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Dongdong Chen,1,2,* Surong Qian,3,* Wenjun Qian,3 Miao Wu,3 Xinlong Wang,3 Haitao Shen,1 Xianming Long,4 Ming Ye,1 Yan Gong,3 Gang Chen1 1Department of Neurosurgery& Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China; 2Department of Neurosurgery, The Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu, 214000, People’s Republic of China; 3Department of Rehabilitation Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital Rehabilitation Medical Center, Gusu School, Suzhou, Jiangsu, 215000, People’s Republic of China; 4Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Gong; Ming Ye, Email gongyan200605@126.com; yeming@suda.edu.cnBackground: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that shows promise for the treatment of Parkinson’s disease (PD). However, there is still limited understanding of the optimal stimulation frequencies and whether rTMS can alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Methods: A PD mouse model was induced intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 1 Hz, 5 Hz, and 10 Hz rTMS. The neurological function, survival of dopaminergic neurons, and protein levels of Tyrosine hydroxylase (TH), α-synuclein(α-syn), and brain-derived neurotrophic factor (BDNF) in the striatum were measured to determine the optimal stimulation frequencies of rTMS treatment in PD mice. The levels of melatonin, cortisol, and the circadian rhythm of Brain and muscle ARNT-like 1 (BMAL1) in PD model mice were detected after optimal frequency rTMS treatment. Additionally, KN-93 and Bmal1siRNA interventions were used to verify that rTMS could alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Results: Administration of 10 Hz rTMS significantly improved neurological function, increased the protein levels of TH and BDNF, and inhibited abnormal aggregation of a-syn. Furthermore, administration of 10 Hz rTMS regulated the secretion profile of cortisol and melatonin and reversed the circadian arrhythmia of BMAL1 expression. After the KN-93 intervention, the MPTP+rTMS+KN-93 group exhibited decreased levels of P- Ca2+/calmodulin-dependent protein kinase II (CaMKII)/CaMKII, P-cAMP-response-element-binding protein (CREB)/CREB, BMALI, and TH. After Bmal1siRNA intervention, the protein levels of BMAL1 and TH were significantly reduced in the MPTP+10 Hz+ Bmal1siRNA group. At the same time, there were no significant changes in the proportions of P-CaMKIIα/CaMKIIα and P-CREB/CREB expression levels. Finally, immunohistochemical analysis showed that the number of TH-positive neurons was high in the MPTP+10 Hz group, but decreased significantly after KN-93 and Bmal1siRNA interventions.Conclusion: Treatment with 10 Hz rTMS alleviated MPTP-induced PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. This study provides a comprehensive perspective of the therapeutic mechanisms of rTMS in PD.Keywords: Parkinson’s disease, transcranial magnetic stimulation, brain and muscle ARNT-like 1, Ca2+/calmodulin-dependent protein kinase II, cAMP-response-element-binding protein

Juncai Lv,1,* Weiwei Yan,1,* Ran Zhang,1 Xi Chen,1,2 Ziyuan Ren,1,2 Dawei Chen,1 Jinming Yu1 1Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 2Cheeloo College of Medicine, Shandong University Cancer Center, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinming Yu; Dawei Chen, Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China, Tel +86-531-8798-4777, Fax +86-531-8798-4079, Email sdyujinming@163.com; dave0505@yeah.netPurpose: There exists a dearth of research concerning non-small cell lung cancer (NSCLC) patients experiencing overall progressive disease concomitant with shrinking lesions after immunotherapy. This is a special type of mixed response. We aim to evaluate the clinical characteristics and treatment options of these patients during immunotherapy.Patients and Methods: We categorized patients into two groups: Progressive Disease with Mixed Responses (PDMR) (n = 31) and Progressive Disease with None Mixed Responses (PDNMR) (n = 144), depending on whether at least one target lesion had shrunk by ≥ 30% at the point of overall progression. Computed tomography scans and magnetic resonance imaging were utilized to evaluate the clinicopathological significance of these patients, and a multivariate analysis was conducted to scrutinize the clinical characteristics and prognosis-influencing factors in these patients.Results: Patients in the PDMR group had worse staging and a greater proportion of previous radiotherapy. The median overall survival (mOS 22 vs 36.4 months; P = 0.019) and median progression-free survival (mPFS 5.83 vs 9.03 months; P = 0.031) of the PDMR group were shorter than PDNMR group. Longer subsequent OS with continued immunotherapy after PDMR compared with patients who do not continue with immunization after PDMR (mOS 23.9 vs 6.5 months; P = 0.024).Conclusion: PDMR was primarily observed in stage IV patients and previously irradiated patients. OS and PFS were inferior in patients with PDMR compared to patients with PDNMR. The continuation of immunotherapy in PDMR patients could extend their survival.Keywords: non-small cell lung cancer, immunotherapy, mixed response, progression

Zhuying Zhang,1,2,* Mai Shi,1,2,* Jinghui Li,3 Dian Chen,1,2 Jie Ren,1,2 Zhenghui Li,1,2 Hsiaohan Tuan,1,2,* Yi Zhao1,2,* 1Department of Dermatology, Beijing Tsinghua Changgung Hospital, Beijing, People’s Republic of China; 2Photomedicine Laboratory, Institute of Precision Medicine, Tsinghua University, Beijing, People’s Republic of China; 3School of Medicine, Tsinghua University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zhao; Hsiaohan Tuan, Department of Dermatology, Beijing Tsinghua Changgung Hospital, No. 168 Litang Road, Changping District, Beijing, 102218, People’s Republic of China, Tel +86-13718646181 ; +86-18610015166, Email zhaoyimd@tsinghua.edu.cn; dxha00337@btch.edu.cnIntroduction: The aging of the skin, which is affected by both external and internal causes, can reflect the external age and the internal health status. While the aging characteristics differ across ethnic groups, the specific changes in skin aging within the Chinese population have been underexplored. Moreover, investigating the similarity of aging skin characteristics between parent-offspring pairs remains uncharted territory. This study aims to fill these gaps by examining the skin aging features of Chinese women and assessing the similarity in aging skin characteristics between mother-daughter pairs.Methods: A total of 40 mother-daughter pairs were recruited and analyzed. The perceived ages of the participants were evaluated, and their aging skin traits were systematically graded. Statistical methods were employed to discern the trends of the aging skin characteristics. By introducing a novel similarity parameter, we compared whether various skin aging characteristics have similar patterns between mothers and daughters.Results: Our findings indicate that age 50 represents a pivotal point in skin aging. Beyond this age, the increase in rhytides and laxity scores accelerated noticeably, whereas the escalation in dyschromia scores became less marked. By introducing similar parameters between mother-daughter pairs and the radar map, we discovered that the skin aging characteristics are remarkably consistent between mother-daughter pairs.Conclusion: Understanding the main aging skin characteristics of different age groups can allow caregivers to devise treatments for preventing skin aging in women of various ages. The mother’s skin aging trend is also significant for the daughter’s skin aging prevention.Plain Language Summary: Skin aging, a complex process influenced by both internal and external factors, exhibits distinct patterns across ethnic groups. Despite this, the specific aging characteristics within the Chinese population and the hereditary similarities between parents and offspring have not been thoroughly investigated. To address this gap, our study focused on the skin aging features of Chinese women and explored the resemblance in these features between mother-daughter pairs. Eighty-seven women from the same community, including 40 mother-daughter pairs, participated in our study. We assessed how old each participant appeared to be and methodically evaluated their skin aging signs by a modified scale. With the introduction of a new similarity parameter, we further examined the extent to which skin aging traits showed parallel trends between mothers and their daughters.Our findings pinpoint age 50 as a pivotal moment in the skin aging trajectory, where the increase in wrinkles and skin laxity becomes more pronounced, contrasting with a deceleration in skin discoloration. Remarkably, a consistent pattern of aging characteristics was observed between mother-daughter pairs, suggesting a potential genetic influence. This study not only sheds light on the specific skin aging patterns among Chinese women but also underscores the significance of genetic factors in shaping these patterns. The insights gained pave the way for developing targeted interventions for skin aging prevention and treatment, emphasizing the importance of considering familial aging trends.Keywords: Chinese female, skin aging pattern, aging characteristics, intergenerational analysis

Jianghao Xiao, Dengkai Chen, Suihuai Yu, Hui Wang, Yiwei Sun, Hanyu Wang, Zhiming Gou, Jingping Wang Key Laboratory of Industrial Design and Ergonomics, Ministry of Industry and Information Technology, Northwestern Polytechnical University, Xi’an, 710072, People’s Republic of ChinaCorrespondence: Jianghao Xiao, Key Laboratory of Industrial Design and Ergonomics, Ministry of Industry and Information Technology, Northwestern Polytechnical University, 127 Youyi West Road, Xi’an, 710072, People’s Republic of China, Tel +86 15528076860, Email xiaojianghao@mail.nwpu.edu.cnPurpose: Exposure to artificial light influences human performance, which is essential for maintaining healthy work and sleep. However, existing research has not explored the intrinsic links between sleep performance and human states over time under prebedtime light exposure interventions (LEIs).Methods: To investigate the time-dependent effects of altered prebedtime light exposure, four LEI groupings (#L1 - #L4) and a Time factor (D8, D9, and D10) were chosen for sleep experiments in enclosed spaces. Forty-eight young adults recruited were available for data analysis. Subjective alertness (SA), negative affect (NA), subjective sleep, and objective sleep were measured via the Karolinska Sleepiness Scale, Positive and Negative Affect Schedule, Next-day Self-assessment Sleep Quality, and joint assessment of wrist actigraphy and sleep diaries, respectively. Statistical analysis was used for the effects of light exposure on the human states (corresponding to the SA and NA) and sleep performance, while the process model helped construct the associations between the two.Results: The statistical effects revealed that the Time had a significant main effect on subjective sleep and changes in prebedtime alertness; the LEI had a significant main effect only on sleep onset latency (SOL). After undergoing altered prebedtime light exposure, the mean SA increased at prebedtime of D9 (p = 0.022) and D10 (p = 0.044); No significant effect on the NA was observed; Mean subjective sleep had a significant increase from D8 to D10. Moreover, five actigraphy-estimated sleep parameters were interrelated. In light of this, a chained pathway relationship was identified. The SOL played a mediating predictor between prebedtime state and objective sleep, which was linked to the awakening state through subjective sleep.Conclusion: Our study suggests that time-dependent effects of altered prebedtime light exposure on sleep performance are associated with human states at prebedtime and awakening, with implications for its prediction of sleep health.Keywords: prebedtime light exposure, sleep performance, non-visual effects, alertness, negative affect, sleep onset latency

Qian Zeng,1 Lu Liu,1 Ying Chen,1 Daohong Chen,1 Ziyang Zhou,1 Wenjiao Hu,1 Siyao Gong,1 Bin He,1 Wenchuan Qi,1,2 Chao Wang,1,3 Zuoqin Yang,4 Shuguang Yu,1,2 Ling Zhao1,2 1Department of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Key Laboratory of Acupuncture for Senile Disease, Chengdu University of Traditional Chinese Medicine, Ministry of Education, Chengdu, People’s Republic of China; 3Sub-health Management Center, Sichuan Integrative Medicine Hospital, Chengdu, People’s Republic of China; 4Department of Acupuncture and Tuina, Chengdu Pidu District Hospital of Traditional Chinese Medicine, Sichuan, People’s Republic of ChinaCorrespondence: Ling Zhao, Department of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu City, Sichuan Province, 611137, People’s Republic of China, Tel +86 28 6180 0000, Email zhaoling@cdutcm.edu.cnBackground: Acupuncture has been used as an adjuvant therapy for Chronic obstructive pulmonary disease (COPD). However, systematic reviews (SRs) and meta-analyses (MAs) have reported inconsistent results and unknown quality. This overview aimed to summarize the current SRs/MAs to provide evidence for the effectiveness and safety of acupuncture in the treatment of COPD.Methods: SRs/MAs were searched via eight databases from their establishment to December 31, 2023. The methodological quality was assessed by A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). The risk of bias was assessed using the Risk of Bias in Systematic Review (ROBIS) tool. The Preferred Reporting Items for Systematic Reviews and Meta-analyses for Acupuncture (PRISMA-A) to evaluate the reporting quality. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to determine the strength of evidence. In addition, we also conducted an analysis of the acupuncture points used in the primary RCTs.Results: Twenty-two SRs/MAs were included in this overview. Based on the assessment using AMSTAR 2, nineteen SRs/MAs were “critically low”. Eight SRs/MAs had a low risk of bias. Based on PRISMA-A, the reporting completeness of eighteen SRs/MAs were more than 70%. As for GRADE assessment, only three outcome measures were of high quality. COPD patients can benefit from moxibustion, acupoint application, acupoint catgut embedding, manual acupuncture, and electroacupuncture, as indicated by effectiveness in measures including lung function, 6MWD, mMRC, CAT, and acute exacerbation. In addition, the efficacy of TENS needed to be further demonstrated. The commonly used acupuncture points in the RCTs include BL13, BL23, and EX-B1.Conclusion: Evidence from SRs showed that acupuncture is beneficial to lung function, acute exacerbation, 6MWD, mMRC and CAT. For SGRQ and brog scale, acupuncture should be used selectively, but this finding should still be taken with caution.Keywords: acupuncture, COPD, systematic reviews, overview

