and pathways.Results·The induced expression of HsCT14 and its truncated mutant HsCT14∆CIR significantly reduced the hatching rate of nematode eggs, with a more pronounced effect observed in HsCT14-expressing strains. Differential interference contrast (DIC) microscopy imaging revealed significant morphological abnormalities in embryos expressing HsCT14 during the comma stage. Nematodes expressing HsCT14 or HsCT14∆CIR exhibited developmental arrest in larvae and substantially lower larval-to-adult transformation rates compared to the GFP control. The impact was more pronounced in nematodes expressing HsCT14 than those with HsCT14∆CIR. The expression of Macaca fascicularis CT14 (MfCT14) exhibited significant effects on the hatching rate and adult transformation rate, similar to that of HsCT14, while the expression of Microcebus murinus CT14 (MmCT14) displayed significantly reduced impact compared to HsCT14 and MfCT14. Smart-seq results indicated that CT14 expression affected various biological processes in nematode embryos, related to ATP-dependent chromatin remodeling and DNA replication.Conclusion·Ectopic expression of the cancer-testis antigen CT14 significantly disrupts both embryonic and larval developments in C. elegans, with the CIR sequence substantially enhancing this effect. It suggests that CT14 may play an important regulatory role in biological development by affecting gene expression in multiple pathways, including chromatin remodeling.

The importance of decellularized extracellular matrix (dECM) as a natural biomaterial in tissue engineering and regenerative medicine is rapidly growing. The core objective of the decellularization process is to eliminate cellular components while maximizing the preservation of the ECM’s primary structure and components. Establishing a rapid, effective, and minimally destructive decellularization technique is essential for obtaining high-quality dECM to construct regenerative organs. This study focused on human umbilical cord tissue, designing different reagent combinations for decellularization protocols while maintaining a consistent processing time. The impact of these protocols on the decellularization efficiency of human umbilical cord tissue was evaluated. The results suggested that the composite decellularization strategy utilizing trypsin/EDTA + Triton X-100 + sodium deoxycholate was the optimal approach in this study for preparing decellularized human umbilical cord dECM. After 5 h of decellularization treatment, most cellular components were eliminated, confirmed through dsDNA quantitative detection, hematoxylin and eosin (HE) staining, and DAPI staining. Meanwhile, Masson staining, periodic acid-silver methenamine (PASM) staining, periodic acid-Schiff (PAS) staining, and immunofluorescent tissue section staining results revealed that the decellularized scaffold retained extracellular matrix components, including collagen and glycosaminoglycans (GAGs). Compared to native umbilical cord tissue, electron microscopy results demonstrated that the microstructure of the extracellular matrix was well preserved after decellularization. Furthermore, Fourier-transform infrared spectroscopy (FTIR) findings indicated that the decellularization process successfully retained the main functional group structures of extracellular matrix (ECM) components. The quantitative analysis of collagen, elastin, and GAG content validated the advantages of this decellularization process in preserving and purifying ECM components. Additionally, it was confirmed that this decellularized matrix exhibited no cytotoxicity in vitro. This study achieved short-term decellularization preparation for umbilical cord tissue through a combined decellularization strategy.

Objective: To investigate whether acupoint penetration acupuncture (APA) could regulate chondrocyte autophagy and apoptosis via the PI3K/Akt-mTOR signaling pathway to reduce cartilage degeneration in knee osteoarthritis (KOA) rats. Methods: KOA was induced in rats via intra-articular injection of sodium iodoacetate resolution. Forty male Sprague-Dawley rats were randomly assigned to blank control, model, APA, electro-acupuncture (EA), and sham model groups (n = 8) and those in the APA and EA groups received their respective therapies. Following completion of the treatment course, histological examinations of cartilage and muscle were conducted. Levels of apoptosis- and autophagy-related factors, including Bax, Bcl-2, mTOR, ULK-1, and Beclin-1 protein, and mRNAs were assessed. Additionally, β-endorphin (β-EP) concentrations in the brain and serum were measured. Results: Histological analysis revealed that APA alleviated cartilage and muscle damage compared with the model group. APA inhibited cartilage degeneration by modulating the expression of apoptosis- and autophagy-related proteins and mRNA, thus preventing chondrocyte apoptosis. In the APA group, Bax and mTOR protein levels were significantly lower than those in the model group (both P = .024). Conversely, the Bcl-2 expression level was significantly higher than that in the EA group (P = .035). Additionally, ULK-1 expression was significantly lower than that in the EA group (P = .045). The mRNA level of Bax was significantly higher than that in the blank control group (P

