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Jingxia Mao,1,2,&ast; Guibo Yang,1,3,&ast; Qin Su,1,4,&ast; Zhonghong Zeng,1 Jueying Lin,2 Lin Kong,3 Lidun Zhang,4 Lidan Liu,1 Yihua Yang,1 Hongbo Wu1 1Guangxi Reproductive Medical Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Obstetrics, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Obstetrics, The Maternity and Child Health Care of Guangxi Zhuang Autonomous Region, Nanning, People’s Republic of China; 4Department of Obstetrics, The First People’s Hospital of Yulin, Yulin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongbo Wu; Yihua Yang, Guangxi Reproductive Medical Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China, Email 19587200@qq.com; workyyh@163.comObjective: To assess the safety and efficiency of in vitro fertilization/ intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) on maternal and neonatal perinatal outcomes in women (≥ 40y) with singleton pregnancies.Methods: This multi-center retrospective cohort study, carried out from January 2018 to June 2023, enrolled 1762 women (≥ 40y) with singleton pregnancies of at least 28 weeks. Participants were divided into two groups: the IVF/ICSI-ET group (204 cases) and the spontaneous conception (SC) group (1558 cases). After 1:2 propensity score matching (PSM), the two groups were compared for maternal and neonatal outcomes. The SC group (1558 cases) was further divided by age into the < 43 years group (1195 cases) and the ≥ 43 years group (363 cases) for subgroup analysis.Results: Adverse maternal and neonatal outcomes were comparable between the IVF/ICSI-ET group and the SC group, with a higher cesarean section rate (78% vs 67.5%, P =0.013), an increased maternal ICU admissions rate (5.5% vs 1.3%, P =0.008), and a lower birth defects rate (1.1% vs 4.6%, P =0.037) in the IVF/ICSI-ET group. Subgroup analysis showed that women aged ≥ 43 years had higher incidences of gestational diabetes, gestational hypertension, cesarean section, and neonatal asphyxia compared to women aged < 43 years.Conclusion: This study indicated IVF/ICSI-ET is relatively safe for women ≥ 40 years with singleton pregnancies. However, advanced maternal age deteriorated maternal and neonatal outcomes, and IVF/ICSI-ET further heightened the risk of cesarean section and maternal ICU admissions. Therefore, enhanced care and vigilance are crucial for women over 40 undergoing IVF/ICSI-ET.Keywords: in-vitro fertilization, intracytoplasmic sperm injection, advanced maternal age, maternal outcomes, neonatal outcomes

Zixiang Geng,1,2,&ast; Tiancheng Sun,1,2,&ast; Jie Yu,1,2,&ast; Ning Wang,1,2 Qiang Jiang,1,2 Peige Wang,1,2 Guangyue Yang,1,2 Yifei Li,3 Yue Ding,4 Jiange Zhang,5 Guoqiang Lin,5 Yongfang Zhao1,2 1Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5The Research Center of Chiral Drugs, Innovation Research Institute of Traditional, Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zixiang Geng, Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email gengzx@foxmail.com Yongfang Zhao, Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email zhaoyongfang@shutcm.edu.cnBackground: Cinobufagin, the primary active compound in toad venom, is commonly used for anti-tumor, anti-inflammatory, and analgesic purposes. However, its specific bone-protective effects remain uncertain. This research aims to ascertain the bone-protective properties of cinobufagin and investigate underlying mechanisms.Methods: Mice were ovariectomized to establish an osteoporosis model, followed by intraperitoneal injections of cinobufagin and cinobufagin-treated RAW.264.7-derived exosomes for therapy. MicroCT, HE staining, and TRAP staining were employed to evaluate bone mass and therapeutic outcomes, while mRNA sequencing and immunoblotting were utilized to assess markers of bone metabolism, inflammation, and lipid peroxidation. Osteoblast and osteoclast precursor cells were differentiated to observe the impact of cinobufagin-treated exosomes derived from RAW264.7 cells on bone metabolism. Exosomes characteristics were studied using transmission electron microscopy and particle size analysis, and miRNA binding targets in exosomes were determined by luciferase reporting.Results: In ovariectomized mice, cinobufagin and cinobufagin-treated exosomes from RAW264.7 cells increased trabecular bone density and mass in the femur, while also decreasing inflammation and lipid peroxidation. The effect was reversed by an exosomes inhibitor. In vitro experiments revealed that cinobufagin-treated exosomes from RAW264.7 cells enhanced osteogenic and suppressed osteoclast differentiation, possibly linked to Upregulated miR-3102-5p in RAW-derived exosomes. MiR-3102-5p targets the 3′UTR region of alox15, thereby suppressing its expression and reducing the lipid peroxidation process in osteoblasts.Conclusion: Overall, this study clarified cinobufagin’s bone-protective effects and revealed that cinobufagin can enhance the delivery of miR-3102-5p targeting alox15 through macrophage-derived exosomes, demonstrating anti-lipid peroxidation and anti-inflammatory effects. Keywords: osteoporosis, cinobufagin, exosomes, miR-3102-5p

Huaqiong Wu,1,&ast; Guifen Yang,2,&ast; Shaohua Zhang,2 Jinxiang Luo,1 Pei Zhou,1 Yuhua Chen1 1Department of Radiodiagnosis, Central War Zone General Hospital of Wuhan, Wuhan, Hubei, People’s Republic of China; 2Department of Internal Medicine-Cardiovascular, Central War Zone General Hospital of Wuhan, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaohua Zhang, Department of Internal Medicine-Cardiovascular, Central War Zone General Hospital of Wuhan, No. 627, Wuluo Road, Wuchang District, Wuhan, Hubei, 430070, People’s Republic of China, Tel +8618062579072, Email zhangshaohua1258@163.com Jinxiang Luo, Department of Radiodiagnosis, Central War Zone General Hospital of Wuhan, No. 627, Wuluo Road, Wuchang District, Wuhan, Hubei, 430070, People’s Republic of China, Tel +8602750773333, Email luojinxiang2020@21cn.comObjective: To investigate the correlation between risk factors for coronary stenosis and the degree of coronary artery stenosis based on coronary computed tomography angiography (CCTA).Methods: Two hundred seventy-eight patients with coronary artery disease who received treatment in our hospital between January 2020 and January 2021 were selected as the experimental group, and 100 healthy people who received physical examination in our hospital during the same period were selected as the control group (age and gender matched with the study group). The clinical data and CCTA data of the two groups of patients were collected and compared. Computed tomography fractional flow reserve (FFRCT) values were calculated based on the CCTA data of the patients in the study group, risk factors for coronary artery stenosis were analysed and the correlation between the risk factors and CT flow reserve fraction was explored.Results: The serum total bilirubin (BIL), apolipoprotein A (apoA), low-density lipoprotein cholesterol (LDL-C), uric acid, total cholesterol (TC) and mean platelet volume levels were higher in the experimental group than in the control group (P < 0.05). Unconditional logistic regression analysis showed that LDL-C, uric acid, TC, triglyceride, serum total BIL and apoA were independent risk factors for coronary heart disease (P < 0.05). Serum total BIL (r = 0.27), apoA (r = − 0.30), uric acid (r = − 0.48), TC (r = − 0.35), triglyceride (r = − 0.73) and LDL-C (r = − 0.65) showed a negative correlation with FFRCT values (P < 0.05). A positive correlation was detected between high-density lipoprotein cholesterol and FFRCT values (r = 0.37, P < 0.05).Conclusion: Triglycerides, LDL-C, uric acid, TC, serum total BIL and apoA are risk factors for coronary artery stenosis that should be closely monitored and receive active intervention in clinical practice.Keywords: coronary heart disease, coronary artery stenosis, computed tomography angiography, risk factors, computed tomography fractional flow reserve

Ya Gao,1 Shuyue Li,1 Jian Zhang,1 Yidan Zhang,1 Yuan Zhao,1 Shuming Zhang,2 Lujie Zuo,3 Guofeng Yang1 1Department of Geriatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Internal Medicine, Fuping County Hospital, Baoding, Hebei, 073200, People’s Republic of China; 3Department of Otolaryngology, Head and Neck Surgery, Children’s Hospital of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Guofeng Yang, Department of Geriatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email yanggf@hebmu.edu.cnBackground: Parkinson’s disease (PD) is a neurodegenerative movement disorder that impacts various systems, including the substantia nigra (SN) par compacta (SNpc) and extranigral regions like the spinal cord. The presence of persistent inflammation in the SN and spinal cord is associated with movement difficulties in PD. Atractylenolide-I (ATR-I) is a natural sesquiterpene recognized for its anti-inflammatory and neuroprotective effects. This research aimed to assess the impact of ATR-I treatment on motor function and inflammation in MPTP-induced subacute PD mice, particularly focusing on the role of ATR-I in spinal cord inflammation.Methods: The motor functions of the mice were assessed using suspension and gait tests. Dopaminergic neuronal loss in the SNpc and microglial activation in both the SNpc and spinal cord were evaluated through immunofluorescence staining. The levels of inflammatory mediators in the spinal cord were measured using RT-qPCR analysis. The expressions of SIRT1 and PGC-1α in the spinal cord were analyzed through Western blotting and RT-qPCR.Results: ATR-I treatment improved motor deficits in MPTP-induced mice. Moreover, ATR-I reduced the loss of dopamine neurons and microglial activation in the SNpc of MPTP-induced mice. Additionally, ATR-I suppressed spinal cord inflammation by decreasing microglial activation and the mRNA expression of TNF-α, IL-1β, and iNOS in MPTP-induced mice. Interestingly, ATR-I also upregulated SIRT1 and PGC-1α levels in the spinal cord of MPTP-induced mice.Conclusion: These findings suggest that ATR-I exhibits anti-inflammatory and neuroprotective properties in PD. The attenuation of spinal cord inflammation via the SIRT1/PGC-1α pathway may contribute to enhancing motor function, highlighting ATR-I as a potential therapeutic avenue for PD.Keywords: Parkinson’s disease, atractylenolide-I, spinal cord, inflammation, SIRT1, PGC‑1&#x03B1

Guangming Yang,1,&ast; Jian Zhang,2,&ast; Qian Liu,2 Erqing Chai2 1The First Clinical School of Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu Province, 730000, People’s Republic of China; 2Gansu Provincial Hospital, Lanzhou, Gansu Province, 730000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Erqing Chai, Email 18809407241@163.comAbstract: Inflammation of the frontal sinus is a relatively common clinical condition among paranasal sinusitis and is curable through anti-infection treatments, with a rare progression to frontal sinus abscess. An even rarer complication is the development of intracranial epidural empyema secondary to frontal sinus abscess. In this report, we describe a case of a 14-year-old male with a frontal sinus abscess that led to intracranial infection and was complicated by an epidural abscess misdiagnosed as an epidural hematoma. The primary symptoms were headache, dizziness, and fever. Following combined antibiotic therapy and surgical intervention, including maxillary and frontal sinus window drainage, the patient was cured. A follow-up period of three months showed no recurrence, indicating a favorable outcome.Keywords: sinusitis, frontal sinus abscess, intracranial infection, epidural abscess