Tiantian Guo,1 Yao Wang,1 Dixuan Chen,2 Sifan Cui,2 Shuyue Guo,1 Yixing Feng,1 Jialin Zhu,1 Luchen Chang,1 Jiawei Zhang,2 Xiujun Gao,2 Xi Wei1 1Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, 300060, People’s Republic of China; 2School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, 300070, People’s Republic of ChinaCorrespondence: Xi Wei, Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, People’s Republic of China, Email weixi@tmu.edu.cn Xiujun Gao, School of Biomedical, Engineering and Technology, Tianjin Medical University, No. 22, Meteorological Station Road, Tianjin, 300070, People’s Republic of China, Email gaoxiujun12242@tmu.edu.cnPurpose: Chemotherapy remains the primary therapeutic approach for advanced Hepatocellular Carcinoma (HCC). The therapeutic effect of chemotherapy is limited and the toxic side effects are serious. The aim of this study is to develop a nanobubble that is ultrasonically responsive to reduce the toxic side effects of direct chemotherapy.Methods: We developed curcumin/doxorubicin-cis-aconitic anhydride-polyethylene glycol nanobubble (C/DCNB) surface modified with acid-sensitive polyethylene glycol (PEG). And it is loaded with curcumin (CUR) and doxorubicin (DOX), as liposomes at the nanoscale for diagnosis and therapy of tumors.Results: In this study, the acid-sensitive PEG on the surface layer of nanobubbles serves to stabilize them in the blood circulatory system and in normal tissues, while peeling off in the acidic tumor microenvironment (pH 6.8). C/DCNB can identify tumor sites through contrast-enhanced ultrasound (CEUS). And ultrasound-mediated nanobubbles promote permeability of the tumor vascular, thus improving the enhanced permeability and retention (EPR) effects in the tumor, leading to the accumulation of nanobubbles in the tumor. After endocytosis of nanobubbles, drugs are released and curcumin generates reactive oxygen species (ROS) under ultrasound conditions. CUR can enhance the sensitivity of tumor cells to DOX by inhibiting the expression of P-glycoprotein. In vitro and vivo experiments demonstrate that C/DCNB can facilitate contrast-enhanced ultrasound imaging while simultaneously delivering drugs, enabling both imaging and treatment.Conclusion: The combination of C/DCNB and ultrasound provides an effective strategy for improving the efficiency of HCC therapy and imaging. Keywords: combination of sonodynamic therapy and chemotherapy, the synergistic effect of two drugs, integration of diagnosis and treatment, ultrasound

Rongping Chen,1,* Jing Li,2,* Danqi Chen,3,* Weiheng Wen,1 Susu Zhang,1 Jitong Li,1 Yuting Ruan,1 Zhen Zhang,1 Jia Sun,1 Hong Chen1 1Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Endocrinology, HuaZhong University of Science and Technology Union ShenZhen Hospital, Guangdong, People’s Republic of China; 3Institute for Prevention and Control of Chronic Noncommunicable Diseases, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Chen; Jia Sun, Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Email chenhong123@smu.edu.cn; sunjia@smu.edu.cnObjective: Several oral antidiabetic regimens are available for treating type 2 diabetes mellitus (T2DM), dipeptidyl peptidase-4 inhibitors (DPP4i) being one of them. We conducted a network meta-analysis (NMA) comparing DPP4i plus metformin (Met) combination with other Met-based oral antidiabetic drug (OAD) combinations used in treating patients with T2DM.Methods: We searched PubMed and Embase from inception until 19th April, 2022 for phase II and phase III trials in patients with T2DM on Met-based traditional OADs. The primary outcome was assessed by change in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour post-prandial blood glucose (2h-PPG). The secondary safety outcomes assessed were hypoglycemic events, serious adverse events (SAEs), cardiovascular (CV) events, and gastrointestinal (GI) events.Results: Sixty-two trials were included in the analysis. The combination of DPP4i + Met revealed a comparable mean reduction in HbA1c levels to the glinides (Gli) + Met combination (mean difference [MD]: − 0.03%, 95% CI: 0.69, − 0.65), although the difference was not statistically significant. The mean HbA1c reduction with DPP4i + Met was greater than with sulfonylureas (SU) + Met (MD: − 0.05, 95% CI: − 0.29, 0.39), thiazolidinedione (TZD) + Met (MD: − 0.69, 95% CI: − 1.39, − 0.02), and SU + TZD (MD: 0.21; 95% CI: − 1.30, 1.71), with no statistical significance. DPP4i + Met demonstrated a non-significant lower incidence of CV events in comparison to TZD + Met (RR: 1.01, 95% CI: 0.46, 2.45) and SU + Met (RR: 1.06, 95% CI: 0.61, 2.06).Conclusion: DPP4i in combination with Met was efficacious and had a well-tolerated safety profile compared with other traditional OADs. This combination can be considered as a suitable treatment option for patients with T2DM.Keywords: dipeptidyl peptidase-4 inhibitors, efficacy, safety, metformin, type 2 diabetes mellitus

Lu Liu,1,* Zili Tang,1,* Qian Zeng,1,* Wenchuan Qi,1 Ziyang Zhou,1 Daohong Chen,1 Dingjun Cai,1– 3 Ying Chen,1 Shiqi Sun,1 Siyao Gong,1 Bin He,1 Shuguang Yu,1– 3 Ling Zhao1– 3 1Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu City, Sichuan Province, People’s Republic of China; 2Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, Sichuan, People’s Republic of China; 3Key Laboratory of Acupuncture for Senile Disease (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu City, Sichuan Province, China*These authors contributed equally to this workCorrespondence: Ling Zhao; Shuguang Yu, College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu City, Sichuan Province, 611137, People’s Republic of China, Tel +86 28 6180 0000, Email zhaoling@cdutcm.edu.cn; ysg28588@126.comBackground: Electroacupuncture (EA), with varying stimulation intensities, has demonstrated therapeutic potentials in both animal and clinical studies for the treatment of chronic obstructive pulmonary disease (COPD). However, a comprehensive investigation of the intensity-related effects, particularly 1mA and 3mA of EA, and the underlying mechanisms remains lacking.Methods: A COPD rat model was established by prolonged exposure to cigarette smoke and intermittent intratracheal instillation of lipopolysaccharide. EA treatment was administered at acupoints BL13 (Feishu) and ST36 (Zusanli), 20 minutes daily for 2 weeks, with intensities of 1mA and 3mA. EA effectiveness was evaluated by pulmonary function, histopathological change, serum level of inflammatory cytokines, and level of oxidative stress markers in serum and lung tissues. Transcriptome profiling and weighted gene co-expression network analysis (WGCNA) were performed to reveal gene expression patterns and identify hub genes. Real-time quantitative PCR (RT-qPCR) and Western blot (WB) were performed to detect the mRNA and protein expression levels, respectively.Results: EA at both 1mA and 3mA exerted differing therapeutic effects by improving lung function and reducing inflammation and oxidative stress in COPD rats. Transcriptome analysis revealed distinct expression patterns between the two groups, functionally corresponding to shared and intensity-specific (1mA and 3mA) enriched pathways. Eight candidate genes were identified, including Aqp9, Trem1, Mrc1, and Gpnmb that were downregulated by EA and upregulated in COPD. Notably, Msr1 and Slc26a4 exclusively downregulated in EA-1mA, while Pde3a and Bmp6 upregulated solely in EA-3mA. WGCNA constructed 5 key modules and elucidated the module–trait relationship, with the aforementioned 8 genes being highlighted. Additionally, their mRNA and protein levels were validated by RT-qPCR and WB.Conclusion: Our results demonstrated that 1mA and 3mA intensities induce distinct gene expression patterns at the transcriptional level, associated with shared and 1mA vs 3mA-specific enriched pathways. Genes Mrc1, Gpnmb, Trem1, and Aqp9 emerge as promising targets, and further studies are needed to elucidate their functional consequences in COPD.Keywords: chronic obstructive pulmonary disease, electroacupuncture, intensity, transcriptome profiling, weighted gene co-expression network analysis

Jie Liu,1,&ast; Xiajie Huang,1,&ast; Hongjie Su,1 Jie Yu,1 Xinyu Nie,1 Kaibing Liu,1 Wencong Qin,1 Yongxin Zhao,1 Yongfeng Su,1 Xiaocong Kuang,2 Di Chen,3 William W Lu,4 Yan Chen,1 Qikai Hua1 1Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Yulin Campus of Guangxi Medical University, Yulin, Guangxi, People’s Republic of China; 3Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 4Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong&ast;These authors contributed equally to this workCorrespondence: Yan Chen; Qikai Hua, Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China, Email cy003@connect.hku.hk; hqk100@yeah.netPurpose: Management of severe diabetic foot ulcers (DFUs) remains challenging. Tibial cortex transverse transport (TTT) facilitates healing and limb salvage in patients with recalcitrant DFUs. However, the underlying mechanism is largely unknown, necessitating the establishment of an animal model and mechanism exploration.Methods: Severe DFUs were induced in rats, then assigned to TTT, sham, or control groups (n=16/group). The TTT group underwent a tibial corticotomy, with 6 days each of medial and lateral transport; the sham group had a corticotomy without transport. Ulcer healing was assessed through Laser Doppler, CT angiography, histology, and immunohistochemistry. Serum HIF-1α, PDGF-BB, SDF-1, and VEGF levels were measured by ELISA.Results: The TTT group showed lower percentages of wound area, higher dermis thickness (all p < 0.001 expect for p = 0.001 for TTT vs Sham at day 6) and percentage of collagen content (all p < 0.001) than the other two groups. The TTT group had higher perfusion and vessel volume in the hindlimb (all p < 0.001). The number of CD31+ cells (all p < 0.001) and VEGFR2+ cells (at day 6, TTT vs Control, p = 0.001, TTT vs Sham, p = 0.006; at day 12, TTT vs Control, p = 0.003, TTT vs Sham, p = 0.01) were higher in the TTT group. The activity of HIF-1α, PDGF-BB, and SDF-1 was increased in the TTT group (all p < 0.001 except for SDF-1 at day 12, TTT vs Sham, p = 0.005). The TTT group had higher levels of HIF-1α, PDGF-BB, SDF-1, and VEGF in serum than the other groups (all p < 0.001).Conclusion: TTT enhanced neovascularization and perfusion at the hindlimb and accelerated healing of the severe DFUs. The underlying mechanism is related to HIF-1α-induced angiogenesis.Keywords: distraction osteogenesis, tibial cortex transverse transport, diabetic foot, HIF-1α, angiogenesis

Jialing Xu,1,2 Hao Zhang,1,2 Dan Chen,2 Kaiyong Xu,1,2 Zifa Li,1,2 Hongyun Wu,3 Xiwen Geng,1,2 Xia Wei,4 Jibiao Wu,1,2 Wenqiang Cui,3 Sheng Wei1,2 1The Key Laboratory of Traditional Chinese Medicine Classic Theory of Ministry of Education, Shandong University of Traditional Chinese Medicine, Ji’nan, Shandong, People’s Republic of China; 2Chinese Medicine and Brain Science Interdisciplinary Research Institute, Shandong University of Traditional Chinese Medicine, Ji’nan, Shandong, People’s Republic of China; 3Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji’nan, Shandong, People’s Republic of China; 4NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Shandong Institute for Food and Drug Control, Ji’nan, Shandong, People’s Republic of ChinaCorrespondence: Sheng Wei, Email weisheng@sdutcm.edu.cn; Wenqiang Cui, Email wqcui16@fudan.edu.cnAbstract: Chronic pain (CP) is a leading cause of disability and a potential factor that affects biological processes, family relationships, and self-esteem of patients. However, the need for treatment of CP is presently unmet. Current methods of pain management involve the use of drugs, but there are different degrees of concerning side effects. At present, the potential mechanisms underlying CP are not completely clear. As research progresses and novel therapeutic approaches are developed, the shortcomings of current pain treatment methods may be overcome. In this review, we discuss the retinal photoreceptors and brain regions associated with photoanalgesia, as well as the targets involved in photoanalgesia, shedding light on its potential underlying mechanisms. Our aim is to provide a foundation to understand the mechanisms underlying CP and develop light as a novel analgesic treatment has its biological regulation principle for CP. This approach may provide an opportunity to drive the field towards future translational, clinical studies and support pain drug development.Keywords: chronic pain, light therapy, photoanalgesia, brain regions, molecular targets