Abstract Objective To construct a nomogram for predicting the responsiveness of cardiac resynchronization therapy (CRT) in patients with chronic heart failure and verify its predictive efficacy. Method A retrospective study was conducted including 109 patients with chronic heart failure who successfully received CRT from January 2018 to December 2022. According to patients after six months of the CRT preoperative improving acuity in the left ventricular ejection fraction is 5% or at least improve grade 1 NYHA heart function classification, divided into responsive group and non-responsive group. Clinical data of patients were collected, and LASSO regression analysis and multivariate logistic regression analysis were used to explore relative factors. A nomogram was constructed, and the predictive performance of the nomogram was evaluated using the calibration curve and decision curve analysis (DCA). Results Among the 109 patients, 61 were assigned to the CRT-responsive group, while 48 were assigned to the non-responsive group. LASSO regression analysis showed that left ventricular end-systolic volume, diffuse fibrosis, and left bundle branch block (LBBB) were independent factors for CRT responsiveness in patients with heart failure (P

Abstract Background and objective Developing harmonious doctor-patient relationships is a powerful way to promote the construction of a new pattern of medical reform in developing countries. We aim to analyze the effects of China’s hierarchical medical system on doctor-patient relationships, thus contributing to China’s medical and health system reform. Methods With panel data on prefectural-level cities in China from 2012 to 2019, we used a time-varying difference-in-differences model to evaluate the effect of hierarchical medical treatment policy. Results Hierarchical medical treatment policies can significantly improve doctor-patient relationships, and this conclusion is supported by various robustness tests. And improving doctor-patient relationships can be indirectly realized by the optimization of resource allocation and saving of medical costs. In addition, the marginal effect of the pilot policy on doctor-patient relationships decreased with age within the city population. In focal cities and cities with high levels of fiscal spending on health care, the effect of the pilot policy on doctor-patient relationships was stronger. Conclusion While reinforcing the literature on the doctor-patient relationship, this study also provides a reference for further exploration of the pilot policy of hierarchical medical treatment and the development of new medical and health system reform in developing countries.

Kaixin Wang,1 Lingfei Yang,2 Qingsheng Li,2 Xuan Yang,1 Ziyi Chen,2 Yongyan Zhou,3 Yanjie Jia,1 Zhe Gong1 1Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China; 3Department of Electrocardiogram, Zhoukou Center Hospital, Zhoukou, People’s Republic of ChinaCorrespondence: Yanjie Jia; Zhe Gong, The First Affiliated Hospital of Zhengzhou University, Department of Neurology, Postal FfCode 450052, No. 1 Jianshe East Road, Zhengzhou, People’s Republic of China, Email jiayanjie1971@aliyun.com; gongzhe1415@163.comBackground: Ischemic stroke (IS) is one of the leading causes of death and disability in the world, and alcohol consumption has been gaining attention as an independent risk factor for IS. Blood-brain barrier (BBB) dysfunction and neuroinflammation are the core of cerebral ischemia/reperfusion (I/R) injury, and pericytes play a crucial role in the structure and function. This study is to explore the effects of long-term alcohol consumption on IS and the potential mechanisms of pericytes.Methods: Rat models of long-term alcohol intake followed by transient middle cerebral artery occlusion stroke (EtOH+tMCAO) and cell models of oxygen-glucose deprivation/reoxygenation (OGD/R) with alcohol pre-treatment were constructed.Results: Worsened infarct volume, neurological scores, and BBB disruption were observed in the EtOH+tMCAO group compared with the tMCAO group, and immunofluorescence staining showed increased pericytes NLPR3 inflammasome activation at the ischemic penumbra. In vitro, pericyte mortality and LDH release elevated pre-treated by alcohol after OGD/R, and amplified expression of NLRP3 inflammasome was detected by Western blotting and qPCR. Alcohol pre-treatment activated the TLR4/NF-κB pathway, and transfecting pericytes with TLR4-small interfering RNA (siRNA) to block TLR4 signaling markedly restrained NLRP3 inflammasome over-activation. Injecting TAK-242 in rats alleviated neurological impairment caused by alcohol.Conclusion: Long-term alcohol pre-treatment aggravated ischemic stroke-induced brain damage by activating NLRP3 inflammasome via TLR4/NF-κB signaling pathway in the pericytes.Keywords: cerebral ischemia, chronic ethanol exposure, pericytes, TLR4, NLRP3 inflammasome