Ye Ming,1– 3,&ast; Xinyi He,1– 3,&ast; Zhenxing Zhao,1– 3,&ast; Xuehuan Meng,1– 3 Ye Zhu,1– 3 Hao Tan,1– 3 Guoyin Yang,1– 3 Yun Hu,1– 3 Leilei Zheng1– 3 1College of Stomatology, Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Hu; Leilei Zheng, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China, Tel/Fax +86 23 88860151 ; +86 23 88860161, Email 500188@hospital.cqmu.edu.cn; zhengleileicqmu@hospital.cqmu.edu.cnPurpose: Oxidative stress and mitochondrial dysfunction are potential contributors to the compromised tissue regeneration capacity of alveolar bone in diabetic patients. Berberine, an active plant alkaloid, exhibits multiple pharmacological effects including antioxidation, blood glucose- and blood lipid-lowering properties. However, it remains uncertain whether berberine can improve impaired osteogenesis in type 2 diabetes mellitus (T2DM), and its poor solubility and oral bioavailability also constrain its applications in bone regeneration. Thus, our study aimed to probe the effects of berberine on bone marrow stem cells (BMSCs) in a diabetic microenvironment, with a greater emphasis on developing a suitable nano-delivery system for berberine and assessing its capability to repair diabetic alveolar bone defects.Methods: Firstly, BMSCs were exposed to berberine within a high glucose and palmitate (HG+PA) environment. Reactive oxygen species levels, mitochondrial membrane potential, ATP generation, cell apoptosis, and osteogenic potential were subsequently assessed. Next, we explored the regulatory mechanism of autophagy flux in the positive effects of berberine. Furthermore, a nanocarrier based on emulsion electrospinning for sustained local delivery of berberine (Ber@SF/PCL) was established. We assessed its capacity to enhance bone healing in the alveolar bone defect of T2DM rats through micro-computed tomography and histology analysis.Results: Berberine treatment could inhibit reactive oxygen species overproduction, mitochondrial dysfunction, apoptosis, and improve osteogenesis differentiation by restoring autophagy flux under HG+PA conditions. Notably, Ber@SF/PCL electrospun nanofibrous membrane with excellent physicochemical properties and good biological safety had the potential to promote alveolar bone remodeling in T2DM rats.Conclusion: Our study shed new lights into the protective role of berberine on BMSCs under T2DM microenvironment. Furthermore, berberine-loaded composite electrospun membrane may serve as a promising approach for regenerating alveolar bone in diabetic patients.Keywords: berberine, electrospun nanofibrous membrane, diabetes mellitus, alveolar bone remodeling, autophagy flux

Minghui Wang,1,&ast; Zhiwei Lai,1,&ast; Hua Zhang,1,&ast; Weiqi Yang,2 Fengping Zheng,1 Dehua He,2 Xiaofang Liu,2 Rong Zhong,2 Mulan Qahar,1,2 Guang Yang1– 3 1Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518036, People’s Republic of China; 2Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China; 3Department of Life Sciences, Yuncheng University, Yuncheng, 044011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guang Yang; Mulan Qahar, Email yakoaka@foxmail.com; mulanqahar@126.comBackground: Diabetes mellitus (DM) is known to inhibit skin self-renewal and hair follicle stem cell (HFSC) activation, which may be key in the formation of chronic diabetic wounds. This study aimed to investigate the reasons behind the suppression of HFSC activation in DM mice.Methods: Type 1 DM (T1DM) was induced in 6-week-old mice via streptozotocin, and hair follicle growth was subsequently monitored. RNA sequencing, bioinformatics analyses, qRT‒PCR, immunostaining, and cellular experiments were carried out to investigate the underlying mechanisms involved.Results: T1DM inhibited HFSC activation, which correlated with an increase in caspase-dependent programmed cell death. Additionally, T1DM triggered apoptosis and pyroptosis, predominantly in HFSCs and epidermal regions, with pyroptosis being more pronounced in the inner root sheath of hair follicles. Notably, significant cutaneous immune imbalances were observed, particularly in macrophages. Cellular experiments demonstrated that M1 macrophages inhibited HaCaT cell proliferation and induced cell death, whereas high-glucose environments alone did not have the same effect.Conclusion: T1DM inhibits HFSC activation via macrophage reprogramming-mediated caspase-dependent pyroptosis, and there is a significant regional characterization of cell death. Moreover, T1DM-induced programmed cell death in the skin may be more closely related to immune homeostasis imbalance than to hyperglycemia itself. These findings shed light on the pathogenesis of diabetic ulcers and provide a theoretical basis for the use of hair follicle grafts in wound repair.Keywords: diabetes mellitus, caspases, hair follicle stem cells, chronic wounds, cutaneous immune disorder

Ruien Chen,1,&ast; Huamei Zou,1,&ast; Xiuwen Ye,1,&ast; Bailing Xie,2 Aizhi Zhang,3 Lihua Mo,4 Yu Liu,4 Huanping Zhang,5 Gui Yang,1 Pingchang Yang2 1Department of Otolaryngology, Longgang Central Hospital affiliated to Guangzhou University of Chinese Traditional Medicine Shenzhen Clinical College, Shenzhen, 518116, People’s Republic of China; 2State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, 518055, People’s Republic of China; 3Department of Critical Care Medicine, Second Hospital, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 4Department of General Medicine Practice, Third Affiliated Hospital, Shenzhen University, Shenzhen, 518005, People’s Republic of China; 5Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pingchang Yang; Gui Yang, Email pcy2356@163.com; guiyang1981@hotmail.comIntroduction: The therapeutic efficacy for airway allergies needs to be improved. Th2 polarization is a primary pathological feature of airway allergies. We constructed chimeric antigen-LgDNA (Lactobacillus rhamnosus DNA) nanoparticles (CAP-NPs). The effects of CAP-NPs on reconciling airway Th2 polarization were tested.Methods: In this study, disulfide bond-linked antigen-major histocompatibility complex II (MHC II)-LgDNA nanoparticles (NPs) were constructed and designated CAP-NPs. An airway Th2 polarization mouse model was established to test the effects of CAP-NPs on suppressing the Th2 response.Results: The CAP-NP components of ovalbumin (OVA), major histocompatibility complex II (MHC II), and LgDNA were confirmed in a series of laboratory tests. The CAP-NPs remained stable at pH7.2 for at least 96 h. In in vitro experiments, CAP-NPs bound to the surface of OVA-specific CD4+ T cells, which resulted in apoptosis of the antigen-specific CD4+ T cells. Removal of any of the three components from the NPs abolished the induction of apoptosis of antigen specific CD4+ T cells. CAP-NPs increased the expression of lysine-specific demethylase 5A (KDM5A) in CD4+ T cells. Histone H3K9 and the gene promoter of caspase 8 were demethylated by KDM5A, which led to transcription and expression of the caspase 8 gene. Administration of CAP-NPs significantly alleviated experimental airway Th2 polarization through activating the caspase 8-apoptosis signaling pathway.Discussion: In this paper, we constructed CAP-NPs that could induce antigen-specific CD4+ T cell apoptosis. Administration of CAP-NPs efficiently alleviated experimental airway Th2 polarization.Keywords: airway allergy, T cell, therapy, vaccine, nanoparticle

Shirong Wen,1 Guang Yang,2 Sijia Xu,3 Mingsha Zhang,4 Yan Liu,5 Yujun Pan1 1Department of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China; 3Department of Neurology, The First Hospital of Harbin, Harbin, Heilongjiang, People’s Republic of China; 4State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, People’s Republic of China; 5Department of Health Statistic, School of Public Health of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of ChinaCorrespondence: Yujun Pan; Yan Liu, Email yujunpan@ems.hrbmu.edu.cn; liuyan@ems.hrbmu.edu.cnPurpose: To characterize Subjective Cognitive Decline (SCD) in Parkinson’s disease (PD) and its progression, as well as to assess the impact of rehabilitation training programs on cognitive function in PD patients.Patients and Methods: The study involved 42 patients diagnosed with PD. Participants underwent evaluation using a neuropsychological protocol and were subsequently classified into two groups: those with SCD (PD-SCD+, n= 22) or those without (PD-SCD−, n= 20). After an average follow-up period of 3.0 years (2.7– 4.6 years), cognitive assessments were reiterated with the same group of subjects. Following the re-assessment, all 42 patients participated in a six-month rehabilitation training program, concluding with the reevaluation of cognitive performance.Results: In the follow-up assessment, it was observed that PD-SCD+ experienced a more pronounced annual decline in cognitive function, as measured by the Chinese-Beijing version of Montreal Cognitive Assessment (BJ-MoCA) test and semantic fluency, compared to PD-SCD−. A stepwise logistic regression analysis identified low MMSE scores (P< 0.001), elevated HAMD scores (P= 0.008), male gender (P= 0.026), and the presence of SCD (P= 0.022) associated with diminished language skills in PD patients. Both groups of PD patients exhibited improvements in BJ-MoCA scores after participating a six-month rehabilitation training program. Particularly notable is the statistically significant improvement in language skills observed in patients with PD-SCD+ compared to PD-SCD− patients following rehabilitation training.Conclusion: As PD progresses, individuals with PD-SCD+ tend to experience more pronounced cognitive decline compared to those with PD-SCD−. Semantic fluency emerges as a crucial component for assessing the cognitive subset of PD, potentially serving as an indicator of cognitive decline in individuals with PD. Evidence suggests that rehabilitation training is a viable intervention for individuals diagnosed with PD. This intervention not only improves various cognitive domains but also leads to more substantial enhancements in language skills.Keywords: Parkinson’s disease, subjective cognitive decline, SCD, semantic fluency, rehabilitation training

Salma Firdaus,1,&ast; Lívia Figueiredo Pereira,2,&ast; Ge Yang,3 Yumin Huang-Link4 1Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; 2Pontifical Catholic University of Minas Gerais, Belo Horizonte, Brazil; 3Huizhou Aier Eye Hospital, Aier Eye Hospital Group, Huizhou, Guangdong Province, People’s Republic of China; 4Division of Neurology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden&ast;These authors contributed equally to this workCorrespondence: Ge Yang, Huizhou Aier Eye Hospital, Aier Eye Hospital Group, Huizhou, Guangdong Province, People’s Republic of China, Email geyang95@sina.comPurpose: To compare the interocular symmetry and investigate the intermachine reproducibility of optic disc and macular data measured by spectral-domain high-definition optical coherence tomography (HD-OCT) Cirrus HD-OCT 4000 and HD-OCT 5000 from healthy subjects.Patients and Methods: Forty-three volunteers were examined with both HD-OCT 4000 and HD-OCT 5000 at the same visit. Optic nerve head (ONH) and macular data were acquired using ONH Cube 200× 200 scans and macular volume cube 512× 128 scans, respectively.Results: The average age of the participants was 33 ± 8.6 years. Interocular OCT parameters of ONH and macula showed a high correlation between the right and left eyes regardless of HD-OCT models, displaying a low coefficient of variation (CV). However, the average retinal nerve fiber layer (RNFL) was thicker (96.67± 11.19μm vs 95.3± 10.89μm, p< 0.01), and the average central subfield thickness (261.51± 17.45μm vs 262.51± 17.39 μm, p< 0.01) and cube average thickness (283.91± 13.59μm vs 286.55± 13.09μm, p< 0.05) were thinner when measured by Cirrus 4000 compared to 5000. Intermachine reproducibility and reliability of RNFL and macular parameters exhibited a high intraclass correlation coefficient (ICC) (0.985) and low CV (2.4%). Ganglion cell-inner plexiform layer (GCIPL) measured by two OCT models showed similar values with an average thickness of 85 μm and had high intermachine reproducibility with high ICC (0.993) and low CV (1.2%).Conclusion: High interocular symmetry was observed across both HD-OCT models. Intermachine reproducibility for RNFL and all macular parameters was also high. GCIPL showed minimal intermachine differences with high reproducibility and reliability. Thus, the results imply that GCIPL values measured by two Cirrus OCT models may be used interchangeably.Keywords: neuro imaging, optical coherence tomography, interocular symmetry, intermachine reproducibility, retina, ganglion cell-inner plexiform layer, interchangeability