Dexiu Chen,1 Zhangjing Shi,1 Xiaolan Gao,1 Yuxiang Yang,1 Xianying Lei,1,&ast; Yingchun Hu2,&ast; 1Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Emergency Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingchun Hu, Department of Emergency Medicine, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86-830-3165851, Email huyingchun913@swmu.edu.cn Xianying Lei, Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86-830-3165527, Email leixianying310@swmu.edu.cnPurpose: There are no satisfactory diagnostic biomarkers for sepsis. Accordingly, this study screened biomarkers valuable for sepsis diagnosis and prognosis using data-independent acquisition (DIA) combined with clinical data analysis.Patients and Methods: Serine protease inhibitor Kazal-type 1 (SPINK1) is a differentially expressed protein that was screened using DIA and bioinformatics in sepsis patients (n = 22) and healthy controls (n = 10). The plasma SPINK1 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in an expanded population (sepsis patients, n = 52; healthy controls, n = 10). The diagnostic value of SPINK1 in sepsis was evaluated using receiver operating characteristic (ROC) curve analysis based on clinical data. The prognostic value of SPINK1 for sepsis was evaluated using correlation and survival analyses.Results: DIA quality control identified 78 differential proteins (72 upregulated and six downregulated), among which SPINK1 was highly expressed in sepsis. The ELISA results suggested that SPINK1 expression was significantly elevated in the sepsis group (P < 0.05). ROC analysis of SPINK1 yielded an area under the curve (AUC) of 0.9096. Combining SPINK1 with procalcitonin (PCT) for ROC analysis yielded an AUC of 1. SPINK1 expression was positively correlated with the Sequential Organ Failure Assessment (SOFA) score (r = 3497, P = 0.0053) and APACHE II score (r = 3223, P = 0.0106). High plasma SPINK1 protein expression was negatively correlated with the 28-day survival rate of patients with sepsis (P = 0.0149).Conclusion: The plasma of sepsis patients contained increased SPINK1 protein expression. Combining SPINK1 with PCT might have a high diagnostic value for sepsis. SPINK1 was associated with the SOFA score, APACHE II score, and the 28-day survival rate in patients with sepsis.Keywords: serine protease inhibitor Kazal-type 1, sepsis, DIA, PCT, biomarker

Lili Kang,1 Changle Li,1 Duohui Chen,2 Xinxin Bao3 1School of Health Management, Fujian Medical University, Fuzhou, People’s Republic of China; 2College of Public Health Sciences, Chulalongkorn University, Bangkok, Thailand; 3School of Foreign Language Studies, Inner Mongolia Medical University, Hohhot, People’s Republic of ChinaCorrespondence: Xinxin Bao, School of Foreign Language Studies, Inner Mongolia Medical University, Hohhot, 010110, People’s Republic of China, Email 20120027@immu.edu.cnObjective: This study was conducted to identify the factors (especially parental involvement, academic self-efficacy, and depression) associated with academic performance among Chinese K-12 students during the COVID-19 pandemic.Methods: This cross-sectional study used data from the 2020 China Family Panel Studies (CFPS). The CFPS was conducted from July to December 2020 during the COVID-19 pandemic. A multistage probability sample proportional to size was used for the survey. The final sample consisted of 1747 K-12 students. This study used the 14-item Chinese Parental Involvement and Support Scale, the Responsibility Scale, and the 8-item Center for Epidemiologic Studies Depression Scale to measure parental involvement, academic self-efficacy, and depression, respectively. An ordered probit regression and structural equation models were employed to analyze the factors associated with academic performance. A multiple imputation technique was applied to compute missing values in selected variables.Results: We found that parental involvement and academic self-efficacy were positively associated with good academic performance. In contrast, depression was negatively associated with good academic performance. Moreover, academic stress, male, rural residency, middle school, family size, high income, online gaming daily, reading, and intelligence quotient were statistically significant predictors on academic performance.Conclusion: The empirical findings suggested that parental involvement and academic self-efficacy were positively and significantly associated with good academic performance. However, depression was negatively and significantly associated with good academic performance. These results showed that policymakers and practitioners can help improve academic success and address educational inequalities among K-12 students by implementing a series of reforms.Keywords: parental involvement, academic self-efficacy, depression, academic performance, K-12, COVID-19 pandemic, China

Min Jiang,1,&ast; NanNan Pang,2,&ast; Jing Wang,1 Zheng Li,1 Dan Xu,1 Jing Jing,1 Dan Chen,3 Fengsen Li,1 Jianbing Ding,4 Qifeng Li5 1Xinjiang Key Laboratory of Respiratory Disease Research, Traditional Chinese Medical Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830011, Xinjiang, People’s Republic of China; 2CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, People’s Republic of China; 3School of Public Health, Xinjiang Medical University, Urumqi, 830017, Xinjiang, People’s Republic of China; 4Department of Immunology, College of Basic Medicine, Xinjiang Medical University, Urumqi, 830011, Xinjiang, People’s Republic of China; 5Xinjiang Institute of Pediatrics, Xinjiang Hospital of Beijing Children’s Hospital, Children’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830011, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qifeng Li, Xinjiang Institute of Pediatrics, Xinjiang Hospital of Beijing Children’s Hospital, Children’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830054, People’s Republic of China, Tel +86-991 3056239, Fax +86-991 3056237, Email liqiqi521@sina.comBackground: Studying the potential etiology and pathogenesis of tuberculosis-associated chronic obstructive pulmonary disease (TOPD) from an autoimmunity perspective may provide insights into peripheral blood autoantibodies and immune cells, as well as their interactions.Methods: This study examined the serum autoantibody repertoire in healthy individuals, patients with chronic obstructive pulmonary disease (COPD), patients with pulmonary tuberculosis (TB), and TOPD patients using the HuProtTM protein chip. Autoantigens in the peripheral blood of TOPD patients were verified using ELISA assay. Various epitopes and immune simulation were predicted using bioinformatic methods. Flow cytometry was employed to detect macrophages(M&phis;), T cells, and innate lymphoid cells (ILCs) in the peripheral blood.Results: COPD patients displayed distinct alterations in their IgG and IgM autoantibodies compared to the other groups. GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses revealed that these autoantibodies were associated with regulating macrophages, T cells, and B cells. ELISA results confirmed the upregulation of expression of proliferating cell nuclear antigen (PCNA), Mitogen-Activated Protein Kinase 3 antigen (MAPK3), and threonine protein kinase 1 antigen (AKT1) proteins in the peripheral blood of TOPD patients. Bioinformatic analysis predicted multiple potential epitopes in Th, CTL, and B cells. Immune simulation results demonstrated that PCNA, MAPK3, and AKT1 can activate innate and adaptive immune responses and induce the expression of different cytokines, such as IFN-g and IL-2. Furthermore, data obtained from flow cytometry assay revealed an upregulation in the face of Th1 cells in the peripheral blood of TOPD patients.Conclusion: Tuberculosis infection can effectively induce autoimmune responses, contributing to increased expression of Th1 cells and associated cytokines, ultimately leading to immune dysregulation. Furthermore, the accumulation of pulmonary inflammatory response facilitates the progression of TOPD and is helpful for the clinical diagnosis and the development of targeted therapeutic drugs for this disease.Keywords: chronic obstructive pulmonary disease, COPD, autoantibody, autoimmunity, inflammatory phenotype

Jingjie Wu,1 Erxu Xue,1 Siyuan Huang,2 Yujia Fu,3 Dandan Chen,1 Jing Shao,3 Hui Zhang,4 Leiwen Tang,1 Zhihong Ye1 1Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Nursing Department, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 3School of Nursing, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Nursing Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of ChinaCorrespondence: Zhihong Ye, Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd of East Qingchun Road, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +8613606612119, Email 3192005@zju.edu.cnPurpose: A lack of coordinated care leads to multiple adverse effects for older adults with multimorbidity, including high treatment burdens, adverse health outcomes, reduplicated healthcare service utilization, and catastrophic healthcare expenditure. To foster healthy aging, person-centered integrated care that is responsive to older adults has been proposed by the World Health Organization. The objective of this study was to identify factors that impact the successful implementation of integrated care for older adults with multimorbidity in China.Patients and Methods: From July 2022 to May 2023, 33 healthcare providers and managers involved in the delivery and management of healthcare services for older adults with multimorbidity were recruited from Zhejiang Province, China using purposeful and maximum variation sampling methods. Semi-structured, face-to-face in-depth interviews were conducted by the same interviewer in the participants’ native Chinese language until data saturation was reached. Inductive thematic analysis was used to analyze the data, and then, themes were mapped onto six dimensions using the Rainbow Model of Integrated Care to allow for a comprehensive view of the study’s findings.Results: Eleven themes were generated as facilitators and barriers to integrated care for older adults with multimorbidity in China. These themes include (1) clinical integration: patient-centered care, (2) professional integration: interdisciplinary teams and training, (3) organizational integration: resources and accessibility, (4) system integration: community and funds, incentives, and health insurance, (5) functional integration: electronic health record systems, workforce, and guidelines, and (6) normative integration: shared mission.Conclusion: Guided by the Rainbow Model of Integrated Care, various factors at both micro, meso, and macro levels that impact the implementation of integrated care for older adults with multimorbidity in the Chinese context have been identified in this study. The strategies for future interventions and policies should focus on promoting facilitators and addressing barriers.Keywords: delivery of health care, integrated, aged, older adult, multiple chronic conditions, facilitator, barrier

Tingting Tu,1,2,&ast; Dandan Chen,1,2,&ast; Houjun Jiang,1,2,&ast; Jianhua Ma,1,2 Hongwei Wang,1,2 Cheng Chen1,2 1Department of Radiotherapy, Lianyungang Clinical Institute, Jiangsu University (The Second People’s Hospital of Lianyungang), Lianyungang, Jiangsu Province, People’s Republic of China; 2Department of Radiotherapy, Lianyungang Cancer Hospital, Lianyungang, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng Chen, Department of Radiotherapy, Lianyungang Clinical Institute, Jiangsu University (The Second People’s Hospital of Lianyungang), NO. 161 Xingfu Road, Lianyungang, Jiangsu Province, 222023, People’s Republic of China, Tel +86 518 85775191, Email chenchenggood@163.comPurpose: We aim to observe the potential survival benefits of driver gene-guided targeted therapy in advanced non-small cell lung cancer (NSCLC) patients compared to non-targeted therapy. Additionally, the study aims to assess whether Next-generation sequencing technology (NGS)-guided targeted therapy can provide survival advantages for advanced NSCLC patients compared to conventional Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) gene detection.Methods: Clinical data, genetic testing results, and treatment information of 1663 advanced lung cancer patients diagnosed by pathology from January 2013 to June 2019 in Jiangsu University Affiliated Lianyungang Hospital were collected. Propensity score matching survival analysis was used to evaluate the differences in overall survival(OS) between groups.Results: In the unadjusted survival curve, targeted therapy patients had significantly longer median OS than non-targeted therapy patients (28.3 months vs 15.4 months, Hazard ratio (HR) = 0.5426, 95% confidence interval (CI) 0.4768– 0.6176, P < 0.0001); the conclusion was the same after propensity score matching analysis, with targeted therapy group patients having significantly prolonged OS median (27.5 months vs 14.8 months, HR = 0.5572, 95% CI 0.4796– 0.6474, P < 0.0001). In the unadjusted survival curve, the NGS group had a significantly prolonged median OS compared to the conventional gene detection group (23.4 months vs 21.2 months, HR = 1.243, 95% CI = 1.017– 1.519, P = 0.0495). However, after propensity score matching analysis, no statistically significant difference existed in the median OS between the two patient groups (23.1 months vs 21.5 months, HR = 1.288, 95% CI = 0.9557– 1.735, P = 0.0926). Further analysis demonstrated no advantage in the five-, three-, and two-year survival rates of the NGS group compared to conventional gene detection group patients. However, the one-year survival rate of the NGS group was significantly increased (83.2% vs 68.1%, HR = 0.4890, 95% CI = 0.3170– 0.7544, P = 0.0015).Conclusion: Driver gene-guided targeted precision therapy significantly prolonged the median OS of advanced NSCLC patients compared to non-targeted therapy. NGS detection did not improve the median OS of advanced NSCLC patients compared to conventional EGFR/ALK gene detection but increased the one-year survival rate of patients.Keywords: non-small cell lung cancer, NGS, EGFR, ALK, prognosis