Li Ye,1 Xiwei Sun,2 Yiping Li,1 Yali Zeng,1 Lacuo Zhuoma,1 Dinglun Zhou,2 Qinying He,3 Ju Wang,4 Wei Yang,1 Hang Yu,1 Yihui Yang,1 Shu Liang,1 Dan Yuan1 1Center for AIDS/STD Control and Prevention, Sichuan Center for Disease Control and Prevention, Chengdu, Sichuan, People’s Republic of China; 2West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Center for AIDS/STD Control and Prevention, Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan, People’s Republic of China; 4Center for AIDS/STD Control and Prevention, Liangshan Center for Disease Control and Prevention, Xichang, Sichuan, People’s Republic of ChinaCorrespondence: Dan Yuan; Shu Liang, Email ydtv1130@163.com; liangshu523@163.comBackground: Sichuan Province was severely affected by the HIV, and there was a scarcity of data regarding the survival time and influencing factors for People Living with HIV/AIDS (PLWH) in Sichuan Province who have received Antiretroviral Therapy (ART). Therefore, it is necessary to conduct a survival analysis for PLWH receiving ART.Methods: A retrospective cohort study was conducted on PLWH who had received ART≥ 6 months in Sichuan Province from January 1, 2003, to December 31, 2022. The Kaplan-Meier method was used to calculate median survival time and plot survival curves, while a Cox proportional hazards regression model was applied to analyze factors affecting survival time. Bilateral tests were performed, with P≤ 0.05 considered statistically significant.Results: The cumulative survival rates at 1, 3, 5, and 10 years for the 223,386 subjects were 94.54%, 89.07%, 84.82%, and 76.44%, respectively. Multivariate analysis using the Cox regression model indicated lower mortality risks for females (HR=0.59, 95% CI: 0.54– 0.65), homosexual transmission (HR=0.43, 95% CI: 0.33– 0.55), and baseline BMI≥ 24 (HR=0.81, 95% CI: 0.72– 0.90). Higher mortality risks were associated with age≥ 50 years at diagnosis (HR=3.21, 95% CI: 2.94– 3.50), being unmarried or divorced (HR=1.23, 95% CI: 1.11– 1.37), living separately (HR=1.32, 95% CI: 1.22– 1.43), baseline BMI < 18.5 (HR=1.27, 95% CI: 1.13– 1.41), presence of single-drug resistance (HR=1.25, 95% CI: 1.15– 1.36), baseline WHO stage IV (HR=1.27, 95% CI: 1.09– 1.47), and a diagnosis-to-treatment interval > 12 months (HR=1.27, 95% CI: 1.15– 1.41). Compared to those with CD4(+) T cell count of 200– 350cells/μL, 350– 500cells/μL, and > 500cells/μL at baseline, individuals with < 200cells/μL had higher mortality risks (HR=0.73, 95% CI: 0.67– 0.79; HR=0.57, 95% CI: 0.51– 0.64; and HR=0.58, 95% CI: 0.51– 0.66, respectively).Conclusion: The survival rate for PLWH receiving ART in Sichuan Province was relatively high. Male gender, age over 50 at diagnosis, being unmarried, divorced, or living separately, presence of single-drug resistance, low baseline BMI, baseline CD4+ T cell < 200cells/μL, baseline WHO stage IV, and a diagnosis-to-treatment interval > 12 months were risk factors for the survival of PLWH.Keywords: PLWH, antiretroviral therapy, survival analysis