Jingjing Mu,1,2,&ast; Shiyi Xiong,2,&ast; Guixiang Yang,2 Fengfeng Wang,3 Xuanying Li,2 Qiong Gao,2 Qiang Niu,2 Stanley Sau Ching Wong,3 Xuebing Xu,2 Yauwai Chan,2,&ast; Yalan Li1,&ast; 1Department of Anesthesiology, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510630, People’s Republic of China; 2Department of Anaesthesiology, the University of Hong Kong Shenzhen Hospital, Shenzhen, People’s Republic of China; 3Department of Anaesthesiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong&ast;These authors contributed equally to this workCorrespondence: Yalan Li, Department of Anesthesiology, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510630, People’s Republic of China, Tel +8613500013993, Email tyalan@jnu.edu.cn Yauwai Chan, Department of Anesthesiology, the University of Hong Kong Shenzhen Hospital, Shenzhen, People’s Republic of China, Tel +86 150 0204 8972, Email cywz01@hku.hkPurpose: Although pediatric epidural analgesia is a well-established technique used perioperatively. It is unclear whether a lumbar or caudal epidural is suitable for osteogenesis imperfecta (OI) patients, which may be associated with brittle bones and spine deformity. We conducted a retrospective study to investigate and compare the efficacy of the two continuous epidural techniques in pediatric patients undergoing lower extremity osteotomy surgery using a propensity score-matched analysis (PSMA).Patients and Methods: A total of 274 patients were included. Patients’ age, weight, and height were adjusted using PSMA. 90 patients were matched for further analysis, with 45 patients in the lumbar epidural group (Group L) and 45 patients in the caudal epidural group (Group C). Pain scores were categorized into three grades: mild (0– 3), moderate (4– 6), and severe (7– 10), and compared between the two groups. Additionally, operation time, operation site, blood loss, scoliosis, oral analgesic medications, and catheter or nerve-related complications were compared.Results: There were no significant differences in operation time, operation site, scoliosis, and blood loss between the two groups. The percentage of moderate to severe pain during movement was significantly higher in Group L than in Group C, with 37.5% versus 17.5% on the second-day post-operation (P=0.039). However, no statistically significant difference was observed on other days. Additionally, there was no significant difference in oral medication consumption and complications between the two groups.Conclusion: Both lumbar and caudal epidural analgesia can be effectively used postoperatively, and a caudal epidural should be considered where performing a lumbar epidural is challenging in OI pediatric patients.Plain Language Summary: Osteogenesis imperfecta (OI) is a rare genetic disorder that affects the body’s connective tissues, particularly the bones and ligaments. It is caused by abnormalities in type I collagen, which leads to skeletal fragility known as “brittle bones”. This fragility can cause various issues, including an increased risk of fractures from minor trauma, limb deformities, and unusual fractures such as vertebral compressions. OI patients may also experience spinal manifestations such as scoliosis and kyphosis.Lumbar epidural analgesia has been found to be effective in providing pain relief for surgeries that involve the lower extremities. Additionally, caudal epidural analgesia has also demonstrated its effectiveness in providing postoperative analgesia for surgeries that affect the lower limbs. However, there is still debate about the safety of epidural analgesia in patients with skeletal dysplasias, especially those with OI. Despite this uncertainty, our center, which was supported by the Rare Diseases Public Welfare Organization, has successfully used epidural analgesia since 2015 in the southern part of China for OI surgeries.We conducted a retrospective study to share our experiences of nine years of practice and compare lumbar epidural with caudal epidural using a propensity score matching to balance basic demographics. We also compared the presence of scoliosis. Our findings suggest that both lumbar and caudal epidural analgesia can be safely used in OI patients. In cases where lumbar punctures may pose challenges due to potential spine deformities, the caudal route can be an alternative.Keywords: Lumbar epidural, caudal epidural, osteotomy surgery, osteogenesis imperfecta, cohort analysis, pain management

Kaifei Chu,1,2,&ast; Jie Liu,2,&ast; Xu Zhang,1,2 Minran Wang,1 Wanping Yu,1 Yuyue Chen,1 Lingling Xu,2 Geng Yang,1 Naru Zhang,1 Tiejun Zhao1,2 1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, People’s Republic of China; 2College of Life Sciences, Zhejiang Normal University, Jinhua, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tiejun Zhao; Naru Zhang, Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, People’s Republic of China, Email tjzhao@hzcu.edu.cn; zhangnr@hzcu.edu.cnAbstract: Plant-derived exosome-like nanovesicles (PDNVs) are small nanoscale vesicles containing lipids, RNAs, proteins and some plant natural products secreted by plant cells. Over the last decade, PDNVs have garnered significant interest due to its exceptional therapeutic benefits in the treatment of various diseases. Herbal medicine, as a medicinal plant, plays an important role in the treatment of diseases including cancer. Especially in recent years, the function of herbal medicine derived exosome-like nanovesicles (HMDNVs) in the treatment of cancer has been widely concerned, and has become a research hotspot of nanomedicine. In this review, the biological characteristics, functions and the therapeutic advantages of PDNVs are reviewed, as well as the recent achievements and research progress of HMDNVs in cancer treatment, demonstrating its enormous promise as a cancer therapy, and new insights are provided for future research and development of anti-tumor drugs.Keywords: herbal medicine, plant-derived exosome-like nanovesicles, extracellular vesicles, cancer treatment, nanomedicine

Ying Zhang,1,&ast; Peijun Chen,1,&ast; Tianzhuo Yu,1 Yuehui Yu,2 Xinyi Yan,2 Jie Chu,1 Gaoyi Yang3 1Department of Ultrasonography, Hangzhou Red Cross Hospital (Zhejiang Tuberculosis Diagnosis and Treatment Center), Hangzhou, Zhejiang, People’s Republic of China; 2Division of Health Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Ultrasonography, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gaoyi Yang, Department of Ultrasonography, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China, Email yanggaoyi8@163.comPurpose: To explore the relationship between the initial size and the necrotic rate of lymph nodes evaluated by ultrasound in patients with cervical tuberculous lymphadenitis (CTL) and therapeutic response.Methods: Overall, 55 patients were included in this study. Conventional ultrasound and contrast-enhanced ultrasound examination were performed before anti-tuberculosis chemotherapy. Based on the different therapeutic outcomes, they were divided into responder groups (n = 39) and non-responder groups (n = 16). The relationship between the initial size (maximum area, length diameter, short diameter), rate of necrosis, and therapeutic response were compared and analyzed between two groups.Results: There was a significant difference in maximum area, short diameter and rate of necrosis of lymph nodes between the responder groups and the non-responder groups (P < 0.05). The receiver-operating-characteristic (ROC) curve analysis was used to differentiate the two groups, it showed that the area under the curve was 0.746 for maximum area and 0.721 for short diameter, respectively. The cut-off value for the lymph node maximum area and short diameter based on ROC curve analysis was determined as 3.94cm2 (sensitivity 76.9%, specificity 68.7%) and 1.15cm (sensitivity 59.0%, specificity 93.7%), respectively. A negative correlation was observed between maximum area, short diameter, and therapeutic response.Conclusion: The initial maximum area and short diameter of lymph nodes were found to have a negative correlation with chemotherapy response in patients with CTL. The treatment outcomes are typically unsatisfactory for lymph nodes exhibiting an initial necrosis rate of 50% or higher. These findings may be helpful for evaluating therapeutic response.Plain Language Summary: In this study, we evaluated the relationship between the initial size and the necrotic rate by ultrasound with cervical tuberculous lymphadenitis (CTL) and therapeutic response. We found that the initial maximum area and short diameter of lymph nodes have a negative correlation with chemotherapy response in patients with CTL. The treatment outcomes are typically unsatisfactory for lymph nodes exhibiting an initial necrosis rate of 50% or higher. These findings may be helpful for evaluating therapeutic response in the early stages.Keywords: ultrasound, tuberculous lymphadenitis, cervical, anti-tuberculosis chemotherapy, response

Ningning Wang, Yuanyuan Xu, Guangde Yang, He Chen, Xia Wang, Juanjuan Fu, Li Li, Xiucheng Pan Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Xiucheng Pan, Email xzpxc68@126.comPurpose: There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs.Methods: We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients’ survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated.Results: A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient’s OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024).Conclusion: PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.Keywords: hepatocellular carcinoma, immune checkpoint inhibitors, proton pump inhibitors, chronic hepatitis B virus infection

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

Jianchun Xiao,1,&ast; Fangyu Zhao,1,&ast; Wenhao Luo,1,&ast; Gang Yang,1 Yicheng Wang,1 Jiangdong Qiu,1 Yueze Liu,1 Lei You,1 Lianfang Zheng,2 Taiping Zhang1,3 1Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 2Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 3Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Taiping Zhang, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China, Email zhangtaiping@pumch.cnAim: This article aimed to find appropriate pancreatic cancer (PC) patients to treat with Gemcitabine with better survival outcomes by detecting hENT1 levels.Methods: We collected surgical pathological tissues from PC patients who received radical surgery in our hospital from September 2004 to December 2014. A total of 375 PC tissues and paired adjacent nontumor tissues were employed for the construction of 4 tissue microarrays (TMAs). The quality of the 4 TMAs was examined by HE staining. We performed immunohistochemistry analysis to evaluate hENT1 expression in the TMAs. Moreover, we detected hENT1 expression level and proved the role of hENT1 in cell proliferation, drug resistance, migration and invasion in vivo and vitro.Results: The results indicated that low hENT1 expression indicated a significantly poor outcome in PC patients, including shortened DFS (21.6± 2.8 months versus 36.9± 4.0 months, p< 0.001) and OS (33.6± 3.9 versus 39.6± 3.9, p=0.004). Meanwhile, patients in stage I/II of TNM stage had a longer OS (40.2± 3.4 versus 15.4± 1.7, p=0.002) and DFS (31.0± 3.1 versus 12.4± 1.9, p=0.016) than patients in stage III/IV. Patients in M0 stage had a longer OS (39.7± 3.4 versus 16.2± 1.9, p=0.026) and DFS(30.7± 3.0 versus 11.8± 2.2, p=0.031) than patients in M1 stage, and patients with tumors not invading the capsule had a better DFS than those with tumor invasion into the capsule (30.8± 3.0 versus 12.6± 2.3, p=0.053). Patients with preoperative CA19-9 values ≤ 467 U/mL have longer DFS than that of patients who had preoperative CA19-9 values > 467 U/mL (37.9± 4.1 versus 22.9± 4.0, p=0.04). In the subgroup analysis, a high hENT1 expression level was related to a longer OS(39.4± 4.0 versus 31.5± 3.9, p=0.001) and DFS(35.7± 4.0 versus 20.6± 2.7; p< 0.0001) in the Gemcitabine subgroup.Conclusion: PC patients with high hENT1 expression have a better survival outcomes when receiving Gemcitabine. hENT1 expression can be a great prognostic indicator for PC patients to receive Gemcitabine treatment.Keywords: pancreatic cancer, human equilibrative nucleoside transporter 1, hENT1, gemcitabine chemoresistance, prognostic indicator, survival improvement

Yan Ji,1 Haorong Li,1 Jiguo Li,2 Guangqiang Yang,1 Wenli Zhang,1 Yan Shen,1 Bohui Xu,3 Jianping Liu,1 Jingyuan Wen,4 Wenting Song1 1Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Nanjing Miaobang Meiye Enterprise Management Co, LTD, Nanjing, People’s Republic of China; 3School of Pharmacy, Nantong University, Nantong, 226001, People’s Republic of China; 4School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New ZealandCorrespondence: Wenting Song, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, People’s Republic of China, Email songwenting908@163.com Jingyuan Wen, School of Pharmacy, Faculty of Medical and Health Sciences, the University of Auckland, Auckland, New Zealand, Email j.wen@auckland.ac.nzPurpose: Acne vulgaris is a chronic inflammatory skin disorder centered on hair follicles, making hair follicle-targeted delivery of anti-acne drugs a promising option for acne treatment. However, current researches have only focused on the delivering to healthy hair follicles, which are intrinsically different from pathologically clogged hair follicles in acne vulgaris.Patients and Methods: Azelaic acid (AZA) micro/nanocrystals with different particle sizes were prepared by wet media milling or high-pressure homogenization. An experiment on AZA micro/nanocrystals delivering to healthy hair follicles was carried out, with and without the use of physical enhancement techniques. More importantly, it innovatively designed an experiment, which could reveal the ability of AZA micro/nanocrystals to penetrate the constructed clogged hair follicles. The anti-inflammatory and antibacterial effects of AZA micro/nanocrystals were evaluated in vitro using a RAW264.7 cell model stimulated by lipopolysaccharide and a Cutibacterium acnes model. Finally, both the anti-acne effects and skin safety of AZA micro/nanocrystals and commercial products were compared in vivo.Results: In comparison to commercial products, 200 nm and 500 nm AZA micro/nanocrystals exhibited an increased capacity to target hair follicles. In the combination group of AZA micro/nanocrystals and ultrasound, the ability to penetrate hair follicles was further remarkably enhanced (ER value up to 9.6). However, toward the clogged hair follicles, AZA micro/nanocrystals cannot easily penetrate into by themselves. Only with the help of 1% salicylic acid, AZA micro/nanocrystals had a great potential to penetrate clogged hair follicle. It was also shown that AZA micro/nanocrystals had anti-inflammatory and antibacterial effects by inhibiting pro-inflammatory factors and Cutibacterium acnes. Compared with commercial products, the combination of AZA micro/nanocrystals and ultrasound exhibited an obvious advantage in both skin safety and in vivo anti-acne therapeutic efficacy.Conclusion: Hair follicle-targeted delivery of AZA micro/nanocrystals provided a satisfactory alternative in promoting the treatment of acne vulgaris.Keywords: acne vulgaris, azelaic acid, hair follicle, micro/nanocrystals, targeted delivery