Jingjie Wu,1,&ast; Hui Zhang,2,&ast; Jing Shao,3 Dandan Chen,1 Erxu Xue,1 Siyuan Huang,4 Yujia Fu,3 Leiwen Tang,1 Zhihong Ye1 1Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Nursing Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 3Nursing Faculty, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Nursing Department, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihong Ye, Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3th of East Qingchun Road, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +8613606612119, Email 3192005@zju.edu.cnPurpose: To summarize adverse healthcare outcomes experienced by older adults with multimorbidity and barriers perceived by stakeholders regarding the healthcare systems primarily designed to address individual health conditions. Healthcare elements that aim to provide coordinated, continuous, and comprehensive services for this population were also identified.Patients and Methods: We applied the methodology framework developed by Arksey and O’Malley to guide the review. The three-step search strategy was used to identify relevant English reviews that focused on adverse healthcare outcomes and barriers encountered by older adults with multimorbidity and other stakeholders regarding the single-disease-focused healthcare systems, as well as those concentrated on healthcare elements that aim to provide coordinated, continuous, and comprehensive services for older adults with multimorbidity. Five electronic databases, including PubMed/Medline, CINAHL, Web of Science Core Collection, Cochrane Library, and Embase, were systematically searched from database inception to February 2022. A standardized table was used to extract data. Thematic analysis was then conducted under the guidance of the Rainbow Model of Integrated Care and the Chronic Care Model.Results: Twenty reviews were included in this study. Therapeutic competitions, high healthcare service utilization, and high healthcare costs were three adverse healthcare outcomes experienced by patients. Both patients and healthcare professionals faced various barriers. Other stakeholders, including informal caregivers, healthcare managers, and policymakers, also perceived several barriers. Numerous healthcare elements were identified that may contribute to optimized services. The elements most frequently mentioned included the implementation of shared decision-making, comprehensive geriatric assessments, and individual care plans.Conclusion: This study conducted a comprehensive overview of the current knowledge related to healthcare for older adults with multimorbidity. In the future, it is necessary to develop more coordinated, continuous, and comprehensive healthcare service delivery models based on the healthcare needs of older adults with multimorbidity and the specific characteristics of different countries.Keywords: multiple chronic conditions, aging, healthcare service delivery, long-term care, review

Zitian Liang,1,&ast; Ding Chen,2,&ast; Ye Jiang,1 Zhikang Su,2 Yixing Pi,2 Tao Luo,2 Qianzhou Jiang,1 Li Yang,1 Lvhua Guo2 1Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China; 2Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Yang; Lvhua Guo, Affiliated Stomatology Hospital of Guangzhou Medical University, No. 195 West Dongfeng Road, Guangzhou, 510182, People’s Republic of China, Tel +86-020-81299942, Email 2019686001@gzhmu.edu.cn; 2010686002@gzhmu.edu.cnIntroduction: Effective infection control without irritating the pulp tissue is the key to successful vital pulp therapy. Developing a novel antibacterial biomaterial that promotes dentin regeneration for pulp capping is thus a promising strategy for enhancing vital pulp therapy.Methods: Lithium-doped mesoporous nanoparticles (Li-MNPs) were synthesized using an alkali-catalyzed sol-gel method. The particle size, elemental distribution, surface morphology, pore structure, and ion release from Li-MNPs were measured. Human dental pulp stem cells (hDPSCs) and Streptococcus mutans (S. mutans) were used to evaluate the biological effects of Li-MNPs. In addition, a dental pulp exposure mouse model was used to evaluate the regenerative effects of Li-MNPs.Results: Li-MNPs had a larger surface area (221.18 m2/g), a larger pore volume (0.25 cm3/g), and a smaller particle size (520.92 ± 35.21 nm) than MNPs. The in vitro investigation demonstrated that Li-MNPs greatly enhanced the biomineralization and odontogenic differentiation of hDPSCs through the Wnt/β-catenin signaling pathway. Li-MNPs showed a strong antibacterial effect on S. mutans. As expected, Li-MNPs significantly promoted dentin regeneration in situ and in vivo.Conclusion: Li-MNPs promoted dentin regeneration and inhibited S. mutans growth, implying a possible application as a pulp capping agent in vital pulp therapy.Graphical Abstract: Keywords: lithium, mesoporous nanoparticles, dental pulp stem cells, dentin regeneration, Wnt/β-catenin signaling pathway, antibacterial properties

Lin Chen,1,&ast; Qi Zhang,2,&ast; Zheng Huang,1,&ast; Weiwei Da,1 Shuang Liu,1 Chunchun Xue,1 Chao Ding,1 Deta Chen,1 Tianyou Fan,1 Qi Shi,1 Xiaofeng Li1 1Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Traditional Chinese Medicine, Xuhui District Tianping Street Community Health Center, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofeng Li, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Middle Zhijiang Road, Shanghai, 200071, People’s Republic of China, Tel +86-13816504131, Email lixiaofeng0409@163.comPurpose: Non-specific chronic neck pain (NSCNP) is an increasingly common musculoskeletal disease and an important issue in the global healthcare system. Some studies have shown that the combination of manual therapy and exercise is effective in treating NSCNP but still with several limitations. Traditional Chinese manual therapy (tuina) is a Chinese manual therapy that consists of soft tissue manipulation and spinal manipulation. This study aims to design a randomized controlled trial to assess the effect of a tuina combined with specific therapeutic neck exercise modified protocol for NSCNP patients.Patients and Methods: This is a study protocol for a randomized, participant-, assessor- and analyst-blinded controlled trial. Eighty-eight eligible NSCNP patients will be randomly allocated into tuina combined with specific therapeutic neck exercise group (TSTE group) and tuina combined with sham therapeutic neck exercise group (TS group) in a ratio of 1:1. All participants will receive 8 treatment sessions applied in 4 weeks and then be followed up for another 12 weeks. Clinical data will be collected at baseline, during treatment phase (at the 2- and 4-week) and at the 8-, 12-, 16-week follow-ups. The primary outcome is the changes in neck pain intensity (visual analogue scale). The secondary outcomes include neck disability (Neck Disability Index), cervical range of motion (ROM), neck muscle endurance, cervical muscle cross-sectional area, cervical curvature and analgesic consumption. Adverse events will be collected and recorded throughout the study.Conclusion: We will discuss whether our tuina combined with specific therapeutic neck exercise modified protocol is more effective at improving pericervical muscle endurance, ROM, cervical muscle cross-sectional area and cervical curvature than tuina alone, thereby decreases neck pain and disability in individuals with NSCNP more effectively.Trial Registration: Chinese Clinical Trials Registry, ChiCTR2300067903. Registered on 31 January 2023.Keywords: manual therapy, non-specific neck pain, specific therapeutic exercise, randomized controlled trial

Qin Yang,1,2,&ast; Tiantian Tan,2,&ast; Qin He,2 Chenqi Guo,2 Dan Chen,2 Yulu Tan,2 Jiaxing Feng,2 Xu Song,2 Tao Gong,2 Jia Li3 1School of Pharmacy, North Sichuan Medical College, Nanchong 637100, People’s Republic of China; 2Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China; 3West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Li, West China Hospital of Stomatology, Sichuan University, No. 14, Block 3, Southern Renmin Road, Chengdu, 610041, People’s Republic of China, Tel +862885503503, Email lijia816@163.comIntroduction: Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis.Methods: The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid–cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo.Results: Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-β and inhibiting the secretion of α-SMA and collagen I.Conclusion: Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.Keywords: nanosuspension, LX-2 cells, phytomedicines, surfactant, drug delivery system

Zhirou Xiao,1,&ast; Liping Qu,2,&ast; Haijun Chen,1 Wanting Liu,2 Yi Zhan,2 Jiahui Ling,2 Hongwei Shen,3 Ling Yang,1 Dingqiang Chen2 1Department of Laboratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Clinical Laboratory, Shenzhen Hospital of Southern Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Yang, Department of Laboratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China, Tel/Fax +86-20-83062158, Email jykresearch@126.com Dingqiang Chen, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China, Tel/Fax +86-20-62783335, Email jyksys@126.comBackground: Antibiotic resistance represents a serious global health challenge, particularly with the emergence of strains resistant to last-resort antibiotics such as tigecycline, polymyxin B, and vancomycin. Urgent measures are required to alleviate this situation. To facilitate the judicious use of antibiotics, rapid and precise antimicrobial susceptibility testing (AST) is essential. Heavy water (deuterium oxide, D2O)-labeled Raman spectroscopy has emerged as a promising time-saving tool for microbiological testing.Methods: Deuterium incorporation and experimental conditions were examined to develop and apply a Raman-based AST method to evaluate the efficacy of last-resort antibiotics, including tigecycline, polymyxin B, and vancomycin, against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecium. Essential agreement and categorical agreement were used to assess the metabolism inactivation concentration based on Raman spectroscopy (R-MIC)–a new metric developed in this study—and minimum inhibitory concentration (MIC) determined via the traditional microdilution broth method. Spearman’s rank correlation coefficient was employed to measure the association between R-MIC and MIC values.Results: The Raman-based AST method achieved a 100% categorical agreement (92/92) with the traditional microdilution broth method within five hours, while the traditional method required approximately 24 h. The R-MIC values shared 68.5% (63/92) consistency with the MIC values. In addition, the R-MIC and MIC values were highly correlated (Spearman’s r=0.96), resulting in an essential agreement of 100%.Conclusion: Our optimized experimental method and conditions indicate that Raman-based AST holds great promise as a solution to overcome the time-consuming challenges of traditional AST methods.Keywords: Raman spectroscopy, tigecycline resistant, polymyxin B resistant, vancomycin resistant, antimicrobial susceptibility testing

Yu-Qing Sun,1 Qiang Lv,1 Dong Chen,2 Yuwei Da,3 Xiao-Yan Zhao,4 Jian-Zeng Dong1 1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung & Blood Vessel Diseases, Beijing, People’s Republic of China; 2Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung & Blood Vessel Diseases, Beijing, People’s Republic of China; 3Department of Neurology, Beijing Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Cardiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Jian-Zeng Dong, Email jz_dong@126.comAbstract: The clinical manifestations of Danon disease, which result from the primary deficiency of the lysosome-associated membrane protein 2 gene, include cardiomyopathy, skeletal myopathy, and different degrees of intellectual disability that vary greatly among patients. The present study reports on two cases of Danon disease in two patients who only presented cardiac symptoms. Cardiac symptoms usually occur in adolescence and during a patient’s twenties, and most patients die from heart failure. However, the lab results from these cases suggested that other systems were involved, despite no other clinical symptoms. Significantly, the two patients had elevated serum cardiac troponin I, which often manifests in the acute cardiac phase, especially in severely affected patients with rapidly fatal outcomes. Danon disease is a multi-system involvement disease. Therefore, clinicians must be aware of its complexity when evaluating newly diagnosed patients due to its vastly different clinical course and prognosis and the importance of multidisciplinary management.Keywords: Danon disease, cardiomyopathy, serum cardiac troponin I, management

Diming Wang,1,&ast; Wei Ye,2,&ast; Dongmei Chen,1 Qingming Shi,1 Dongchun Ma3 1Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China; 2Department of Pathology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China; 3Department of Thoracic Surgery, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongchun Ma, Department of Thoracic Surgery, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China, Email madongchun126@126.com Qingming Shi, Department of Oncology, Anhui Chest Hospital, Hefei, 230022, People’s Republic of China, Email shqm0324@163.comAbstract: The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with epidermal growth factor (EGFR) receptor tyrosine kinase inhibitors (TKIs) is a relatively common phenomenon. However, transformation of non-small cell lung cancer (NSCLC) to SCLC following treatment with immunotherapy is very rare. Here, we report a case of a 56-year-old patient diagnosed with driver gene mutation-negative lung squamous cell carcinoma (SCC). He received four cycles of immunotherapy with sugemalimab and chemotherapy with albumin paclitaxel in combination with carboplatin, and a partial response was achieved. Subsequently, the patient received 5 cycles of immunotherapy with sugemalimab. However, he developed rapid progression of mediastinal lymph nodes, and biopsy results showed transformation to SCLC. His tumor did not respond to the next line of carboplatin combined with etoposide, and he died six months after the discovery of SCLC transformation. In conclusion, SCLC transformation is also an important resistance mechanism for lung SCC patients treated with immunotherapy and predicts a very poor outcome. Repeat biopsy is needed for advanced lung SCC that has progressed with immunotherapy.Keywords: lung squamous cell carcinoma, immunotherapy, small cell transformation