Under the background of the “carbon peaking and carbon neutrality goals”, the salt cavern is an important place for geological storage and carbon sequestration. The limited knowledge of the quantity and quality of the salt cavern and immature investigation technology constrains the development and utilization of salt cavern. After analyzing the geological exploration reports on major salt mines, reserves reports, enterprise annual reports, and research articles, a scientific understanding and basic judgment of the amount and utilizability of salt caverns in China are obtained; a technical system of salt cavern resource survey is established through a test with comprehensive detection technology in the concentrated area of salt cavern. The results show that salt cavern resources in China are characterized by abundant reserves, wide distribution, feasible burial depth, and convenient utilization on large scale. The most abundant salt cavern resources occur in the east and central regions. The national salt cavern resources are divided into levels I, II, and III by using an availability evaluation method system of salt cavern resource. Level I accounting for about 29.4%, is mainly distributed in Jiangsu, Hubei, Henan, and other provinces in east and central China. Salt cavern resources in level I are preferred for development and utilization. Level II accounting for about 65.4%, is widely distributed in southwest, northwest, and centra China, and can be used as a prospective area for development and utilization. Salt cavern resources in level III accounting for about 5.2%, are not suitable for development and utilization. Ground geophysical exploration, which can identify the characteristics of the regional geology, salt layer geology, hydrogeology, and salt cavity distribution of the salt mining area, guides the site selection on the salt cavern construction; geophysical exploration of high precision, which can obtain the information of salt mine levels and cavity structure, benefit the construction and operation detection of storage. This study provides the basic data and technical support for the planning and development of salt cavern resources in China.

Abstract Background During the prolonged COVID-19 pandemic, hospitals became focal points for normalised prevention and control. In this study, we investigated the feasibility of an inpatient bed reservation system for cancer patients that was developed in the department?s public WeChat account. We also explored its role in improving operational efficiency and nursing quality management, as well as in optimising nursing workforce deployment. Methods We utilised WeChat to facilitate communication between cancer patients and health care professionals. Furthermore, we collected data on admissions, discharges, average number of hospitalisation days, bed utilisation rate, and the number of bed days occupied by hospitalised patients through the hospital information system and nurses? working hours and competency levels through the nurse scheduling system. The average nursing hours per patient per day were calculated. Through the inpatient bed reservation system, the number of accepted admissions, denied admissions, and cancelled admissions from the reservation system were collected. The impact of the bed reservation system on the department?s operational efficiency was analysed by comparing the number of hospitalisation discharges before and after reservations, as well as the average hospitalisation and bed utilisation rates. By comparing nurses? working hours per month and average nursing hours per patient per day, the system?s impact on nurses? working hours and nursing quality indicators was analysed. Results The average hospitalisation length, bed utilisation rate, and nurses? working hours were significantly lower, and the average number of nursing hours per patient per day was significantly higher after the implementation of the reservation system. The full-cycle bed information management model for cancer patients did not affect the number of discharged patients. Conclusion Patients? ability to reserve bed types from home in advance using the department?s official WeChat-based inpatient bed reservation system allowed nurses to prepare for their work ahead of time. This in turn improved the operational efficiency of the department and nursing quality, and it optimised the deployment of the nursing workforce