Liying Ma,1,2 Yansong Gao,1 Ge Yang,1 Lei Zhao,2 Zijian Zhao,1 Yujuan Zhao,1 Yuhang Zhang,2 Shenhui Li,2 Shengyu Li1 1Institute of Agricultural Products Processing Technology, Jilin Academy of Agricultural Sciences (Northeast Agricultural Research Center of China), Changchun, 130033, People’s Republic of China; 2School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, People’s Republic of ChinaCorrespondence: Shengyu Li, Institute of Agro-Food Technology, Jilin Academy of Agricultural Sciences (Northeast Agricultural Research Center of China), No. 1363 Sheng-Tai Street, Changchun, Jilin Province, 130033, People’s Republic of China, Tel +86 431 87063289, Fax +86 431 87063075, Email lisy720@126.comAim: The inflammatory response plays a pivotal role in the occurrence, progression, and plaque formation of atherosclerosis. The study was performed to investigate the impacts of notoginsenoside R1 on the development of atherosclerosis (AS) and the potential mechanisms.Methods: Rats induced with AS by a high-fat-diet and vitamin D3 were treated with notoginsenoside R1 for six weeks. The ameliorative effect of NR1 on AS rats was assessed by detecting pathological changes in the abdominal aorta, biochemical indices in serum and protein expression in the abdominal aorta, as well as by analysing the gut microbiota.Results: The NR1 group exhibited a noticeable reduction in plaque pathology. Notoginsenoside R1 can significantly improve serum lipid profiles, encompassing TG, TC, LDL, ox-LDL, and HDL. Simultaneously, IL-6, IL-33, TNF-α, and IL-1β levels are decreased by notoginsenoside R1 in lowering inflammatory elements. Notoginsenoside R1 can suppress the secretion of VCAM-1 and ICAM-1, as well as enhance the levels of plasma NO and eNOS. Furthermore, notoginsenoside R1 inhibits the NLRP3/Cleaved Caspase-1/IL-1β inflammatory pathway and reduces the expression of the JNK2/P38 MAPK/VEGF endothelial damage pathway. Fecal analysis showed that notoginsenoside R1 remodeled the gut microbiota of AS rats by decreasing the count of pathogenic bacteria (such as Firmicutes and Proteobacteria) and increasing the quantity of probiotic bacteria (such as Bacteroidetes).Conclusion: Notoginsenoside R1, due to its unique anti-inflammatory properties, may potentially prevent the progression of atherosclerosis. This mechanism helps protect the vascular endothelium from damage, while also regulating the imbalance of intestinal microbiota, thereby maintaining the overall health of the body. Keywords: notoginsenoside R1, inflammation, endothelial damage, gut microbiota

Jinfu Wang,1,&ast; Xiuxia Liu,2,&ast; Xue Xu,3 Haiyun Wang,4 Guan Yang1 1School of Physical Education, South China University of Technology, Guangdong, Guangzhou, People’s Republic of China; 2School of Physical Education, Xiamen University, Fujian, Xiamen, People’s Republic of China; 3School of Finance and Economy, Guangdong Engineering Polytechnic, Guangdong, Guangzhou, People’s Republic of China; 4School of Physical Education, Guangzhou College of Commerce, Guangdong, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyun Wang, School of Physical Education, Guangzhou College of Commerce, Kowloon Avenue No. 206, Guangdong, Guangzhou, 511363, People’s Republic of China, Email 20141002@gcc.edu.cn Guan Yang, School of Physical Education, South China University of Technology, Wushan Road No. 381, Guangdong, Guangzhou, 510641, People’s Republic of China, Tel +86 15626499157, Email yangmp6@scut.edu.cnPurpose: During the period of COVID-19 pandemic, the social restrictions and isolation exerted a significant impact on the sleep quality of Chinese college students. This study aims to delve into the influence of physical activity on the sleep quality of college students as well as the mediating roles of stress and smartphone addiction.Materials and Methods: A cohort of 274 eligible college students (146 males and 128 females) were selected for the investigation. The International Physical Activity Questionnaire Short Form, Stress Perception Scale, Smartphone Addiction Scale, and Pittsburgh Sleep Quality Index were employed to assess the levels of physical activity, stress, smartphone addiction, and sleep quality among college students. For data analysis, descriptive statistics, correlation analysis, and chained mediation effect tests were performed sequentially.Results: The findings revealed: (1) a significant negative correlation between physical activity and stress, smartphone addiction, and sleep quality among college students (r = − 0.216, p < 0.001; r = − 0.224, p < 0.001; r = − 0.259, p < 0.001); (2) independent mediating roles of stress and smartphone addiction in the relationship between physical activity and sleep quality; and (3) chained mediating effects of stress and smartphone addiction in the association between physical activity and sleep quality.Conclusion: This study deepens our comprehension of how physical activity augments the quality of slumber, concurrently emphasizing that mitigating stress levels and alleviating smartphone addiction constitute effective strategies for preventing sleep issues among college students.Keywords: sleep quality, physical activity, smartphone addiction, stress, chain mediating effect, college students

Yumei Liao,1,&ast; Aihong Wang,1,&ast; Wenjuan Sui,2 Abbas Khan,3 Zibo Xiong,1,4,5 Guang Yang1,4,5 1Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, Guangdong, 518036, People’s Republic of China; 2Institute of City Strategy Studies, Guangdong University of Foreign Studies, Guangzhou, Guangdong, 510006, People’s Republic of China; 3Department of Nutrition and Health Promotion, University of Home Economics Lahore Pakistan, Lahore, 54000, Pakistan; 4Institute of Nephrology, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, Guangdong, 518036, People’s Republic of China; 5Shenzhen Clinical Research Centre for Urology and Nephrology, Shenzhen, Guangdong, 518036, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zibo Xiong; Guang Yang, Email xiong0301@163.com; guang.yang@pkuszh.comBackground: Nephrology nursing faces an inevitable challenge when it comes to falls. This study aims to review existing literature on falls in chronic kidney disease (CKD) patients and to discuss potential solutions.Methods: This review explores the characteristics and causes of falls in CKD patients, elucidate the underlying mechanisms, shares better nursing practices, and discusses both current prevention strategies as well as potential future interventions.Results: CKD patients often experience consciousness impairment and motor dysfunction due to factors such as muscle atrophy, nerve damage, malnutrition, anemia, fluid-electrolyte imbalances, hormonal disorders, and dialysis. Additionally, this study not only shares insights from nursing experience with these patients, but also reviews current evidence-based fall prevention strategies and proposes potential new interventions that could be tested in future research.Conclusion: CKD may increase the risk of involuntary falls in patients due to consciousness impairment and motor dysfunction. Advocating for a standardized expert consensus on fall risk assessment and comprehensive care for CKD patients would enhance the nursing framework in nephrology wards and help patients decrease their fall risk and elevate their quality of life.Keywords: falls, chronic kidney diseases, dialysis, nephrology nursing, anemia

Guang Yang,1,&ast; Xiaodong Zhang,2,3,&ast; Zhaopeng Xu,1 Lufa Zhang1,4 1School of International and Public Affairs, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Institute of Population Research, Peking University, Beijing, People’s Republic of China; 3Oxford Institute of Population Ageing, University of Oxford, Oxford, UK; 4Institute of Healthy Yangtze River Delta, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lufa Zhang, No. 1954, Huashan Road, Xuhui District, Shanghai, 200030, People’s Republic of China, Email zhanglf@sjtu.edu.cnPurpose: The siphon effect in the health service market is notably pronounced in many countries. How to measure and identify the determinants contributing to the siphon effect presents a substantial challenge. This study aimed to analyse the effect of two different social medical insurances, the Basic Medical Insurance System for Urban Employees (BMISUE), and the Basic Medical Insurance System for Urban and Rural Residents (BMISURR), on the siphon effect in the health services market.Methods: The data used in this study were from the 2021 Health Life Satisfaction Survey of Yangtze River Delta (HLSSYRD) conducted by Shanghai Jiao Tong University. The logistic model was used to evaluate the association between social medical insurances and individual choices of medical institutions, and the Propensity Score Matching method (PSM) was used to check the robustness of basic results.Results: Residents covered by BMISUE were more likely to choose a general hospital when they first sought medical treatment (OR = 5.377, 95% CI: 4.887, 5.915) relative to those insured by BMISURR. Further analysis showed that BMISUE would accelerate the siphon effect of general hospitals, people insured by BMISUE were still more likely to choose general hospitals despite being close to primary hospitals compared to those insured by BMISURR (OR = 3.240, 95% CI: 2.945, 3.565). Heterogeneity analysis indicated BMISUE had a greater impact on residents aged 15– 59 years and those with high income compared to older people and individuals with low income.Conclusion: Different social medical insurances can substantially affect residents’ first choice of medical institutions. BMISUE with higher benefits level could exacerbate the siphon effect in the health service market. More equitable medical security system should be strengthened to bridge the benefits gap between BMISUE and BMISURR.Keywords: BMISUE, BMISURR, choice of medical institutions, siphon effect, Yangtze River Delta, China

Aguo Cheng,1,2 Suohui Zhang,1,3 Fanda Meng,4 Mengzhen Xing,5 Han Liu,3 Guozhong Yang,3 Yunhua Gao1– 3 1Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry of Chinese Academy of Sciences, Beijing, People’s Republic of China; 2University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 3Beijing CAS Microneedle Technology Ltd, Beijing, People’s Republic of China; 4School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China; 5Key Laboratory of New Material Research Institute, Department of Pharmaceutical Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Yunhua Gao, Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry of Chinese Academy of Sciences, Beijing, People’s Republic of China, Tel +86 (10)82543581, Email yhgao@mail.ipc.ac.cnPurpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum’s barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility.Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance.Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action’s duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1β compared with the methotrexate subcutaneous injection method.Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration. Keywords: nanosuspension, highly lipophilic drugs, dissolving microneedle, cannabidiol, knee synovitis

Juanli Fan,1 Yanmei Gong,2 Gaie Yang1 1Department of Dermatovenereology, Yuncheng Central Hospital, Shanxi Medical University, Yuncheng, Shanxi Province, 044000, People’s Republic of China; 2Department of Oncology, Yuncheng Central Hospital, Shanxi Medical University, Yuncheng, Shanxi Province, 044000, People’s Republic of ChinaCorrespondence: Juanli Fan, Department of Dermatovenereology, Yuncheng Central Hospital, Shanxi Medical University, No. 3690 Hedong East Street, Yanhu District, Yuncheng, 044000, Shanxi Province, People’s Republic of China, Tel +86 13934399917, Email fanjuanli10@126.comBackground: In contemporary times, malignancies characterized by metastatic growth have been subjected to innovative therapeutic approaches involving immunological agents known as Programmed Death Receptor 1 (PD-1) inhibitors. Notwithstanding their remarkable immunotherapeutic effectiveness, these treatments can give rise to undesirable immune-related effects. Sintilimab, a PD-1 inhibitor sanctioned for marketing by the Chinese National Medical Products Administration in 2018, has been associated with 51 reported cases of adverse reactions on the market, excluding psoriasis, up to the present moment.Case Description: Herein, we report the clinical characteristics of a patient with metastatic gastric adenocarcinoma who developed guttate psoriasis after receiving Sintilimab. The patient was an elderly male presenting with papules varying in size from that of rice grains to soybeans, accompanied by scattered erythematous lesions across his body. Notably, an atypical Auspitz’s sign was observed, wherein certain lesions were covered with a minimal amount of scale, coupled with reported persistent itching. The progression of the disease manifested within a span of one week.Conclusion: PD1 inhibitors have been associated with the recurrence, exacerbation, or new onset of psoriasis. Consequently, a personal or family history of psoriasis is an essential risk factor that needs to be considered before PD1 inhibitor medication, which helps with the early diagnosis of psoriasis. Early diagnosis of new-onset guttate psoriasis poses challenges. An early consultation with a dermatologist is recommended, and a conclusive diagnosis can be obtained through a histopathologic examination.Keywords: adverse drug reactions, PD-1 inhibitors, psoriasis, sintilimab