Zhongji Wu,1,&ast; Xiaowen Chen,1,&ast; Kangkang Zhang,1 Zhenwei Liu,1 Haidi Zhang,1 Zhaocong Zheng,2 Xiaodie Zhang,2 Yubiao Chen,3 Yinghui Peng,1 Hui Li,1 Kaiyin Huang,1 Sixiang Tang,1 Li Zhao,1 Dehui Chen1 1The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, People’s Republic of China; 2Guangzhou Medical University, Guangzhou, 510000, People’s Republic of China; 3State Key Laboratory of Respiratory Diseases, Guangzhou, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dehui Chen, 151 Yanjiang West Road, Yuexiu District, Guangzhou City, Guangdong Province, 510000, People’s Republic of China, Tel +86 13922732810, Email dehuichen84@126.comBackground: Bronchiolitis obliterans (BO) is a chronic disease that can arise as a complication of severe childhood pneumonia and can also impact the long-term survival of patients after lung transplantation. However, the precise molecular mechanism underlying BO remains unclear. We aimed to identify BO-associated hub genes and their molecular mechanisms.Methods: BO-associated transcriptome datasets (GSE52761, GSE137169, and GSE94557) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Additional bioinformatics analyses, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) analyses, were performed to determine functional roles and DEG-associated regulatory networks. Prediction of hub genes using the 12 algorithms available in the Cytohubba plugin of Cytoscape software was also performed. Verification was performed using the BO mouse model.Results: Our results revealed 57 DEGs associated with BO, of which 18 were down-regulated and 39 were up-regulated. The Cytohubba plugin data further narrowed down the 57 DEGs into 9 prominent hub genes (CCR2, CD1D, GM2A, TFEC, MPEG1, CTSS, GPNMB, BIRC2, and CTSZ). Genes such as CCR2, TFEC, MPEG1, CTSS, and CTSZ were dysregulated in 2,3-butanedione-induced BO mice, whereas TFEC, CTSS, and CTSZ were dysregulated in nitric acid-induced BO mouse models.Conclusion: Our study identified and validated four novel BO biomarkers, which may allow further investigation into the development of distinct BO diagnostic markers and novel therapeutic avenues.Keywords: bronchiolitis obliterans, biomarkers, pathways, transcriptome, therapeutic targets

Wanhong Peng,1,2,&ast; Si Wang,1,&ast; Minglan Yu,1 Tingting Wang,1 Rongfang He,1 Dongmei Liu,3 Dechao Chen,3 Xuemei Liang,1 Kezhi Liu,1 Bo Xiang1 1Department of Psychiatry, Laboratory of Neurological Diseases and Brain Function, Medical Laboratory Center, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 2The Fourth People’s Hospital of Chengdu, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Psychiatry, Yibin Fourth People’s Hospital, Yibin, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Xiang; Kezhi Liu, Department of Psychiatry, Laboratory of Neurological Diseases and Brain Function, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China, Tel +86-08303165019, Email xiangbo@swmu.edu.cn; kingzliu@163.comObjective: Although electroconvulsive therapy (ECT) has been employed as an effective treatment strategy and to improve mental symptoms in schizophrenia (SCZ), its action mechanisms remain unclear. Our previous study found that some genes and biological pathways were closely related to ECT through genetic technology analysis, such as LTP pathway and EP300. This study combined with healthy controls and symptomatology analysis to further explore the changes of expression of EP300 protein in treatment and related symptoms of SCZ.Methods: One hundred and one patients with SCZ and 45 healthy controls (HCs) were enrolled in this study. Patients with SCZ received acute courses of 6 times bilateral ECT. The peripheral blood of patients with SCZ (BECT: before ECT; AECT: after ECT) and the HCs was collected to calculate the changes of expression level of EP300 protein by enzyme-linked immunosorbent assay. The Positive and Negative Symptoms Scale (PANSS) was used to evaluate the severity of symptoms of SCZ patients and the efficiency of the ECT.Results: There was a statistical difference of EP300 protein expression in patients with SCZ (BECT and AECT) (F = 114.5, p < 0.05). ECT reduced plasma expression level of EP300 protein in patients with SCZ, which was not statistically different from that in HCs (t = 4.47, p = 0.20). The change of the expression level of EP300 protein in patients with SCZ (BECT and AECT) has a positive correlation with reduction rate of positive symptoms (r = 0.228, p < 0.05) and disturbance of thought (r = 0.219, p < 0.05).Conclusion: Our study suggests that the expression level of EP300 protein has a significant change in patients with SCZ treating with ECT, and EP300 may have some connections with positive symptoms and disturbance thought of patients with SCZ.Keywords: EP300, electroconvulsive therapy, schizophrenia

Xuefang Liu,&ast; Suyan Li,&ast; Jingni Xiong, Dandan Chen, Chan Jiang, Liankun Zeng, Youyan Qiu,&ast; Bi-Wen Xia&ast; Department of Endocrine Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Youyan Qiu; Bi-Wen Xia, Department of Endocrine Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, No. 1 Guangming East Road, Zengjiang Street, Zengcheng District, Guangzhou City, Guangdong, 511330, People’s Republic of China, Tel +86-020-62287186, Email qyy20112014@163.com; biwenxia1550@163.comBackground: Thyroxine binding globulin (TBG) deficiency is a rare thyroid disease, mostly caused by genetic mutations and acquired by X-linked recessive inheritance. The clinical features of children with TBG deficiency and their family members were summarised and the Serpina7 gene mutation was analysed, providing a reference for the differentiation of TBG deficiency.Methods: Thyroid function was detected in TBG deficient patients, and genetic analysis was performed using polymerase chain reaction (PCR) and direct DNA sequencing to detect the characteristics of TBG mutants. Using “thyroxine binding globulin, gene and mutation” as keywords, PubMed (biomedical literature database), Web of Science and other databases were searched for relevant studies to collect and summarise relevant information.Results: The TBG (14.7 μg/mL), 70% triiodothyronine (T3) (< 0.3 nmol/L), total T3 (Tr3) (< 0.05 ng/mL) and thyroxine (T4) (14.72 nmol/L) values were lower than normal, while the thyrotropin (TSH) (2.33 uIU/mL), free T3 (FT3) (1.62 pmol/L), and free T4 (FT4) (11.39 pmol/L) values were normal. These values indicate a TBG partially deficient phenotype. Using PCR amplification and direct sequencing of the target gene, a missense mutation in exon 4 of the Serpina7 gene was found in the patient and the father, and the nucleic acid variant was C.909 (exon 4) g > T; the patient was heterozygous and the father was hemizygous. The literature search retrieved a total of 45 studies, most of which were related to mutations in the Serpina7 gene. The mutation locations included exons, introns, enhancers and promoters, with exons the predominant location. A total of 49 variants of the Serpina7 gene were identified.Conclusion: Serpina7 C.909G (P.L303F) is a mutation acquired from the father by X-linked recessive inheritance. The main clinical features of TBG deficiency patients are low serum T4, T3 and TBG levels, normal TSH, FT3 and FT4 levels, and no clinical manifestations.Keywords: thyroxine-binding globulin, deficiency, genes, mutation

Zhuzhu Qin,1,&ast; Xinxin Ye,2,&ast; Huanju Liu,3 Yining Tao,4 Xutong Zheng,1 Yanxia Zhong,5 Danfeng Chen,1 Wan Ye,6 Chenju Zhan7 1School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China; 2Department of Sports and Exercise Science, College of Education, Zhejiang University, Hangzhou, Zhejiang, China; 3Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China; 4Department of Global Public Health, Karolinska Institute, Stockholm, Sweden; 5Department of Nursing, Shijiazhuang Medical College, Shijiazhuang, China; 6Department of Nursing, Xiamen Medical College, Xiamen, Fujian, China; 7Department of Nursing, Mindong Hospital Affiliated to Fujian Medical University, Ningde, China&ast;These authors contributed equally to this workCorrespondence: Wan Ye, Department of Nursing, Xiamen Medical College, Xiamen, Fujian, China, Tel +86 13806086169, Email 200600010142@xmmc.edu.cn Chenju Zhan, Department of Nursing, Mindong Hospital Affiliated to Fujian Medical University, No. 89 HeShan Road, Fuan City, Fujian Province, 355000, China, Tel +86 13809562183, Email zhanchenju@yeah.netObjective: This study investigated factors influencing the knowledge, attitudes, practice profiles, and vaccination intentions among Chinese nursing students and nursing interns toward the coronavirus disease (COVID-19) vaccination.Materials and Methods: The multicenter cross-sectional study was based on a self-reported questionnaire collecting information among nursing students and nursing interns from three major geographic regions of China, and the sample was selected by consecutive sampling. The questionnaire was developed by knowledge, attitudes, and practice (KAP) theory. Univariate and multivariate logistic regression were used for statistical analysis.Results: A total of 3180 nursing students and interns (effective rate: 99.8%) from six Chinese provinces were polled. The vaccine hesitation rate was 9.65% (307/3180), 2230 participants (70.1%) had gotten at least one dose of the vaccine, and 643 participants (67.7%) had indicated a readiness to be vaccinated. The results showed that older age, higher academic background, perfect vaccine management, others’ recommendations, influenza vaccination history, epidemic under control, knowledge of vaccines or intervals, and vaccine knowledge training were associated with higher vaccination rates. Conversely, vaccine hesitancy was caused by a perceived lack of physical need, uncertainty about vaccination requirements, and fear of vaccination.Conclusion: This study provided population-based estimates of COVID-19 vaccine uptake intention among mainland Chinese nursing students and interns. Factors such as age, education, vaccine knowledge, and attitudes influence COVID-19 vaccine behaviour. Relevant authorities should understand the barriers to COVID-19 vaccination from knowledge, attitude and practice, which is significant for formulating effective response strategies in future global public health crises.Graphical Abstract: Keywords: COVID-19, vaccine, knowledge, attitudes, practice, nursing students and interns

Huiying Zhang,1,&ast; Daojun Chen,1,2,&ast; Qianqian Ji,1 Meiyan Yang,1 Rui Ding1 1Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 2School of Medical Technology, Anhui Medical College, Hefei, Anhui, 230601, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Daojun Chen, Email daodaodao1978@163.comBackground: Microcystin-leucine-arginine (MC-LR) is the most abundant and most toxic variant of microcystin isomers. Various experiments have clearly shown that MC-LR has hepatotoxicity and carcinogenicity, but there are relatively few studies on its immune damage effect. In addition, numerous studies have shown that microRNAs (miRNAs) are involved in a wide range of biological processes. Do miRNAs also play a role in inflammatory response caused by microcystin exposure? This is the question to be answered in this study. Moreover, this study can also provides experimental evidence for the significance of miRNA applications.Objective: To investigate the effect of MC-LR on the expressions of miR-146a and pro/anti-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) and to further explore the role of miR-146a in the inflammatory responses caused by MC-LR.Methods: Serum samples from 1789 medical examiners were collected and detect the concentrations of MCs, and 30 serum samples with concentrations of MCs around P25, P50, and p75 were randomly selected for the detection of inflammatory factors. PBMCs from fresh peripheral blood extracted from these 90 medical examiners were subsequently tested for relative miR-146a expression. In vitro, the MC-LR were exposed to the PBMCs to detect the levels of inflammatory factors as well as the relative expression of miR-146a-5p. Then, a miRNA transfection assay was performed to verify the regulation of inflammatory factors by miR-146a-5p.Results: In population samples, the expression of inflammatory factors and miR-146a-5p increased with increasing MCs concentration. In vitro experiments showed that the expression of inflammatory factors and miR-146a-5p in PBMCs increased with MC-LR exposure time or exposure dose too. In addition, inhibiting the expression of miR-146a-5p in PBMCs reduced inflammatory factor levels.Conclusion: miR-146a-5p exerts a promoting effect on the MC-LR-induced inflammatory response by positively regulating inflammatory factor levels.Keywords: microcystin-leucine-arginine, MC-LR, human peripheral blood, mononuclear cells, PBMCs, miR-146a, inflammatory cytokines