Juying Zhang,1 Xia Luo,1 Xin Yang,1 Hanmei Li,1 Qiong Jiang,1 You Yang,1 Menglin Luo,1 Zijun Ma,1 Ping He,1 Linli Feng,1 Ling Li,1 Maochun Zhang,1 Yang Li,2,3 Jinhong Yu1,3 1Department of Ultrasound, Affiliated Hospital of North Sichuan Medical College, Innovation Centre for Science and Technology of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 2Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 3Department of Ultrasound, Yuechi People’s Hospital, Guangan, Sichuan, 638300, People’s Republic of ChinaCorrespondence: Jinhong Yu, Email yujinhong@nsmc.edu.cnPurpose: The incidence of hepatocellular carcinoma (HCC) is continuously increasing, and the mortality rate remains high. Thus, more effective strategies are needed to improve the treatment of HCC.Methods: In this study, we report the use of a visualized glypican-3 (GPC3)-targeting nanodelivery system (named GC-NBs) in combination with sonodynamic therapy (SDT) to enhance the therapeutic efficacy for treating HCC. The obtained nanodelivery system could actively target hepatocellular carcinoma cells and achieve ultrasound imaging through phase changes into nanobubbles under low-intensity ultrasound irradiation. Meanwhile, the released chlorine e6 (Ce6) after the nanobubbles collapse could lead to the generation of reactive oxygen species (ROS) under ultrasound irradiation to induce SDT.Results: Both in vitro and in vivo experiments have shown that GC-NBs can accumulate in tumour areas and achieve sonodynamic antitumour therapy under the navigation action of glypican-3-antibody (GPC3-Ab). Furthermore, in vitro and in vivo experiments did not show significant biological toxicity of the nanodelivery system. Moreover, GC-NBs can be imaged with ultrasound, providing personalized treatment monitoring.Conclusion: GC-NBs enable a visualized antitumour strategy from a targeted sonodynamic perspective by combining tumour-specific targeting and stimuli-responsive controlled release into a single system. Keywords: Glypican-3, nanodelivery system, ultrasound imaging, sonodynamic therapy, hepatocellular carcinoma

Qiu Chen,1 Ji-Lei Zhang,1 Jie-Shun Yang,2 Qing Jin,1 Jun Yang,3 Qiang Xue,1 Xue-feng Guang1 1Department of Cardiology, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Key Laboratory of Cardiovascular Disease of Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Qiang Xue; Xue-feng Guang, Department of Cardiology, Yan’ an Hospital Affiliated to Kunming Medical University, No. 245 Renmin Dong Road, Kunming, Yunnan Province, 650051, People’s Republic of China, Email xueqiang3513@126.com; gxfyayy@163.comPurpose: Necroptosis, a monitored form of inflammatory cell death, contributes to coronary heart disease (CHD) progression. This study examined the potential of using necroptosis genes as diagnostic markers for CHD and sought to elucidate the underlying roles.Methods: Through bioinformatic analysis of GSE20680 and GSE20681, we first identified the differentially expressed genes (DEGs) related to necroptosis in CHD. Hub genes were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest analysis after studying immune infiltration and transcription factor-miRNA interaction networks according to the DEGs. Quantitative polymerase chain reaction and immunohistochemistry were used to further investigate hub gene expression in vivo, for which a diagnostic model was constructed and the predictive efficacy was validated. Finally, the CHD group was categorized into high- and low-score groups in accordance with the single-sample gene set enrichment analysis (ssGSEA) score of the necroptosis genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GSEA, and further immune infiltration analyses were performed on the two groups to explore the possible roles of hub genes.Results: Based on the results of the LASSO regression and random forest analyses, four genes were used to construct a diagnostic model to establish a nomogram. Additionally, an extensive analysis of all seventeen necroptosis genes revealed notable distinctions in expression between high-risk and low-risk groups. Evaluation of immune infiltration revealed that neutrophils, monocytes, B cells, and activated dendritic cells were highly distributed in the peripheral blood of patients with CHD. Specifically, the high CHD score group exhibited greater neutrophil and monocyte infiltration. Conversely, the high-score group showed lower infiltration of M0 and M2 macrophages, CD8+ T, plasma, and resting mast cells.Conclusion: TLR3, MLKL, HMGB1, and NDRG2 may be prospective biomarkers for CHD diagnosis. These findings offer plausible explanations for the role of necroptosis in CHD progression through immune infiltration and inflammatory response.Keywords: atherosclerosis, cell death, inflammations, diagnostic biomarkers, necroptosis, immune infiltration