Guodong Yang,1– 3 Shuang Zhou,4 Yue Feng,5 Jiaran Lang,1– 3 Yaxin Chen,1– 3 Huipeng Ren1– 3 1Mental Health Center, Hebei Medical University and Hebei Technical Innovation Center for Mental Health Assessment and Intervention, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Psychiatry, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4The Sixth People’s Hospital of Hebei Province, Baoding, Hebei, 071000, People’s Republic of China; 5Maternity & Child Care Center of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Huipeng Ren, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email renhuipeng@126.comPurpose: In clinical work, it has been found that the prevalence of hyperuricemia (HUA) is significantly higher in younger patients with psychiatric disorders, but there are few studies in this area. The present study aims to evaluate the prevalence of HUA and the relationship between the HUA and age in hospitalized patients with psychiatric disorders in the real world, and to provide a theoretical basis for clinical staff to pay attention to the metabolic indicators of younger patients and for future related studies.Methods: This is a cross-sectional evaluation of a cohort of 1761 patients with psychiatric disorders of hospitalized. The categories of disorders designed for study included: Depression, Bipolar disorder, Schizophrenia, Anxiety, Obsessive-Compulsive disorder, Acute and transient psychotic disorder, Dissociative(conversion) disorders, Conduct disorders and Tic disorders. In addition, based on age, the participants are stratified into three groups. The authors used Kruskal–Wallis tests, chi-square tests, and multiple linear logistic regression to verify the relationship between HUA and age among hospitalized patients with psychiatric disorders.Results: Overall, the estimated prevalence of HUA was 35.4%. The prevalence of HUA was significantly higher in individuals with 17 years and under compared to those with 45 years and above (P < 0.001). After adjusting for confounders, the prevalence of HUA remained higher at 17 years and under than at 45 years and above. Bipolar disorder can lead to an increased prevalence of HUA (P< 0.05).Conclusion: The prevalence of HUA was higher in hospitalized patients with psychiatric disorders, and the prevalence was inversely proportional to age.Keywords: hyperuricemia, uric acid, age, psychiatric disorders, bipolar disorder

Ge Yang,1 Salma Firdaus,2 Lívia Figueiredo Pereira,3 Yumin Huang-Link4 1Huizhou Aier Eye Hospital, Aier Eye Hospital Group, Huizhou, Guangdong Province, People’s Republic of China; 2Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; 3Pontifical Catholic University of Minas Gerais, Belo Horizonte, Brazil; 4Division of Neurology, Department of Biomedical and Clinical Sciences, Linköping University Hospital, Linköping, SwedenCorrespondence: Ge Yang, Huizhou Aier Eye Hospital, Aier Eye Hospital Group, Huizhou, Guangdong Province, People’s Republic of China, Tel +86 15626454300, Email geyang95@sina.com

Guoqiang Yang,1– 3 Jiraporn Kantapan,3 Maryam Mazhar,4,5 Qiongdan Hu,1,5,6 Xue Bai,5,7 Yuanxia Zou,1,3 Honglian Wang,1 Sijin Yang,4,5 Li Wang,1,5 Nathupakorn Dechsupa3 1Research Center for Integrated Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Acupuncture and Rehabilitation Department, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 3Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; 4National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 5Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, People’s Republic of China; 6Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; 7Department of Neurology and National Traditional Chinese Medicine Clinical Research Base, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, People’s Republic of ChinaCorrespondence: Li Wang; Nathupakorn Dechsupa, Email wangli120@swmu.edu.cn; nathupakorn.d@cmu.ac.thBackground: Intracerebral hemorrhage (ICH), a devastating form of stroke, is characterized by elevated morbidity and mortality rates. Neuroinflammation is a common occurrence following ICH. Mesenchymal stem cells (MSCs) have exhibited potential in treating brain diseases due to their anti-inflammatory properties. However, the therapeutic efficacy of MSCs is limited by the intense inflammatory response at the transplantation site in ICH. Hence, enhancing the function of transplanted MSCs holds considerable promise as a therapeutic strategy for ICH. Notably, the iron-quercetin complex (IronQ), a metal-quercetin complex synthesized through coordination chemistry, has garnered significant attention for its biomedical applications. In our previous studies, we have observed that IronQ exerts stimulatory effects on cell growth, notably enhancing the survival and viability of peripheral blood mononuclear cells (PBMCs) and MSCs. This study aimed to evaluate the effects of pretreated MSCs with IronQ on neuroinflammation and elucidate its underlying mechanisms.Methods: The ICH mice were induced by injecting the collagenase I solution into the right brain caudate nucleus. After 24 hours, the ICH mice were randomly divided into four subgroups, the model group (Model), quercetin group (Quercetin), MSCs group (MSCs), and pretreated MSCs with IronQ group (MSCs+IronQ). Neurological deficits were re-evaluated on day 3, and brain samples were collected for further analysis. TUNEL staining was performed to assess cell DNA damage, and the protein expression levels of inflammatory factors and the cGAS-STING signaling pathway were investigated and analyzed.Results: Pretreated MSCs with IronQ effectively mitigate neurological deficits and reduce neuronal inflammation by modulating the microglial polarization. Moreover, the pretreated MSCs with IronQ suppress the protein expression levels of the cGAS-STING signaling pathway.Conclusion: These findings suggest that pretreated MSCs with IronQ demonstrate a synergistic effect in alleviating neuroinflammation, thereby improving neurological function, which is achieved through the inhibition of the cGAS-STING signaling pathway.Keywords: mesenchymal stem cells, IronQ, intracerebral hemorrhage, cGAS/STING/NFκB, inflammatory response

YuJian He,1,2,&ast; Guang Yang,1,&ast; Pengpeng Wang,1,3 Xu Wang,1,3 Zuying Xiong,1 Yan He,1,&ast; Zibo Xiong1,&ast; 1Renal Division, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China; 2Renal Division, PKU-Shenzhen Clinical Institute of Shantou University Medical College, Shenzhen, People’s Republic of China; 3Renal Division, PKU-Shenzhen Clinical Institute of Shenzhen University Medical College, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zibo Xiong, Renal Division, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China, Tel +86-13510880599, Email xiong0301@163.comPurpose: Antibiotic administration leads to alterations in pathogenic organisms and antibiotic resistance, posing a significant risk to peritoneal dialysis patients’ health. This study aimed to investigate changes in the cause-specific peritonitis, pathogen profiles, antibiotic resistance, and the prognostic factors among patients with peritoneal dialysis-associated peritonitis (PDAP) at our center.Patients and Methods: We included 463 PDAP patients who attended Peking University Shenzhen Hospital between 2002 and 2023. We analyzed the effects of empirical treatment regimens with cefazolin and ceftazidime or gentamicin.Results: From 2002 to 2023, we observed that gram-positive staphylococci emerged as the primary causative agents, while the proportion of gram-negative bacillary, enteric peritonitis, and catheter-associated peritonitis decreased significantly. However, the overall cure rate for PDAP and gram-negative bacillary peritonitis declined significantly from 2014 to 2023. Notably, we observed no increase in antibiotic resistance associated with antibiotic drugs use. In addition, reduced lymphocyte counts due to the prevalence of 2019 coronavirus disease (COVID-19) emerged as an independent risk factor for treatment failure in cases of gram-negative bacillary peritonitis.Conclusion: We did not observe elevated antibiotic resistance in our center when employing empirical dosing strategies involving cefazolin, ceftazidime, or gentamicin. Additionally, we found that a decrease in lymphocyte count due to the COVID-19 epidemic was a significant risk factor for treatment failure in cases of gram-negative bacillary peritonitis at our center. This study provides a foundation for developing clinical treatment strategies for PDAP.Keywords: antibiotic resistance, COVID-19, lymphocyte count, peritoneal dialysis, peritonitis, pathogen spectrum

Guanghua Yang,1,&ast; Jiaxi Pu,1,&ast; Sibo Zhu,2 Yong Shi,3 Yi Yang,3 Jiangnan Mao,3 Yongkang Sun,1 Bin Zhao1 1Department of General Surgery, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, People’s Republic of China; 2School of Life Sciences, Fudan University, Shanghai, 200438, People’s Republic of China; 3Cinoasia Institute, Shanghai, 200438, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Zhao, Department of General Surgery, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Gaoqiao, Pudong New Area, Shanghai, 200137, People’s Republic of China, Tel +86 13918468421, Email zhaobin0727@sina.com Yongkang Sun, Department of Ultrasound, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, No. 358, Datong Road, Gaoqiao, Pudong New Area, Shanghai, 200137, People’s Republic of China, Tel +86 13601659860, Email elangwang@126.comBackground: Thyroidectomy is commonly performed for benign or malignant thyroid tumors, often resulting in hypothyroidism. Levothyroxine (LT4) supplementation is crucial to maintain hormone levels within the normal range and suppress TSH for cancer control. However, determining the optimal dosage remains challenging, leading to uncertain outcomes and potential side effects.Methods: We analyzed clinical examination data from 510 total thyroidectomy patients, including demographic information, blood tests, and thyroid function. Using R, we applied data preprocessing techniques and identified 274 samples with 98 variables. Principal Component Analysis, correlation analysis, and regression analysis were conducted to identify factors associated with optimal LT4 dosage.Results: The analysis revealed that only eight variables significantly influenced the final satisfactory dosage of LT4 in tablets: Benign0/Malignant1 (benign or malignant), BQB (electrophoretic albumin ratio), TP (total protein), FDP (fibrin degradation products), TRAB_1 (thyroid-stimulating hormone receptor antibody), PT (prothrombin time), MONO&num; (monocyte count), and HCV0C (hepatitis C antibody). The resulting predictive model was: .Conclusion: Parameters such as benign/malignant status, TRAB_1, and BQB ratio during medication can serve as observational indicators for postoperative LT4 dosage. The calculated linear model can predict the LT4 dosage for patients after thyroidectomy, leading to improved treatment effectiveness and conserving medical resources.Keywords: thyroid, levothyroxine, dosage, model, prediction

Jiaming Shen,1,2,&ast; Xia Wang,2,&ast; Guangde Yang,2,&ast; Li Li,2 Juanjuan Fu,2 Wei Xu,3 Qingqiao Zhang,3 Xiucheng Pan2 1Department of Gastroenterology, People’s Hospital of Jingjiang, Taizhou, People’s Republic of China; 2Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3Department of Interventional Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiucheng Pan, Tel +8618052268129, Email xzpxc68@126.comPurpose: Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy.Patients and Methods: Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan–Meier analysis were used to determine prognostic factors for OS.Results: As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050– 0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031– 3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1– 2 and grade 3– 4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034).Conclusion: Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy. Keywords: HBV-related HCC, TACE, TKI, ICI, liver injury, survival time

Gongxin Yang,1,&ast; Jikai Xia,2,&ast; Xiaoqing Dai,1,&ast; Hongbo Zhao,1 Weiqing Gao,1 Weilong Ding,1 Xiaofeng Tao,1 Ling Zhu1 1Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200001, People’s Republic of China; 2Department of Radiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, 264100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofeng Tao; Ling Zhu, Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200001, People’s Republic of China, Email cjr.taoxiaofeng@vip.163.com; zhuling011@126.comIntroduction: Magnetic resonance imaging (MRI) is an important tool for the accurate diagnosis of malignant tumors in clinical settings. However, the lack of tumor-specific MRI contrast agents limits diagnostic accuracy.Methods: Herein, we developed αv integrin receptor-targeting multi-crystalline manganese oxide (MCMO) as a novel MRI contrast agent for accurate diagnosis of tumors by coupling iRGD cyclopeptide PEGylation polymer onto the surface of MCMO (iRGD-pMCMO).Results: The MCMO consisted of numerous small crystals and exhibited an oval structure of 200 nm in size. The iRGD-pMCMO actively recognizes tumor cells and effectively accumulates at the tumor site, consequently releasing abundant Mn2+ ions in a weakly acidic and high-GSH-expressing tumor microenvironment. Subsequently, Mn2+ ions interact with cellular GSH to form Mn-GSH chelates, enabling efficient T1-weighted MR contrast imaging. In vivo experiments indicated that iRGD-pMCMO significantly improved T1-weighted images, achieving an accurate diagnosis of subcutaneous and orthotopic tumors. The results verified that the T1 contrast effect of iRGD-pMCMO was closely associated with the expression of GSH in tumor cells.Conclusion: Altogether, the novel tumor-targeting, highly sensitive MRI contrast agent developed in this study can improve the accuracy of MRI for tumor diagnosis. Keywords: multi-crystalline manganese oxide, MRI contrast agent, tumor targeting, tumor selectivity, accurate diagnosis