Nianqi Cui,1,2,&ast; Hui Zhang,3,&ast; Sijie Gan,4 Yuping Zhang,1 Dandan Chen,5 Pingping Guo,5 Jingjie Wu,5 Zhuang Li,6 Jingfen Jin1,7,8 1Nursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU), Hangzhou, Zhejiang, People’s Republic of China; 2School of Nursing, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 4Product Development Center, Zhejiang Xinhua Mobile Media Co. Ltd, Hangzhou, Zhejiang, People’s Republic of China; 5Faculty of Nursing, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 6Medical Faculty, Yunnan College of Business Management, Kunming, Yunnan, People’s Republic of China; 7Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China; 8Dean’s Office, Changxing Branch Hospital of SAHZU, Huzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhuang Li, Medical Faculty, Yunnan College of Business Management, No. 296 Haitun Road, Wuhua District, Kunming, Yunnan, 650106, People’s Republic of China, Tel + 86 15198859387, Fax +86 0871-68314770, Email lz15198859387@163.com Jingfen Jin, Nursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU), No. 88 Jiefang road, Shangcheng District, Hangzhou, Zhejiang, 310009, People’s Republic of China, Tel + 86 137 5711 8239, Fax +86 0571-87783887, Email zrjzkhl@zju.edu.cnPurpose: Physical restraints are used routinely in intensive care units (ICUs) and have negative effects. It is critical to identify the impact factors of physical restraints on critically ill patients. The present study investigated the prevalence of physical restraints and impact factors associated with their use in a large cohort of critically ill patients over one year.Patients and Methods: A retrospective cohort study was performed in multiple ICUs at a tertiary hospital in China in 2019 using observational data from electronic medical records. The data consisted of demographics and clinical variables. Logistic regression was used to assess the independent impact factors for the use of physical restraint.Results: The analysis consisted of 3776 critically ill patients with a prevalence of physical restraint use of 48.8%. The logistic regression analysis indicated that physical restraint use was associated with independent risk factors, including surgical ICU admission, pain, tracheal tube placement, and abdominal drainage tube placement. Physical restraint use was associated with independent protective factors, including male sex, light sedation, muscle strength, and ICU length of stay.Conclusion: The prevalence of physical restraint use in critically ill patients was high. Tracheal tubes, surgical ICU, pain, abdominal drainage tubes, light sedation, and muscle strength were independent variables associated with the use of physical restraint. These results will assist health professionals in identifying high-risk physical restraint patients based on their impact factors. Early removal of the tracheal tube and abdominal drainage tube, pain relief, light sedation, and improvements in muscle strength may help reduce the use of physical restraints.Keywords: critical care, restraints, physical, epidemiology, nursing

Daohong Chen, Qian Zeng, Lu Liu, Ziyang Zhou, Wenchuan Qi, Shuguang Yu, Ling Zhao Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Ling Zhao; Shuguang Yu, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 37, Twelve Bridge Road, Chengdu, Sichuan Province, People’s Republic of China, Email zhaoling@cdutcm.edu.cn; ysg@cdutcm.edu.cnBackground: The pathogenesis of chronic obstructive pulmonary disease (COPD) has been studied in relation to the microbiome, providing space for more targeted interventions and new treatments. Numerous papers on the COPD microbiome have been reported in the last 10 years, yet few publications have used bibliometric methods to evaluate this area.Methods: We searched the Web of Science Core Collection for all original research articles in the field of COPD microbiome from January 2011 to August 2022 and used CiteSpace for visual analysis.Results: A total of 505 relevant publications were obtained, and the number of global publications in this field is steadily increasing every year, with China and the USA occupying the first two spots in international publications. Imperial College London and the University of Leicester produced the most publications. Brightling C from the UK was the most prolific writer, while Huang Y and Sze M from the USA were first and second among the authors cited. The American Journal of Respiratory and Critical Care Medicine had the highest frequency of citations. The top 10 institutions, cited authors and journals are mostly from the UK and the US. In the ranking of citations, the first article was a paper published by Sze M on changes in the lung tissue’s microbiota in COPD patients. The keywords “exacerbation”, “gut microbiota”, “lung microbiome”, “airway microbiome”, “bacterial colonization”, and “inflammation” were identified as cutting-edge research projects for 2011– 2022.Conclusion: Based on the visualization results, in the future, we can use the gut–lung axis as the starting point to explore the immunoinflammatory mechanism of COPD, and study how to predict the effects of different treatments of COPD by identifying the microbiota, and how to achieve the optimal enrichment of beneficial bacteria and the optimal consumption of harmful bacteria to improve COPD.Keywords: COPD, microbiome, bibliometric analysis, CiteSpace, gut microbiome, respiratory microbiome, bacterial colonization

Zhongbao Wang,1 Yunshao Zheng,2 Yunli Fan,2 Yunming Fan,2 Xianbiao Su,2 Bingrui Wang,2 Jing Li,2 Diancai Chen,2 Fengxia Sun,2 Shen Li,2 Jiashu Ma,1 Xianwei Li,2 Ludong Bai,2 Ranran Li2 1Department of Psychiatry, Jining Medical University, Jining, People’s Republic of China; 2Department of Psychiatry, Shandong Mental Health Center, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Ranran Li, Department of Psychiatry, Shandong Mental Health Center, Shandong University, 49 East Wenhua Road, Jinan, Shandong, 250014, People’s Republic of China, Tel +86 18678777190, Email dtlrr113@126.comBackground: Most antipsychotic drugs are dopamine receptor antagonists that usually lead to abnormal increases in prolactin concentrations and the development of hyperprolactinemia (HPRL), which in turn causes sexual dysfunction in patients. Peony-Glycyrrhiza Decoction (PGD) enhanced dopamine D2 receptors (DRD2) and dopamine transporter (DAT) and significantly reversed the expression of DRD2 and DAT. Therefore, we hypothesized that PGD might effectively improve hyperprolactinemia and alleviate sexual dysfunction in patients.Methods: We performed an 8-week randomized controlled study on 62 subjects with schizophrenia who were randomized into two groups. The experimental group was treated with the PGD intervention, and the control group did not receive treatment. The primary outcome indicators were the levels of sex hormones and the total Arizona Sexual Experience Scale (ASEX) score.Results: There was a significant difference in PRL levels between the two groups at weeks 4 and 8. From the beginning to the end of the experiment, there was a significant increase in PRL levels in the control group, while there was no significant change in the experimental group. The ASEX scale assessed sexual function in both groups, and patients in the experimental group showed an improvement in sexual function at week 8. During the experiment, the two groups found no differences between Positive and Negative Syndrome Scale (PANSS) scores and Treatment Emergent Symptom Scale (TESS) scores.Conclusion: PGD significantly improved the patient’s sexual function but was less effective in reducing prolactin levels and may prevent further increases in prolactin levels.Keywords: hyperprolactinemia, antipsychotics, Peony-Glycyrrhiza Decoction, schizophrenia, sexual function, adverse effects

Claire A Coyne,1,2 Briahna T Yuodsnukis,1 Diane Chen1– 3 1Potocsnak Family Division of Adolescent and Young Adult Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 2Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USACorrespondence: Claire A Coyne, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Avenue, Box 161B, Chicago, IL, 60611-2605, USA, Tel +1 312 227 6316, Fax +1 312 227 9446, Email ccoyne@luriechildrens.orgAbstract: Transgender and gender diverse (TGD) youth and their families are seeking medical and mental health care at increasing rates. As the number of multidisciplinary pediatric gender programs expands, we consider the history and evidence base for gender affirmative care and highlight existing models of care that can flexibly accommodate the diverse needs of TGD youth and their families. Comprehensive multidisciplinary care includes both medical and mental health providers who work collaboratively with TGD youth and their caregivers to assess gender-related support needs and facilitate access to developmentally appropriate medical and mental health interventions. In addition to direct health-care services, multidisciplinary care for TGD youth and their families extends into community training, education, community outreach, nonmedical programming, and advocacy for TGD youth.Keywords: transgender, gender diversity, gender-affirming care, multidisciplinary care

Guangtao Fu,1,&ast; Rongjie Wu,1,2,&ast; Ruiying Zhang,1,&ast; Duanyong Chen,1 Haotao Li,1 Qiujian Zheng,1,3 Yuanchen Ma1 1Department of Orthopedics, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 2Shantou University Medical College, Shantou, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanchen Ma, Tel +86-18688889132, Email myc998@qq.com; Qiujian Zheng, Tel +86-13802740561, Email zhengqiujian@gdph.org.cnBackground: Vitamin D deficiency is a common comorbidity in geriatric hip fracture patients. However, there is still an ongoing debate regarding the influence of preoperative Vitamin D status on postoperative mortality in hip fracture patients.Methods: Elderly patients (≥ 60 years) who underwent surgical interventions for unilateral hip fracture from 2015 to 2020 in our center were included. We retrospectively retrieved the demographic data from the electronic medical database. Preoperative serum total 25-hydroxy-Vitamin D was set as the independent variable and patients were classified as the Vitamin D deficiency (< 20ng/mL) and the control groups consequently. Clinical outcomes include all-cause mortality, walking ability, and major postoperative complications in the first postoperative year. Propensity score matching (PSM) was performed in a ratio of 1:1 in the two groups for further comparison.Results: A total of 210 patients were included and 121 patients (57.6%) were diagnosed with Vitamin D deficiency. Patients in the Vitamin D deficiency group were much older and therefore preferred peripheral nerve block, and had significantly higher proportions of females, preoperative dementia, higher ASA grade, and lower baseline serum albumin level. Overall, 79 patients were identified in the Vitamin D deficiency and control groups after PSM, respectively. Patients diagnosed with Vitamin D deficiency showed a significantly higher one-year mortality (21.5% vs 6.3%, P=0.011) and a much lower one-year independent walking rate (67.1% vs.84.8%, P=0.016) after the matching. Regarding the dataset before PSM and after PSM, the AUC for serum Vitamin D for predicting one-year mortality was 0.656 (P=0.006) and 0.695 (P=0.002), respectively.Conclusion: Our retrospective PSM-design study provides new evidence that Vitamin D deficiency was associated with a significantly higher mortality and poor walking ability in the first year after surgical intervention based on southern Chinese populations.Keywords: vitamin D deficiency, mortality, hip fracture, propensity score match, Chinese population

Bao Sun,1,2,&ast; Yingshuang Tang,2,&ast; Dan Chen,3 Yanning Bai,4 Yuanyuan Zhang,5 Suning Chen,2 Yi Qiao,2 Jingwen Wang2 1Department of Pharmacy, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Pharmacy, Xijing Hospital, Fourth Military Medical Unversity, Xi’an, Shaanxi, People’s Republic of China; 3Department of pharmacy, 404 Hospital of Mianyang, Mianyang, Sichuan, People’s Republic of China; 4Department of Clinical Pharmacy, Yan’ an University Affiliated Hospital, Yan’an, Shaanxi, People’s Republic of China; 5Department of Pharmacy, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Qiao; Jingwen Wang, Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi, People’s Republic of China, Email 694305040@qq.com; wangjingwen8021@163.comAbstract: Biliary cryptococcosis infection is extremely rare and difficult for preoperative diagnosis. We report a rare case of 61-year-old woman with biliary cryptococcal infection. To explore the general rule and case characteristics of biliary cryptococcal infection and provide a reference for future diagnosis and treatment, we consulted the PubMed database for reported biliary cryptococcal infection from 1985 to 2021. Including the present one, we collected 12 reports, among which half were male and five were younger than 18 years old. Clinical manifestations were mainly jaundice, while in vitro examination revealed bile duct dilatation and bile duct stenosis. In 8 cases (66.67%), symptoms improved or healed after antifungal treatment. Although preoperative misdiagnosis of cryptococcal infection is high, the antifungal treatment is quite effective. Thus, early accurate diagnosis can effectively improve the cure rate of biliary cryptococcosis infected patients.Keywords: biliary cryptococcosis, obstructive jaundice, Cryptococcus neoformans, literature analysis