Dongrui Xu,1,&ast; Xiaoyi Yang,1,&ast; Wenjuan Wu,2 Jiankang Yang1 1School of Basic Medical Sciences, Dali University, Dali, Yunnan, People’s Republic of China; 2Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiankang Yang, School of Basic Medical Sciences, Dali University, Dali, Yunnan, People’s Republic of China, Email jkyang1984@126.com Wenjuan Wu, Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China, Email wuwj1021@126.comBackground: Despite the availability of numerous therapies, the treatment of acne vulgaris remains challenging. Novel drug targets for acne vulgaris are still needed.Methods: We conducted a Mendelian randomization analysis to explore possible drug targets for acne vulgaris. We utilized summary statistics obtained from the dataset of acne vulgaris, including 399,413 individuals of European ancestry. We gathered genetic instruments for 566 plasma proteins from genome-wide association studies. In order to strengthen the findings from Mendelian randomization, various methods were employed, including bidirectional Mendelian randomization analysis, Bayesian co-localization, phenotype scanning, and single-cell analysis. These methods facilitated the identification of reverse causality, the search for reported variant-trait associations, and the determination of the cell types that is the primary source of protein. Furthermore, using the plasma proteins in the deCODE cohort, we conducted a replication of the Mendelian randomization analysis as an external validation.Results: At the significance level of Bonferroni (P < 8.83× 10− 5), a protein-acne pair was discovered through Mendelian randomization analysis. In plasma, increasing TIMP4 (OR = 1.15; 95% CI, 1.09– 1.21; P = 1.01× 10− 7) increased the risk of acne vulgaris. The absence of reverse causality was observed in the TIMP4 protein. According to Bayesian co-localization analysis, TIMP4 shared the same variant with acne vulgaris (PPH4 = 0.93). TIMP4 was replicated in deCODE cohort (OR = 1.17; 95% CI, 1.10– 1.24; P = 1.48× 10− 7). Single-cell analysis revealed that TIMP4 was predominantly detected in myeloid cells in blood, and was detected in almost all cell types in skin tissue.Conclusion: The integrative analysis revealed that the level of plasma TIMP4 has a direct influence on the risk of developing acne vulgaris. This implies that TIMP4 protein could serve as a potential target for the development of drugs aimed at treating acne vulgaris.Keywords: plasma proteome, acne vulgaris, drug target, biomarker, Mendelian randomization, TIMP4

Abstract Patients with multiple myeloma (MM) experience relapse and drug resistance; therefore, novel treatments are essential. Clotrimazole (CTZ) is a wide-spectrum antifungal drug with antitumor activity. However, CTZ’s effects on MM are unclear. We investigated CTZ’s effect on MM cell proliferation and apoptosis induction mechanisms. CTZ’s effects on MM.1S, NCI- H929, KMS-11, and U266 cell growth were investigated using Cell Counting Kit-8 (CCK-8) assay. The apoptotic cell percentage was quantified with annexin V-fluorescein isothiocyanate/7-amino actinomycin D staining. Mitochondrial membrane potential (MMP) and cell cycle progression were evaluated. Reactive oxygen species (ROS) levels were measured via fluorescence microscopy. Expression of apoptosis-related and nuclear factor (NF)-κB signaling proteins was analyzed using western blotting. The CCK-8 assay indicated that CTZ inhibited cell proliferation based on both dose and exposure time. Flow cytometry revealed that CTZ decreased apoptosis and MMP and induced G0/G1 arrest. Immunofluorescence demonstrated that CTZ dose-dependently elevated in both total and mitochondrial ROS production. Western blotting showed that CTZ enhanced Bax and cleaved poly ADP-ribose polymerase and caspase-3 while decreasing Bcl-2, p-p65, and p-IκBα. Therefore, CTZ inhibits MM cell proliferation by promoting ROS-mediated mitochondrial apoptosis, inducing G0/G1 arrest, inhibiting the NF-κB pathway, and has the potential for treating MM.

Abstract Background Foot-and-mouth disease (FMD) is a devastating disease affecting cloven-hoofed animals, that leads to significant economic losses in affected countries and regions. Currently, there is an evident inclination towards the utilization of nanoparticles as powerful platforms for innovative vaccine development. Therefore, this study developed a ferritin-based nanoparticle (FNP) vaccine that displays a neutralizing epitope of foot-and-mouth disease virus (FMDV) VP1 (aa 140–158) on the surface of FNP, and evaluated the immunogenicity and protective efficacy of these FNPs in mouse and guinea pig models to provide a strategy for developing potential FMD vaccines. Results This study expressed the recombinant proteins Hpf, HPF-NE and HPF-T34E via an E. coli expression system. The results showed that the recombinant proteins Hpf, Hpf-NE and Hpf-T34E could be effectively assembled into nanoparticles. Subsequently, we evaluated the immunogenicity of the Hpf, Hpf-NE and Hpf-T34E proteins in mice, as well as the immunogenicity and protectiveness of the Hpf-T34E protein in guinea pigs. The results of the mouse experiment showed that the immune efficacy in the Hpf-T34E group was greater than the Hpf-NE group. The results from guinea pigs immunized with Hpf-T34E showed that the immune efficacy was largely consistent with the immunogenicity of the FMD inactivated vaccine (IV) and could confer partial protection against FMDV challenge in guinea pigs. Conclusions The Hpf-T34E nanoparticles stand out as a superior choice for a subunit vaccine candidate against FMD, offering effective protection in FMDV-infected model animals. FNP-based vaccines exhibit excellent safety and immunogenicity, thus representing a promising strategy for the continued development of highly efficient and safe FMD vaccines.