Guanyu Yang, Qinjun Chu Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Qinjun Chu, Email jimmynetchu@163.com

Guanyu Yang Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Guanyu Yang, Email anesygy@qq.com

Xiaoyu Li,1 Feng Bai,2 Xinmei Liu,1 Guangyu Yang1 1Department of Otorhinolaryngology Head and Neck Surgery, First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Otorhinolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Guangyu Yang, Department of Otorhinolaryngology Head and Neck Surgery, First Hospital of Jilin University, No. 1 of Xinmin Street, Chaoyang District, Changchun, 130021, People’s Republic of China, Tel +86-43188785539, Fax +86-43188785505, Email sryyxf@jlu.edu.cnAbstract: Hospice care is to improve the quality of life and help patients die comfortably, peacefully and dignified by controlling pain and discomfort symptoms and providing physical, psychological and spiritual care and humanistic care in the final stage of the patient’s life. Hospice care clients were primarily cancer patients at first and then slowly extended to other critically patients. Hospice care can alleviate the physical, psychosocial and mental problems of patients with advanced cancer, meet the diversified and multi-level health service needs of patients, improve the quality of life of patients and their families, and also save medical expenditure and improve the efficiency of medical resources. At present, there were few studies on hospice care for Chinese patients with advanced cancer. In this study, the needs of hospice care for patients with advanced cancer were reviewed from physical comfort and pain reduction, dignity maintenance, social support, and help calm death, and specific screening and evaluation tools for hospice care for patients with advanced cancer. And this study was summarized to review the influencing factors of hospice care in order to provide a reference for clinical hospice care practice for patients with advanced cancer in China.Keywords: advanced cancer, hospice care, influencing factors, clinical practice, evaluation tools

Guojian Yang,&ast; Le Li,&ast; Xi Peng, Guodong Tang, Naixin Zheng, Ying Zhao, Hui Li, Huiping Zhang, Fucheng Sun, Hu Ai Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hu Ai, Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, People’s Republic of China, Tel +86 18601025086, Email aihumd@aliyun.comPurpose: Coronary angiography-derived fractional flow reserve (caFFR) is a novel computational flow dynamics (CFD)-derived assessment of coronary vessel flow with good diagnostic performance. Herein, we performed a retrospective study to evaluate the reproducibility of caFFR findings between observers and investigate the diagnostic performance of caFFR for coronary stenosis defined as FFR ≤ 0.80, especially in the grey zone (0.75≤caFFR ≤ 0.80).Patients and Methods: A total of 150 patients (167 coronary vessels) underwent caFFR (with FlashAngio used for calculation of flow variables) and subsequent invasive fractional flow reserve (FFR) measurements. Outcomes, including reproducibility, were compared for vessels in and outside the grey zone.Results: The correlation of caFFR findings was good between the two laboratories (r = 0.723, p< 0.001). The AUC of ROC were both high for caFFR-CoreLab1 and caFFR-CoreLab2 (0.975 and 0.883). The diagnostic accuracy, sensitivity, specificity, and negative and positive predictive values were not significantly different between the two laboratories (p> 0.05). caFFR had a strong correlation with measures to FFR (r=0.911, p

Yinxia Zheng, Xianfeng Li, Yan Xia, Xiaoqin Li, Genglin Yang, Rui Shi, Ying Feng Urumqi Maternal and Child Health Hospital, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Ying Feng, Email 623245060@qq.comObjective: To Analysis of the mediation effects of adverse mental health outcomes in HIV-infected women of childbearing age from multiple perspectives including discrimination perception, social capital, and other factors.Methods: A cross-sectional survey was conducted among 553 people in Xinjiang region of China using Survey scale. AMOS was used to identify factors that influenced the “discrimination perception/mental resilience/social capital-depression-poor mental health outcomes” pathway.Results: A total of 44.85% and 42.13% of the study participants had anxiety and depression symptoms, as perceived discrimination increased, the higher the level of depression in HIV-infected women of childbearing age. Correlation coefficient among depression with poor mental health outcomes was also significant. Psychological resilience, social capital and depression have mediating effects on perceived discrimination and poor mental health outcomes, discrimination perception had an indirect effect on depression through social capital and an indirect effect on adverse mental health outcomes through depression and psychological resilience. The modified model has a good fitting effect.Conclusion: Discrimination perception was shown to affect adverse mental health outcomes by impacting mental resilience, depression, and social capital. The findings suggest the need for measures to reduce adverse mental health outcomes by decreasing discrimination perception, increasing social capital, and enhancing psychological resilience.Keywords: women of childbearing age, HIV-infected, psychological resilience, discrimination perception, mental health

Dehai Wu,1,&ast; Guanqun Liao,2,&ast; Yuanfei Yao,3,&ast; Lining Huang,4 Bowen Dong,5 Yong Ma,6 Guangchao Yang6 1Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Department of Hepatobiliary Surgery, Foshan Hospital Affiliated to Southern Medical University, Foshan, People’s Republic of China; 3Key Laboratory of Tumor Immunology in Heilongjiang, Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 4Department of Hepatobiliary Surgery, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, People’s Republic of China; 5Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, People’s Republic of China; 6Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangchao Yang; Yong Ma, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China, Tel +86 13796000181 ; +86 13836006500, Email guangchaoyang@hrbmu.edu.com; doctormy80@163.comBackground: The aim of this study is to explore the role of acetyl-CoA acyltransferase 2 (ACAA2) in the progression of hepatocellular carcinoma (HCC).Methods: Bulk RNA data and single-cell RNA data were acquired from The Cancer Genome Atlas and Gene Expression Omnibus. Both in vitro and in vivo studies were used to determine the effect of ACAA2 on the progression of HCC, and RNA sequencing analysis was performed to explore the mechanism.Results: We found downregulation of ACAA2 was involved in the malignant progression of HCC. The patient with low ACAA2 level had an immunosuppressive microenvironment in the HCC and predicted to have a poor prognosis. Decreased ACAA2 facilitated HCC proliferation and metastasis by activating the nuclear factor-κB (NFκB) signaling pathway. And increased CXCL1 induced by NFκB signaling pathway might be responsible for low level of ACAA2 related immunosuppressive microenvironment. Furthermore, the expression of ACAA2 was also detected in immune cells. The expression of ACAA2 in CD4+TCF7+T, CD4+FOXP3+T, CD8+GZMK+T, and CD8+KLRD1+T cells was inversely correlated with the composition of CD8+PDCD1+T cells in HCC. This effect might be due to the CCL5-CCRs and HLA-E-KLRCs ligand-receptor networks.Conclusion: In a conclusion, downregulated ACAA2 promoted the progression of hepatocellular carcinoma and might be participated in the formation of immunosuppressive microenvironment. ACAA2 could be served as a favorable indicator for the prognosis of HCC and an ideal biomarker for immunotherapy.Keywords: hepatocellular carcinoma, acetyl-CoA acyltransferase 2, immunotherapy, nuclear factor-κB signaling pathway, biomarker

Junlong Ma,1,2,&ast; Jie Huang,1,&ast; Chan Zou,1 Qian Wu,1 Jinlian Xie,1 Xingfei Zhang,1 Xiaoyan Yang,1 Shuang Yang,1 Ziteng Wu,3 Yan Jiang,3 Sen Yu,3 Xuqing Zhang,4 Guoping Yang,1,5 Mingyuan Li1 1The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 2Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 3Nanjing Delova Biotech Co., Ltd., Nanjing, Jiangsu, 210042, People’s Republic of China; 4King-eagle Med Co., Ltd., Changsha, Hunan, 410013, People’s Republic of China; 5Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingyuan Li, Email lmyuan3@126.comBackground: Meloxicam is a selective cyclooxygenase-2 inhibitor used for pain relief, but its poor solubility limits its clinical applications. QP001 is a novel intravenous formulation of meloxicam developed with PEG and pH regulator to improve its solubility. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of QP001 in Chinese healthy subjects.Methods: The trial consisted of three parts. Part I was a two-period crossover study to evaluate bioavailability, in which 10 healthy were either intravenously infused with 15mg QP001 (test) or orally given 15mg MobicⓇ (reference). Part II was a single-arm design to assess the pharmacokinetic (PK) characteristics after 30 mg single- and multiple-dose QP001 in 10 subjects. In part III, we investigated the PKs and tolerability of QP001 at a high dose (60 mg) in another 10 subjects. The PK parameters and treatment-emergent adverse events (TEAEs) were evaluated.Results: A total of 30 subjects were enrolled in the study. QP001 was well tolerated and safe without significant TEAEs in all three study parts. The PK characteristics of QP001 were linear following a single-dose range of 15– 60 mg (Cmax and AUC0-t were 5.82– 17.66 μg/mL and 58.08– 251.17 μg∙h/mL, respectively). After five consecutive daily 30 mg doses, the accumulation index was around 1.98, which indicated a minimal accumulation of QP001. Compared to the tablet dosage form, the relative bioavailability of QP001 reached 116.85%. Additionally, the PK profile of QP001 showed no gender difference.Conclusion: QP001 was well tolerated in healthy Chinese subjects after single ascending doses up to 60 mg and multiple-dose of 30 mg. Based on the PK and safety results, QP001 is a promising once-daily intravenous COX-2 inhibitor candidate for managing pain.Trial Registration: The trial is registered at chinadrugtrials.org.cn (ChiCTR2100047884).Keywords: meloxicam, phase I trial, pharmacokinetic, safety, novel formulation

Changtai Zhao,1,&ast; Guang Yang,2,&ast; Bingzhou Ji,2 Hongfu Jin,2 Shinen Naranmandakh,3 Yusheng Li2,4 1Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 2Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Department of Chemistry, School of Arts and Sciences, National University of Mongolia, Ulaanbaatar, 14201, Mongolia; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yusheng Li; Shinen Naranmandakh, Email liyusheng@csu.edu.cn; smandakh@num.edu.mnBackground: Osteoarthritis (OA) is a painful and complex joint disease. The unique mechanisms and potential interventions of OA-induced pain have attracted researchers’ attention in recent years. Bibliometric and visualization analysis is a comprehensive scientific method that integrates mathematical and statistical approaches to explore research priorities in a specific field. However, there are few studies on OA pain using bibliometric analysis.Purpose: This study aimed to explore research trends and hotspots in OA pain research field, offer practical guidance to researchers looking for top-notch scholars/institutions/countries, and provide suggestions for journal submissions by analyzing the existing literature.Methods: Raw data were extracted from Web of Science Core Collection. Microsoft Excel, the R package “bibliometrix”, VOSviewer and CiteSpace software were used to analyze data and visualize relevant results.Results: A total of 2493 articles were included for further bibliometric and visualization analysis. During the investigated period, 2021 with 343 publications was the most productive year. Fillingim, Roger B. and Bennell, Kim L. with 32 articles were the most productive authors. Most publications were from the USA (797 articles, 20,727 citations). Rehabilitation and treatment of OA pain were the hotspots in OA pain research area. The top-contributing journal was Osteoarthritis and Cartilage. Boston University (91 articles; 4050 citations) was the most active institution.Conclusion: The total publications of OA pain generally increasing over the time in the last decade, and the escalating rate remained a high level. This is the first comprehensive bibliometric study in OA pain research field, and it will offer practical guidance to researchers in this field.Graphical Abstract: Keywords: osteoarthritis pain, bibliometric analysis, research trends, VOSviewer, CiteSpace