Yuyuan Shi,1,&ast; Ying Zhao,2,&ast; Wen Kang,2 Wei Lu,3 Dong Chen,3 Jun Tao,3 Jing Li,3 Ruifa Yu,3 Jiajia Zhao,3 Rui Tang,3 Zhaogang Teng,3 Lixing Weng1 1College of Geography and Biological Information, Nanjing University of Posts and Telecommunications, Nanjing, People’s Republic of China; 2Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 3Key Laboratory for Organic Electronics & Information Displays and Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials, Jiangsu National Synergetic Innovation Centre for Advanced Materials, Nanjing University of Posts and Telecommunications, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaogang Teng; Lixing Weng, Email iamzgteng@njupt.edu.cn; lxweng@njupt.edu.cnIntroduction: Photodynamic therapy (PDT) has attracted increasing attention for tumor treatment because of its minimal invasiveness and specific spatiotemporal selectivity. However, insufficient tumor accumulation and low cellular uptake of photosensitizers limit its therapeutic efficacy.Methods: In this study, flexible hollow human serum albumin/catalase nanocapsules (HSA/CATs) were created using a core-assisted protein-coating method and combined with the photosensitizer chlorin e6 (HSA/CAT@Ce6) for PDT.Results and Discussion: Transmission electron microscopy (TEM) images demonstrate that HSA/CAT nanocapsules are flexible, with a uniform diameter (310 nm) and a well-defined hollow structure. Thanks to their flexibility, HSA/CAT@Ce6 nanocapsules show a higher cellular uptake than rigid nanoparticles. The nanocapsules effectively generate reactive oxygen species (ROS) in 4T1 cells because of their high cellular uptake and catalytic capacity, remarkably enhancing their in vitro PDT efficacy. In addition, the in vivo tumor accumulation of HSA/CAT@Ce6 nanocapsules is significantly larger than that of rigid nanoparticles and Ce6, meaning they are highly effective in tumor cell ablation. This demonstrates that our flexible nanoplatform holds great promise for enhancing PDT of tumor.Keywords: flexible nanoplatform, human serum albumin, sufficient tumor accumulation, high cellular uptake, photodynamic therapy

Ning Yan,1,&ast; Dapeng Chen,1,&ast; Ruiping Pan,2 Li Zhang,3 Juan Ma,4 Zhengjun Zhang,1 Yuqi Dang,5 Liqun Wang,6 Xueping Ma,1,7 Shaobin Jia1,7 1Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Department of Chinese Medicine, The Second People’s Hospital of Shizuishan, Shizuishan, 753000, People’s Republic of China; 3Department of Endocrinology, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 4Clinical Medical College, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 5Department of Endocrinology, Yinchuan Hospital of Traditional Chinese Medicine, Yinchuan, 750001, People’s Republic of China; 6Department of Epidemiology and Statistics, School of Public Health and Management, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 7Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueping Ma; Shaobin Jia, Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China, Tel +8613519290991 ; +8613995078969, Email maxueping4033@126.com; jsbxn@163.comPurpose: This study aimed to evaluate the relationship between social capital (SC) and hypertension among type 2 diabetes mellitus (T2DM) patients, considering the moderation effects of depressive symptoms.Patients and Methods: A total of 1761 Chinese T2DM patients completed measure scales of social capital and epidemiological survey depression scale (CES-D). The Bootstrap methods PROCESS program is employed to test the moderation model.Results: The prevalence of hypertension among T2DM patients was 39.3%. The SC was negatively correlated with the CES-D score (r=− 0.18, P< 0.01); the SC was also negatively correlated with diastolic blood pressure (r=− 0.05, P< 0.05); and the CES-D score was positively correlated with systolic blood pressure (r=0.05, P< 0.05). Both logistic regression analysis and the Bootstrap method showed that depressive symptoms weakened the protective effect of SC on hypertension, there existed a moderating effect of depressive symptoms on the relationship between SC and hypertension among T2DM patients.Conclusion: Depressive symptoms may be one crucial moderator of the relationship between SC and hypertension in a representative sample of Chinese diabetes patients. The findings indicate that improving SC and mental health may help manage hypertension among T2DM patients.Keywords: social capital, depressive symptoms, hypertension, moderation, type 2 diabetes mellitus

Minxi Lao,1,2,&ast; Hui Ouyang,3,&ast; Nannan Li,1 Hao Li,1 Peiyin Dai,1 Zhongping Zhan,1 Dongying Chen1 1Department of Rheumatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Digestive Medicine Center, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongying Chen; Zhongping Zhan, Department of Rheumatology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2 nd Road, Guangzhou, 510080, People’s Republic of China, Email chendy3@mail.sysu.edu.cn; zhanchuyue@163.comPurpose: To investigate the clinical features of infection, and associated factor for in-hospital mortality in a southern Chinese cohort with polymyositis/dermatomyositis (PM/DM).Patients and Methods: Clinical data were retrospectively reviewed from 2015 to 2022 from a tertiary hospital in southern China. Associated factors for infection and in-hospital mortality were analyzed by multivariate logistic regression analysis.Results: A total of 554 patients with PM/DM were included, and 35.6% (197/554) of them developed 404 episodes of infection. Half of the patients developed infection within 4 months after disease onset. Bacterial infection was predominant (249/404, 61.6%). Lung was the most involved (242/404, 59.9%). Gram-negative bacteria the leading pathogens (64/84, 76.2%). Patients with anti-MDA5 positive were prone to develop severe infections (35.1% vs 16.4%, P< 0.001) and had higher mortality (11.7% vs 3.4%, P=0.01). The in-hospital mortality was 6.5% (36/554). Infection was the leading cause of death (20/36, 55.6%). Older age (adjusted odds ratio (OR): 1.05, 95% confidential interval (CI): 1.02– 1.09, P=0.004), ILD (adjusted OR: 2.76, 95% CI: 1.11– 6.84, P=0.03), number of episodes of infection (adjusted OR: 1.91, 95% CI: 1.53– 2.38, P< 0.001), and elevated serum creatinine (Scr) (adjusted OR: 6.83, 95% CI: 1.77– 26.40, P=0.01) were associated with in-hospital mortality.Conclusion: Infection is an early complication in PM/DM with a high proportion of lung involvement and predominance of gram-negative bacteria. It is a major contributor to in-hospital mortality. Older age, ILD, and number of episodes of infection are associated with poor prognosis.Keywords: dermatomyositis, polymyositis, infection, MDA5, mortality

Xueping Wang, Zhixing Guo, Xingping Wu, Da Chen, Fang Wang, Lewei Yang, Min Luo, Shaocong Wu, Chuan Yang, Lamei Huang, Liwu Fu State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Liwu Fu, State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Cancer Center, Sun Yat-sen University, 651 Dongfengdong Road, Guangzhou, 510060, People’s Republic of China, Email fulw@mail.sysu.edu.cnIntroduction: Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed.Methods: This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated.Results: Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P< 0.01; PFS: 2.00 vs 5.00 months, P< 0.001, respectively). The HPD prediction nomogram included APTT (P< 0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P< 0.01), the presence of liver metastasis (P< 0.05), and more than two metastatic sites (P< 0.05). Then, patients were divided into two groups by the “HPD score” calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%).Conclusions: The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.Keywords: PD-1/PD-L1 inhibitors, hyperprogressive disease, non-small cell lung cancer, nomogram

Qin Li,1,* Dongqiong Chen,2,* Fang Ye,3 Xiaoying Wang,4 Shangsong Yang,1 Li Wang,5 Weibo Wen2 1Department of Basic Theory of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, People’s Republic of China; 2Department of Gynecology, the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, People’s Republic of China; 3TCM for AIDS Project Office, Linxiang Hospital of Traditional Chinese Medicine, Lincang, People’s Republic of China; 4Research and Teaching Management Section, Kunming Municipal Hospital of Traditional Chinese Medicine, Kunming, People’s Republic of China; 5Clinical Research Centre for the Prevention and Treatment of AIDS in Chinese Medicine, Yunnan Institute of Traditional Chinese Medicine, Kunming, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weibo Wen, Department of Gynecology, the First Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, People’s Republic of China, Email weibowen1968@hotmail.com Li Wang, Clinical Research Centre for the Prevention and Treatment of AIDS in Chinese Medicine, Yunnan Institute of Traditional Chinese Medicine, Kunming, People’s Republic of China, Email wanglichina1234567890@hotmail.comIntroduction: We aimed to investigate whether there were changes in fundus picture and retinal microvascularity of patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) who were treated with highly active antiretroviral therapy (HAART).Methods: From July 2015 to November 2016, 130 HIV/AIDS patients were collected by the Yunnan Institute of Traditional Chinese Medicine, including 63 treatment-naïve patients and 67 that received HAART for 12 months. Fundus picture lesions, retinal microvascular diameters, CD4+ T lymphocyte count and HIV-1 plasma viral loads were compared between the two groups. The recruited patients were mainly young and middle-aged, with more males than females. There were no significant differences in smoking history, comorbidities and opportunistic infections between the two groups.Results: According to the analysis results from SPSS 20.0 software, the number of CD4+ T lymphocytes in the treated patients (563.34± 2.56 cells/μL) increased significantly (P=0.009) as compared with untreated patients (451.37± 2.10 cells/μL), and the HIV-1 plasma viral load reduced considerably (4794 vs 0 copy/mL, P=0.000). No significant differences were observed from the fundus picture of patients after effective HAART therapy, including the retinal artery diameter, venous diameter and arteriovenous diameter ratio.Keywords: fundus, retinal microvascular, HIV/AIDS, HAART

Xiaodong Feng,1,&ast; Guiliang Zhang,1,&ast; Shiyang Zhang,2 Dihong Chen,3 Mengxue Zhou,1 Lihua Zeng,1 Tianmin Yang1 1Department of Critical Care Medicine, Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China; 2Department of Gastroenterology, Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China; 3Mianzhu People’s Hospital, Mianzhu, 618200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Feng, Department of Critical Care Medicine, Mianzhu People’s Hospital, No. 268, Section 1, Nanjing Avenue, Mianzhu, Sichuan Province, 618200, People’s Republic of China, Tel +8613518265506, Email fxd_3dek1@163.comPurpose: To explore an effective model to promote the homogeneous development of intensive care units (ICUs) in grassroot, impoverished and remote areas.Methods: A three-level remote alliance model (in-place and online assistance) was adopted to guide the cross-talk of ICUs between counties and cities. The observed indicators included the mortality of ICU patients and those with APACHE II scores ≥ 15 points, deep vein thrombosis, ventilator-associated pneumonia, the completion rate of septic shock goals in 3-hour and 6-hour bundles, and the rates of patient transfers.Results: After the implementation of the remote alliance, there was significant reduction in the mortality of ICU patients in the county and city-level tertiary hospitals (7.6% vs 4.5%, P = 0.004; OR = 1.734, 95% CI 1.189– 2.532) and the mortality rates of patients with APACHE II scores ≥ 15 points (11.9% vs 7.1%, P = 0.004; OR = 1.763, 95% CI 1.189– 2.614). There was a significant reduction in the incidence of ventilator-associated pneumonia (0.9% vs 5.0%, P < 0.001) and deep vein thrombosis (52.4% vs 13.6%, P < 0.001). The completion rate of 3-hour bundle therapies for septic shock was significantly improved (95.7% vs 68.4%, P < 0.001), as well as 6-hour bundle therapies for septic shock (97.9% vs 81.6%, P < 0.001). The hospital transfer rate decreased significantly in the grassroots and impoverished areas (2.6% vs 4.7%, P < 0.001).Conclusion: A three-level remote alliance might be helpful in improving the quality of critical care in remote areas and promoting the homogeneous development of disciplines.Keywords: medical quality, remote alliance, in-place and online, critical care medicine, mortality rate

Tianyu Jin,1,&ast; Danyu Chen,2,&ast; Zhicai Chen,3 Dujin Feng,4 Manqi Zheng,5 Peng Wang,6 Chao Xu6 1Department of Neurology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurology, Tongxiang First People’s Hospital, Tongxiang, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, People’s Republic of China; 4Department of Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 5Department of Psychiatry, The Third Hospital of Quzhou, Quzhou, People’s Republic of China; 6Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Xu; Peng Wang, Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College. No.158 Shangtang Road, Hangzhou, People’s Republic of China, 310014, Email raymond1202@126.com; 1979wwww@163.comBackground: We aimed to investigate the association of post-thrombolytic D-dimer elevation with symptomatic intracranial hemorrhage (sICH) and functional outcome in AIS patients receiving intravenous thrombolysis.Methods: We retrospectively reviewed our database for patients with AIS who received intravenous thrombolysis between August 2018 and December 2021. ΔD-dimer was calculated as follow-up D-dimer minus baseline D-dimer. Poor functional outcome was defined as 3 months modified Rankin score (mRS) 3– 6. sICH was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points at 24 hours. Binary logistic regression analysis was used to investigate the association of post-thrombolytic D-dimer parameters with sICH and poor functional outcome. The receiver operating characteristic (ROC) curve derived optimal cut-off of different D-dimer parameters was determined at the maximal Youden’s Index.Results: A total of 325 patients were finally included. After controlling for clinical variables, follow-up D-dimer level (OR 1.230; 95% CI 1.119 to 1.351; P < 0.001) and ΔD-dimer (OR 1.347; 95% CI 1.165 to 1.559; P < 0.001) were independently associated with poor functional outcome. Additionally, follow-up D-dimer level (OR 1.095; 95% CI 1.009 to 1.188; P = 0.030) was independently related to sICH. The optimal cut-off value of follow-up D-dimer level for predicting sICH was 4185 μg/L (area under the curve 0.760; sensitivity 76.0%; specificity 81.3%); and the optimal cut-off value of follow-up D-dimer level and ΔD-dimer as a predictor for poor functional outcome was projected to be 3838 μg/L and 2190 μg/L, which yielded a sensitivity and a specificity of 62.3%, 84.5% and 73.8%, 85.2%, respectively.Conclusion: Elevated follow-up D-dimer levels are associated with sICH and poor functional outcome in AIS patients following intravenous rt-PA. Moreover, post-thrombolytic D-dimer elevation, measured by ΔD-dimer, was a better predictive biomarker for long-term outcome at 3 months.Keywords: acute ischemic stroke, D-dimer, intravenous thrombolysis, hemorrhagic transformation, outcome