Yuan Gao,1– 3,&ast; Ce Zong,1,&ast; Ying Yao,4 Haixu Zhao,5 Yuan Song,4 Ke Zhang,1 Hongxun Yang,1 Hongbing Liu,1 Yunchao Wang,1 Yusheng Li,1– 3 Jing Yang,1– 3 Bo Song,1– 3 Yuming Xu1– 3 1Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, People’s Republic of China; 3Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou, Henan, People’s Republic of China; 4School of Health and Nursing, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 5School of Public Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuming Xu, Department of Neurology, the First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Erqi District, Zhengzhou, Henan Province, People’s Republic of China, 450052, Tel/Fax +86 13903711125, Email xuyuming@zzu.edu.cnPurpose: We aimed to explore the association between fibrinogen-to-albumin ratio (FAR) and the risk of incident stroke (IS) in a cohort of cerebral small vessel disease (CSVD) patients.Patients and Methods: Participants were screened from a prospective CSVD database. Clinical data, hematologic measures and imaging findings were collected. The primary outcome was IS during follow-up, with a secondary outcome of composite vascular events (CVE) including IS, myocardial infarction (MI), and vascular deaths. Univariate and multivariate COX proportional risk models, along with competing risk models, were employed to identify factors associated with outcomes. Restricted cubic spline (RCS) and subgroup analyses were conducted to assess the association between FAR and the risk of IS and CVE in CSVD patients.Results: In the final analysis of 682 CSVD patients over a median observation period of 34.0 [24.0– 53.0] months, there were 33 cases of IS (4.84%, 1.55/100 person-years), 4 incidents of MI (0.59%, 0.19/100 person-years), 15 non-vascular deaths (2.20%, 0.70/100 person-years), and 37 occurrences of CVE (5.43%, 1.74/100 person-years). Multivariate Cox regression analysis revealed a significant positive correlation between elevated FAR and both IS (HR 1.146; 95% CI 1.043– 1.259; P=0.004) and CVE (HR 1.156; 95% CI 1.063– 1.257; P=0.001) in CSVD patients. Multivariate competing risk model showed the similar results (IS: HR 1.16; 95% CI 1.06– 1.27; P=0.001, CVE: HR 1.15; 95% CI 1.05– 1.26; P=0.003). RCS analysis indicated a linear relationship between FAR and the risks of both IS (P for non-linearity =0.7016) and CVE (P for non-linearity =0.6475), with an optimal cutoff value of 8.69, particularly in individuals over 60 years of age.Conclusion: Elevated FAR demonstrated an independent and linear association with IS and the development of CVE in CSVD patients.Keywords: cerebral small vessel disease, incident stroke, fibrinogen-to-albumin ratio, inflammation

Yuncheng Ni,1,&ast; Ranglang Huang,2,&ast; Shuang Yang,3 Xiao Yan Yang,3 Shan Zeng,3 An Yao,3 Jie Huang,3 Guoping Yang3,4 1Department of Pain, The Third Xiangya Hospital and Institute of Pain Medicine, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 2Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 3Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 4Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Huang; Guoping Yang, Email cellahuang1988@163.com; ygp9880@126.comBackground: Oliceridine is a novel G protein‐biased ligand μ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain.Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs).Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85– 2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed.Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg.Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).Keywords: pharmacokinetics, oliceridine, chronic pain, G-protein-biased ligand, phase I trial