Yichun Zhang, Jun Peng, Wenjun Sun, Haipeng Zhang, Guang Yang Department of Pharmacy, Hebei Yanda Hospital, Langfang City, Hebei Province, People’s Republic of ChinaCorrespondence: Yichun Zhang, Department of Pharmacy, Hebei Yanda Hospital, Yanjiao Simhuilan West Road, Sanhe City, Langfang City, Hebei Province, 065200, People’s Republic of China, Tel +86-316-3306055, Email yi2022chun@163.comObjective: Home pharmaceutical care delivers individualised, whole-process and continuous pharmaceutical services and health education. This study aims to explore the feasibility of home pharmaceutical services as a combination of medical and nursing care.Methods: Patient information was collected from 1 October 2020 to 30 September 2021 and was analysed and evaluated. We then developed a family medication plan and investigated its effectiveness and any issues encountered during the implementation process.Results: A total of 102 patients received services, and 100% of the patients were satisfied with these. Moreover, using home pharmaceutical care saved approximately USD1,359.64 (RMB9,360.45) in outpatient costs and USD41,077.76 (RMB282,700) in inpatient costs, and the number of hospitalisations was reduced by 16%.Conclusion: It is beneficial to make home pharmaceutical services available as a combination of medical and nursing care. Pharmacists can help patients solve medication-related problems and reduce the number of hospitalisations and medical costs through standardised service models while ensuring safe, effective, economical and rational drug use for patients.Keywords: medical care, nursing, home care, home pharmacist, standard services

Yue Xie,1,&ast; Yaning Jin,2,&ast; Shuyue Li,3 Baoxi Shen,4 Liping Ma,5 Lujie Zuo,6 Ya Gao,3 Guofeng Yang3 1Department of Neurology, the Second Medical Center and National Clinical Research Center for Geriatric Disease, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 2Chaoyang Second Retired Cadre Rest Center of Beijing Garrison, Beijing, 100853, People’s Republic of China; 3Department of Geriatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Neurosurgery, the First Medical Centre, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 5Department of Neurology, Xinzhou People’s Hospital, Shanxi, 034000, People’s Republic of China; 6Department of Otolaryngology, Head and Neck Surgery, Children’s Hospital of Hebei Province, Shijiazhuang, Hebei, 050000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ya Gao; Guofeng Yang, Department of Geriatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email elegance86@163.com; gf_yanghb@126.comIntroduction: Alzheimer’s disease (AD) is the most common type of dementia, impacting approximately 50 million individuals globally. However, the current treatments available for AD are only symptomatic and have limited efficacy. This study aimed to investigate whether Leonurine could alleviate cognitive dysfunction in a mouse model of AD and explore its underlying molecular mechanisms.Methods: In this study, male APP/PS1 mice were orally administered Leonurine for two consecutive months. The cognitive functions of the mice were then evaluated using novel object recognition (NOR) and Morris water maze (MWM) tests. Hippocampal neuronal damage was observed through Nissl staining, Aβ levels were determined through ELISA, oxidative stress activity was detected through biochemical methods, and the nuclear factor erythroid-2-related factor 2 (Nrf-2) pathway was analyzed using western blot and real-time quantitative polymerase chain reaction analysis.Results: Our results demonstrated that Leonurine treatment markedly improved cognitive functions, as indicated by the improved performance in the model. Additionally, histopathology showed a reduction in hippocampal neuronal damage. This can be attributed to the potential of Leonurine to reduce Aβ 1-40 and Aβ 1-42 levels and alleviate oxidative stress. Its antioxidant effect is linked to the activation of the Nrf-2 signaling pathway in APP/PS1 mice, which promotes Nrf-2 nuclear translocation and expression of HO-1 and NQO-1.Conclusion: These findings suggest that Leonurine could be explored further as it could emerge as a promising drug for AD treatment.Keywords: Alzheimer’s disease, cognitive deficit, Leonurine, Nrf-2, oxidative stress

Guanyu Yang,&ast; Pin Zhang,&ast; Liumei Li, Jingjing Wang, Pengfei Jiao, Jie Wang, Qinjun Chu Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinjun Chu, Tongbai North Road 16, Zhongyuan District, Zhengzhou, Henan, People’s Republic of China, Tel/Fax +86 13643711142, Email mzk123456@zzu.edu.cnPurpose: This study aims to compare the conventional lung protective ventilation strategy (LPVS) with driving pressure-guided ventilation in obese patients undergoing laparoscopic sleeve gastrectomy (LSG).Methods: Forty-five patients undergoing elective LSG under general anesthesia were randomly assigned to the conventional LPVS group (group L) or the driving pressure-guided ventilation group (group D) using random numbers generated by Excel. The primary outcome was the driving pressure of both groups 90 min after pneumoperitoneum.Results: After 30 min of pneumoperitoneum, 90 min of pneumoperitoneum, 10 min of closing the pneumoperitoneum, and restoring the supine position, the driving pressure of group L and group D were 20.0 ± 2.9 cm H2O vs 16.6 ± 3.0 cm H2O (P < 0.001), 20.7 ± 3.2 cm H2O vs 17.3 ± 2.8 cm H2O (P < 0.001), and 16.3 ± 3.1 cm H2O vs 13.3 ± 2.5 cm H2O (P = 0.001), respectively; the respiratory compliance of groups L and D were 23.4 ± 3.7 mL/cm H2O vs 27.6 ± 5.1 mL/cm H2O (P = 0.003), 22.7 ± 3.8 mL/cm H2O vs 26.4 ± 3.5 mL/cm H2O (P = 0.005), and 29.6 ± 6.8 mL/cm H2O vs 34.7 ± 5.3 mL/cm H2O (P = 0.007), respectively. The intraoperative PEEP in groups L and group D was 5 (5– 5) cm H2O vs 10 (9– 11) cm H2O (P < 0.001).Conclusion: An individualized peep-based driving pressure-guided ventilation strategy can reduce intraoperative driving pressure and increase respiratory compliance in obese patients undergoing LSG.Keywords: lung protective ventilation strategy, driving pressure-guided ventilation, respiratory compliance, driving pressure, obese

Yefu Yu,1,&ast; Guier Yang,2,&ast; Yanan Wang,1 Faxiang Jin,1 Huiyu Wang,1 Zhongqiang Yu,3 Lanqing Li,4 Xiangcheng Li,4 Junshun Gao,4 Wenfang Xu1 1Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University, Shaoxing, 312000, People’s Republic of China; 2Emergency Ward of Affiliated Hospital of Shaoxing University, Shaoxing, 312000, People’s Republic of China; 3Department of Imaging, Affiliated Hospital of Shaoxing University, Shaoxing, 312000, People’s Republic of China; 4Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, 310016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenfang Xu, Department of Clinical Laboratory, Affiliated Hospital of Shaoxing University, 999 Zhongxing South Road, Yuecheng District, Shaoxing, People’s Republic of China, Tel +8613857589470, Email 0052019050@usx.edu.cn Junshun Gao, Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 3 Qingchun East Road, Shangcheng District, Hangzhou, People’s Republic of China, Email gjs_919@zuaa.zju.edu.cnBackground: Actinomadura geliboluensis was first isolated in 2012 in Gelibolu, Canakkale, Turkey, and has not been reported to be isolated from humans until now. We have isolated it from the bronchoalveolar lavage fluid (BLF) of a patient with pneumonia and found its drug resistance. It is the first time that Actinomadura geliboluensis has been isolated from humans since its discovery and naming. This case may provide new ideas and methods for the clinical diagnosis and treatment of pulmonary actinomycosis.Case Description: The patient was a 75-year-old male who was hospitalized in a township hospital and failed to improve after penicillin treatment. After admission to our hospital, the patient was treated with piperacillin/tazobactam according to clinical guidelines for 14 days. Actinomadura geliboluensis was isolated from the patient’s BLF and was identified by 16S rRNA sequencing. This report shows the biological characteristics and in vitro drug susceptibility testing, as well as the genomics analysis based on next-generation sequencing (NGS). The results demonstrated that Actinomadura geliboluensis was easy to be mistakenly identified as Actinomyces dental caries by using the Merieux ANC identification card. Based on the MIC test, Actinomadura geliboluensis was susceptible to tetracyclines, quinolones and sulfonamides, but resistant to carbapenems, penicillins and cephalosporins. The K-B test results showed Actinomadura geliboluensis was highly sensitive to piperacillin/tazobactam. Genomic analysis based on NGS showed that the Actinomadura geliboluensis belongs to Planobispora rosea EF-Tu mutants conferring resistance to inhibitor GE2270A, AAC(3)-VIIa, vanRO, chrB, and mexY.Conclusion: Actinomycetes is generally sensitive to Penicillin but Actinomadura geliboluensis is not. In vitro drug susceptibility test is needed to support individualized drug use to avoid delay in the disease.Keywords: Actinomadura geliboluensis, pulmonary actinomycosis, antibiotic resistance, next generation sequencing, genomics

Guang Yang,1,2,&ast; Lishan Tan,1,&ast; Hua Yao,3 Zuying Xiong,1 Jun Wu,4,5 Xiaoyan Huang1 1Division of Renal Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, 518000, People’s Republic of China; 2Department of Life Sciences, Yuncheng University, Yuncheng, 044006, People’s Republic of China; 3Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical College, Guilin, 541004, People’s Republic of China; 4Department of Burn and Plastic Surgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China; 5Human Histology & Embryology Section, Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, Verona, Venetia, 37134, Italy&ast;These authors contributed equally to this workCorrespondence: Xiaoyan Huang; Jun Wu, Email huangxiaoyan@pku.org.cn; junwupro@126.comAbstract: Burns are a seriously underestimated form of trauma that not only damage the skin system but also cause various complications, such as acute kidney injury (AKI). Recent clinical studies have shown that the proportion of chronic kidney diseases (CKD) in burn patients after discharge is significantly higher than that in the general population, but the mechanism behind this is controversial. The traditional view is that CKD is associated with hypoperfusion, AKI, sepsis, and drugs administered in the early stages of burns. However, recent studies have shown that burns can cause long-term immune dysfunction, which is a high-risk factor for CKD. This suggests that burns affect the kidneys more than previously recognized. In other words, severe burns are not only an acute injury but also a chronic disease. Neglecting to study long-term kidney function in burn patients also results in a lack of preventive and therapeutic methods being developed. Furthermore, stem cells and their exosomes have shown excellent comprehensive therapeutic properties in the prevention and treatment of CKD, making them increasingly the focus of research attention. Their engineering strategy further improved the therapeutic performance. This review will focus on the research advances in burns on the development of CKD, illustrating the possible mechanism of burn-induced CKD and introducing potential biological treatment options and their engineering strategies.Keywords: inflammation, acute kidney injury, chronic kidney diseases, stem cells, exosomes, sepsis, cytokine storm

Po Li,1 Zhiyong Dong,2 Wenhui Chen,2 Gang Yang1 1Department of General Surgery, Second People’s Hospital of Zhangye City, Zhangye, 734000, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaCorrespondence: Gang Yang, Department of General Surgery, Second People’s Hospital of Zhangye City, No. 270 Linsong West Street, Binhe New District, Ganzhou District, Zhangye, Gansu, People’s Republic of China, Tel +86 1899361927, Fax +0936 8215086, Email yg8755@126.com Wenhui Chen, Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, No. 613 Huangpu Avenue West, Guangzhou, People’s Republic of China, Tel +86 13129349492, Fax +86 20 38688608, Email jnucwh2019@163.comBackground: Previous studies of obstructive sleep apnea (OSA) in relation to stroke have been noted. However, the exact causality remains to be clearly defined. We aimed to adopt a two-sample Mendelian randomization study to investigate the causal effects of OSA on stroke and its subtypes.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of OSA on stroke and its subtypes, including, based on publicly genome-wide association studies (GWAS) databases. The inverse variance weighted (IVW) method was used as the main analysis. MR-Egger regression, weighted mode, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed methods and were adopted as supplementary analysis to ensure the robustness of the results.Results: Genetically predicted OSA was not related to the risk of stroke (odds ratio (OR), 0.99, 95% CI, 0.81– 1.21, p = 0.909), and its subtypes, ischemic stroke (IS) (OR, 1.01, 95% CI, 0.82– 1.23, p = 0.927), large vessel stroke (LVS) (OR, 1.05, 95% CI, 0.73– 1.51, p = 0.795), cardioembolic stroke (CES) (OR, 1.03, 95% CI, 0.74– 1.43, p = 0.855), small vessel stroke (SVS) (OR, 1.13, 95% CI, 0.88– 1.46, p = 0.329), lacunar stroke (LS) (OR, 1.07, 95% CI, 0.74– 1.56, p = 0.721) as well as intracerebral hemorrhage (ICH) (OR, 0.37, 95% CI = 0.09, 1.48, p = 0.160) (Wald ratio method). Other supplementary MR methods also confirmed similar results.Conclusion: There may be no direct causal relationship between OSA and stroke or its subtypes.Keywords: obstructive sleep apnea, stroke, Mendelian randomization, causal association

Jin Lei,1,&ast; Sibo Yang,1,&ast; Bowen Chen,2,&ast; Linzhi Zhang,3 Tao Yan,3 Gangqi Yang,1 Yue Chen,1 Yinyin Li,3 Yinying Lu,1,3,4 Shi Zuo1,5 1School of Clinical Medicine, Guizhou Medical University, Guiyang, People’s Republic of China; 2 302 Clinical Medical School, Peking University, Beijing, People’s Republic of China; 3Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China; 4Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua, Beijing, People’s Republic of China; 5Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yinying Lu; Shi Zuo, Tel +86 13301256799 ; +86 13908516978, Email luyinying1973@163.com; drzuoshi@gmc.edu.cnBackground: Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC).Methods: The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated.Results: Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3– 4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238).Conclusion: The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.Keywords: hepatitis C virus, hepatitis C virus reactivation, hepatocellular carcinoma, tyrosine kinase inhibitor, programmed death-1 inhibitor

Aifan Li,1,&ast; Tianyi Han,2,&ast; Yongfang Li,1 Gaiqing Yang,3 Yuchao Zhang,4 Yanyang Huang,2 Baixue Zhou,2 Guoying Song,2 Ying He2 1Department of Neurology, The First People’s Hospital of Zhengzhou, Zhengzhou, 450000, People’s Republic of China; 2Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China; 3Department of Geriatric Medicine, the Center Hospital of Zhengzhou Affiliated Zhengzhou University, Zhengzhou, 450004, People’s Republic of China; 4Department of Genetics, First Affiliated Hospital of Xinxiang Medical College, Xinxiang, 453100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying He; Guoying Song, Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China, Tel +86-13938517041 ; +86-13633827880, Email heying39@163.com; songguoying226@zzu.edu.cnBackground and Purpose: Studies have shown that matrix metalloproteinase (MMP-2,3,9) plays an important role in the pathologic process of ischemic stroke (IS). The aim of this study was to investigate the relationship between C1306T, 1612– 5A/6A, C-1562T polymorphisms of MMP-2,3,9 genes and IS in Chinese Han population.Methods: The polymorphisms of MMP-2(C1306T), − 3(1612– 5A/6A), − 9(C-1562T) gene were detected by PCR-RFLP and SNaPshot sequencing. Then, stratified analysis was used to study the relationship between IS subtypes and MMP-2,3,9 polymorphisms.Results: For the MMP-2 gene C1306T polymorphism, TT genotype and T allele were significantly associated with a reduced risk of IS (P = 0.015, P = 0.003, respectively). T allele was significantly associated with a reduced risk of small artery occlusion (SAO) subtype compared with the control group (P = 0.012, OR = 0.550, 95% CI = 0.065– 1.291). For the MMP-3 gene-1612 (5A/6A) polymorphism, 5A/5A genotype was significantly increased in the IS group (P = 0.011, OR = 0.370, 95% CI = 0.168– 0.814), especially in the large-artery atherosclerosis (LAA) subtype (P = 0.001, OR = 2.345) as compared to the control group.Conclusion: Our study suggested that the T allele of MMP-2 may be a protective factor of IS, especially in SAO subtype, while the 5A/5A gene of MMP-3 may increase the risk of IS, especially in LAA subtype in Chinese Han population.Keywords: ischemic stroke, matrix metalloproteinase, polymorphism, association study

Mengnan Li,1,2 Jian Zhang,1,2 Guimei Yang,1,2 Jiaxin Zhang,1,2 Minmin Han,1,2 Yi Zhang,3 Yunfeng Liu1 1Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Yi Zhang, Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China, Email yizhang313@163.com Yunfeng Liu, Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Tel +86 18703416196, Email nectarliu@163.comAbstract: Pituitary adenomas have recently become more common and their incidence is increasing yearly. Functional pituitary tumors commonly secrete prolactin, growth hormones, and adrenocorticotropic hormones, which cause diseases such as prolactinoma, acromegaly, and Cushing’s disease, but rarely secrete luteinizing, follicle-stimulating, thyroid-stimulating, and melanocyte-stimulating hormones. In addition to the typical clinical manifestations of functional pituitary tumors caused by excessive hormone levels, some pituitary tumors are also accompanied by abnormal glucose metabolism. The effects of these seven hormones on glucose metabolism are important for the treatment of diabetes secondary to pituitary tumors. This review focuses on the effects of hormones on glucose metabolism, providing important clues for the diagnosis and treatment of related diseases.Keywords: pituitary adenoma, glucose metabolism, prolactin, growth hormones, glucocorticoids

Meijing Shen,&ast; Xianghao Chen,&ast; Jingyue He, Lin Xiong, Rengui Tian, Guangwu Yang, He Zha, Kaifeng Wu Department of Laboratory Medicine, the First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kaifeng Wu; He Zha, Department of Laboratory Medicine, the First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, People’s Republic of China, Email kiphoonwu@126.com; zhahe666@126.comPurpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has seriously threatened public health worldwide. This study aimed to investigate the antimicrobial resistance patterns, sequence types (STs), virulence and carbapenemase genes of CRKP isolates from patients in Zunyi, China.Methods: CRKP isolates were collected from the First People’s Hospital of Zunyi between January 2018 and December 2020. Antimicrobial susceptibility was determined using a VITEK® 2 analyzer and confirmed using either the broth dilution method, Kirby–Bauer method, or E-test assays. Carbapenemase production was examined using a modified carbapenem inactivation method. STs of the studied isolates were determined by multilocus sequence typing, and the presence of carbapenemase and virulence genes was examined using polymerase chain reaction assays.Results: In total, 94 CRKP isolates were collected. All studied isolates produced carbapenemase, and the most common carbapenemase gene was New Delhi metallo-β-lactamase (NDM; 72.3%), followed by Klebsiella pneumoniae carbapenemase (KPC; 24.5%), and Verona integron-encoded metallo-β-lactamase (VIM; 3.2%). Of the studied isolates, 74.3% exhibited multidrug-resistant (MDR) phenotype, and 25.7% were either pandrug-resistant (PDR) or extensively drug-resistant (XDR) phenotypes. The most prevalent sequence type was ST2407 (37.2%), followed by ST76 (21.3%) and ST11 (11.7%). The NDM gene was present in 97.1% of ST2407 isolates and 90.0% of ST76 isolates, whereas the KPC gene was present in 90.9% of ST11 isolates. The majority of the isolates carried wabG, uge, and fimH virulence genes, with prevalence rates of 94.7%, 92.6%, and 94.7%, respectively.Conclusion: This study describes NDM-producing ST2407 and ST76, as well as KPC-producing ST11, as the major clonal types of CRKP isolates in Zunyi, China. All CRKP isolates were resistant to multiple types of antibiotics, and the majority of isolates carried carbapenemase and virulence genes. Clonal spread of NDM-producing CRKP ST2407 and ST76, and KPC-producing CRKP ST11 should be strictly monitored.Keywords: Klebsiella pneumoniae, antimicrobial resistance patterns, virulence genes, sequence types, carbapenemase genes

Hui Zhang,1,&ast; Guizhao Yang,1,&ast; Rongqiong Jiang,1 Dan Feng,1 Yuqin Li,1 Yong Chen,2 Guohua Yuan1 1Institute of Rheumatism and Immunology, the Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of Rheumatism and Immunology, the People’s Hospital of Jianyang City, Jianyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohua Yuan, Institute of Rheumatism and Immunology, the Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China, Tel +8615983777907, Fax +8608172262301, Email ghyuan1981@139.comPurpose: Rheumatoid arthritis (RA) is a systemic inflammatory disorder with unknown etiology. Oxidative stress and immune imbalance play a critical role in the pathogenesis of rheumatoid arthritis. Bilirubin has recently been recognized as a potent antioxidant as well as an immunomodulatory agent of physiological importance. The aim of this study was to explore whether increased bilirubin concentrations are correlated with good clinical prognosis of rheumatoid arthritis.Patients and Methods: In this cross-sectional study, we included 197 healthy individuals and 197 RA patients in the Affiliated Hospital of North Sichuan Medical College from October 2020 to February 2022. The latter were classified into three classes of disease activity according to DAS28-ESR: remission and low (DAS28-ESR< 3.2), moderate (3.2≤DAS28-ESR≤ 5.1), and high (DAS28ESR> 5.1). Based on the clinical and laboratory data, we evaluated the association of bilirubin levels with disease activity in RA using multivariable ordered logistic regression.Results: The levels of total bilirubin and total bilirubin/albumin ratio were significantly lower (P < 0.001; P < 0.001) in RA patients compared with healthy controls. In RA patients, Spearman’s rank correlation analysis revealed that bilirubin and total bilirubin/albumin ratio were negatively correlated with disease activity and inflammatory marker (C-reactive protein, erythrocyte sedimentation rate, Interleukin-6). In multivariable ordered logistic regression, higher total bilirubin (OR=0.77, 95% CI: 0.67– 0.89, p< 0.001) independently predicted lower disease activity.Conclusion: Bilirubin levels remain associated with a reduction of disease activity, suggesting that bilirubin may be a protective factor for RA aggravation.Keywords: rheumatoid arthritis, bilirubin, bilirubin/albumin ratio, diagnostic marker, multivariate analysis

Guocan Yu,1 Ting Lin,2 Yuehui Yu,3 Peijun Chen,2 Menghan Chen,3 Ying Zhang,4,&ast; Gaoyi Yang4,&ast; 1Zhejiang Tuberculosis Diagnosis and Treatment Center, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Division of Health Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Ultrasound, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhang; Gaoyi Yang, Department of Ultrasound, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, No. 208 East Huancheng Road, Hangzhou, Zhejiang, People’s Republic of China, Email zhangying5201@163.com; yanggaoyi8@163.comPurpose: To evaluate the accuracy of Mycobacterium tuberculosis (MTB)-RNA in the rapid diagnosis of lymph node tuberculosis (LNTB). Moreover, the difference in the diagnostic accuracy of MTB-RNA using different specimens was determined.Methods: We included patients with suspected LNTB who met the inclusion criteria and retrospectively analyzed their clinical data. The sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and area under the curve (AUC) of MTB-RNA and culture were calculated and its diagnostic accuracy for LNTB was evaluated in comparison with the final clinical diagnosis.Results: Overall, 285 patients were included in the study. The overall sensitivity, specificity, PPV, NPV, and AUC of MTB-RNA were 40.6%, 100.0%, 100.0%, 17.0%, and 0.70, respectively. These values were 30.8%, 100.0%, 100.0%, 16.0%, and 0.65, respectively, for tissue specimens; 34.2%, 100.0%, 100.0%, 24.6%, and 0.67, respectively, for puncture specimens; and 57.14%, 100.0%, 100.0%, 5.3%, and 0.79, respectively, for pus specimens. These values of culture were 24.4%, 100.0%, 100.0%, 13.9%, and 0.62, respectively, for all specimens; 17.6%, 100.0%, 100.0%, 13.8%, and 0.59, respectively, for tissue specimens; 25.3%, 100.0%, 100.0%, 22.4%, and 0.63, respectively, for puncture specimens; and 31.0%, 100.0%, 100.0%, 3.3%, and 0.65, respectively, for pus specimens.Conclusion: The diagnostic efficacy of MTB-RNA for the rapid diagnosis of LNTB was moderate, but its sensitivity was low. The lymph node pus specimens were the most sensitive for MTB-RNA testing, followed by puncture specimens; tissues were the least sensitive. Pus specimens should be preferably obtained in case only this test is to be used for diagnosis.Keywords: LNTB, pus, puncture, tissue, sensitivity, diagnostic accuracy