Zhihuan Zhang, Wenhan Huang, Feifeng Ren, Lei Luo, Jun Zhou, Mengxue Tian, Zhongjie Wang, Dandan Chen, Lin Tang Department of Rheumatology and Immunology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin Tang, Department of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China, Email hopetang@163.comPurpose: To explore the risk factors for thrombi occurring in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and establish a risk prediction model to better predict the risk of thrombosis in patients with AAV.Patients and Methods: We retrospectively analyzed 117 AAV patients who had been hospitalized in The Second Affiliated Hospital of Chongqing Medical University between October 2010 and December 2021. For all patients, we recorded demographic characteristics and clinical data, analyzed the risk factors for thrombosis in AAV patients and then developed a risk prediction model.Results: Stepwise logistic regression analysis indicated that a high complement C3 level, a high BVAS score and a high Padua score were independent risk factors for thrombosis in AAV patients. According to multivariate analysis, a predictive model for thrombus risk was successfully established; the area under the ROC curve(AUC) was 0.803 (95% CI: 0.716– 0.890) and the maximum Youden index, sensitivity and specificity were 0.487, 59.0% and 89.7%, respectively.Conclusion: A high complement C3 level, high BVAS score, and a high Padua score were shown to be independent risk factors for thrombosis in AAV patients. We developed a risk prediction model based on these three risk factors that could predict the risk of thrombosis in AAV patients to some extent.Keywords: antineutrophil cytoplasmic antibody, thromboembolism, risk factors, risk prediction model

Jiacheng Fang, Yuxuan Zhang, Delong Chen, Yiyue Zheng, Jun Jiang Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of ChinaCorrespondence: Jun Jiang, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, 310009, People’s Republic of China, Tel/Fax +86 135 8870 6891, Email jiang-jun@zju.edu.cnAbstract: Exosomes are a pluripotent group of extracellular nanovesicles secreted by all cells that mediate intercellular communications. The effective information within exosomes is primarily reflected in exosomal cargos, including proteins, lipids, DNAs, and non-coding RNAs (ncRNAs), the most intensively studied molecules. Cardiac resident cells (cardiomyocytes, fibroblasts, and endothelial cells) and foreign cells (infiltrated immune cells, cardiac progenitor cells, cardiosphere-derived cells, and mesenchymal stem cells) are involved in the progress of ventricular remodeling (VR) following myocardial infarction (MI) via transferring exosomes into target cells. Here, we summarize the pathological mechanisms of VR following MI, including cardiac myocyte hypertrophy, cardiac fibrosis, inflammation, pyroptosis, apoptosis, autophagy, angiogenesis, and metabolic disorders, and the roles of exosomal cargos in these processes, with a focus on proteins and ncRNAs. Continued research in this field reveals a novel diagnostic and therapeutic strategy for VR.Keywords: exosomes, ventricular remodeling, extracellular vesicles, heart failure, microRNAs, myocardial infarction

Michael J Thorpy,1 Isabelle Arnulf,2 Nancy Foldvary-Schaefer,3 Anne Marie Morse,4 Karel Šonka,5 Patricia Chandler,6 Luke Hickey,7 Abby Chen,6 Jed Black,6,8 Amanda Sterkel,6 Dan Chen,9 Richard K Bogan,10 Yves Dauvilliers11,12 1Albert Einstein College of Medicine, Bronx, NY, USA; 2Sleep Disorder Unit, Pitié-Salpêtrière Hospital and Sorbonne University, Paris, France; 3Cleveland Clinic Sleep Disorders Center, Department of Neurology, Lerner College of Medicine, Cleveland, OH, USA; 4Janet Weis Children’s Hospital, Geisinger, Danville, PA, USA; 5Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 6Jazz Pharmaceuticals, Palo Alto, CA, USA; 7Jazz Pharmaceuticals, Philadelphia, PA, USA; 8Stanford University Center for Sleep Sciences and Medicine, Palo Alto, CA, USA; 9Formerly Jazz Pharmaceuticals, Palo Alto, CA, USA; 10University of South Carolina School of Medicine, Columbia, SC, USA; 11Sleep and Wake Disorders Centre, Department of Neurology, Gui de Chauliac Hospital, Montpellier, France; 12University of Montpellier, INSERM Institute Neuroscience Montpellier (INM), Montpellier, FranceCorrespondence: Michael J Thorpy, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA, Tel +1 718 920-4841, Fax +1 718 798-4352, Email michael.thorpy@einsteinmed.orgPurpose: To report the efficacy and safety of lower-sodium oxybate (LXB; Xywav®) during the open-label titration and optimization period (OLT) and stable-dose period (SDP) in a clinical study for the treatment of idiopathic hypersomnia.Patients and Methods: Data were collected during treatment titration and optimization in a phase 3 randomized withdrawal trial in adults (18– 75 years of age) with idiopathic hypersomnia who took LXB treatment (once, twice, or thrice nightly, administered orally) in the OLT (10– 14 weeks), followed by the 2-week, open-label SDP. Endpoints included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change, Clinical Global Impression of Change, Functional Outcomes of Sleep Questionnaire (FOSQ)-10, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP).Results: The safety population included 154 participants; the modified intent-to-treat population comprised 115 participants. During open-label treatment, mean (SD) ESS scores improved (decreased) from 15.7 (3.8) at baseline to 6.1 (4.0) at end of SDP, and IHSS scores improved (decreased) from 31.6 (8.3) to 15.3 (8.5). Improvements were also observed during OLT in each individual IHSS item and in FOSQ-10 and WPAI:SHP scores. Thirty-five (22.7%) participants discontinued during OLT and SDP, 22 (14.3%) due to treatment-emergent adverse events (TEAEs) during OLT and SDP. The most frequent TEAEs in the first 4 weeks were nausea, headache, dizziness, and dry mouth; TEAE incidence decreased throughout OLT and SDP (weeks 1– 4, n = 87 [56.5%]; weeks 13– 16, n = 39 [31.7%]).Conclusion: During open-label treatment with LXB, participants showed clinically meaningful improvements in idiopathic hypersomnia symptoms and in quality of life and functional measures. TEAE incidence declined over LXB titration and optimization.Keywords: excessive daytime sleepiness, hypersomnolence, quality of life, pharmacotherapy

Huiyu Wang,1,&ast; Dingyi Gu,1,&ast; Datian Chen,2,&ast; Jie Mei,1 Xuejing Yang,1 Junli Ding,1 Junying Xu,1 Meilin Wang,3 Chaoying Liu,1 Dong Hua1 1Comprehensive Cancer Center, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Department of Oncology, Haimen People’s Hospital Affiliated to Nantong University, Haimen, 226100, People’s Republic of China; 3The School of Public Health, Nanjing Medical University, Nanjing, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meilin Wang; Chaoying Liu, Email meilin_wang210@126.com; liuchaoying666@163.comPurpose: The aim of this study was to explore the clinical significance of deglycosylated PD-L1 level and its correlation with EGFR and ALK mutation in lung adenocarcinoma.Materials and Methods: We estimated the intensity of both native and deglycosylated PD-L1 signals using a 28– 8 antibody on lung adenocarcinoma tissue microarray sections. We analyzed the difference in the H-score between tumor and paratumor tissues, as well as that before and after deglycosylation. Correlations between EGFR or ALK status and PD-L1 expression were analyzed. We also evaluated the differences among survival curves.Results: The expression level of PD-L1 in lung adenocarcinoma tissues was significantly higher than that in paratumor tissues (P< 0.0001). Deglycosylation significantly enhanced the detection of PD-L1 in tumor tissues (P< 0.0001). There was no statistical significance between the signal intensity of deglycosylated PD-L1 and the survival of patients (P=0.9099). However, the response to deglycosylation of PD-L1 was significantly correlated with the survival of patients with stage N1-N3 (P=0.0435) and stage T3-T4 (P=0.0366) and male patients (P=0.0258). A statistical trend was found in the correlation between the response to deglycosylation of PD-L1 and the survival of patients with grade II–III plus grade III (P=0.0973). Correlation between EGFR or ALK status and the expression of PD-L1 was not found (P> 0.05).Conclusion: PD-L1 deglycosylation enhances the detection of PD-L1 when utilizing a 28– 8 antibody. Moreover, the response to deglycosylation of PD-L1 may predict the survival of certain patients with lung adenocarcinoma.Keywords: programmed death ligand 1, deglycosylation, lung adenocarcinoma, mutation, survival

Guoyan Tang,1,&ast; Fengyan Wang,1,&ast; Zhenyu Liang,1,&ast; Cuixia Liang,2,&ast; Jinling Wang,3,&ast; Yuqiong Yang,1 Wanyi Tang,1,4 Weijuan Shi,1 Guoqiang Tang,3 Kai Yang,5 Zihui Wang,1 Qiasheng Li,1 Hualin Li,1 Jiaxuan Xu,1 Deyan Chen,2 Rongchang Chen5 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Neusoft Medical Systems Co., Ltd, Shenyang, People’s Republic of China; 3Qingyuan Chronic Disease Prevention Hospital, Qingyuan Occupational Disease Prevention Hospital, Qingyuan, People’s Republic of China; 4Qingyuan People’s Hospital, the Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen Institute of Respiratory Diseases, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongchang Chen, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen Institute of Respiratory Diseases, Shenzhen, People’s Republic of China, Email chenrc@vip.163.com Zhenyu Liang, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email 490458234@qq.comBackground: Pulmonary vascular alteration is an important feature of chronic obstructive pulmonary disease (COPD), which is characterized by distal pulmonary vascular pruning in angiography. We aimed to further investigate the clinical relevance of pulmonary vasculature in COPD patients using non-contrast computed tomography (CT).Methods: Seventy-one control subjects and 216 COPD patients completed the questionnaires, spirometry, and computed tomography (CT) scans within 1 month and were included in the study. Small pulmonary vessels represented by percentage of cross-sectional area of pulmonary vessels smaller than 5 mm2 or 5– 10 mm2 to the total lung fields (%CSA< 5 or %CSA5– 10, respectively) were measured using ImageJ software. Spearman correlation was used to investigate the relationship between %CSA< 5 and airflow limitation. A receiver operating characteristic (ROC) curve was built to evaluate the value of %CSA< 5 in discriminating COPD patients from healthy control subjects. Segmented regression was used to analyze the relationship between %CSA< 5 and %LAA-950 (percentage of low-attenuation areas less than − 950 HU).Results: We found a significant correlation between %CSA< 5 and forced expiratory volume in one second (FEV1) percentage of predicted value (%pred) (r = 0.564, P < 0.001). The area under the ROC curve for the value of %CSA< 5 in distinguishing COPD was 0.816, with a cut-off value of 0.537 (Youden index J, 0.501; sensitivity, 78.24%; specificity, 71.83%). Since the relationship between %CSA< 5 and %LAA-950 was not constant, performance of segmented regression was better than ordinary linear regression (adjusted R2, 0.474 vs 0.332, P < 0.001 and P < 0.001, respectively). As %CSA< 5 decreased, %LAA-950 slightly increased until an inflection point (%CSA< 5 = 0.524) was reached, after which the %LAA-950 increased apparently with a decrease in %CSA< 5.Conclusion: %CSA< 5 was significantly correlated with both airflow limitation and emphysema, and we identified an inflection point for the relationship between %CSA< 5 and %LAA-950.Keywords: computed tomography, pulmonary vascular pruning, airflow limitation, emphysema, chronic obstructive pulmonary disease

Donghe Chen,1 Chengdong Chang,2 Yafei Zhang,1 Shuye Yang,1 Guolin Wang,1 Lili Lin,1 Xin Zhao,1 Kui Zhao,1 Xinhui Su1 1Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Kui Zhao; Xinhui Su, Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, People’s Republic of China, Tel/Fax +86-571-87236428, Email zhaokui0905@zju.edu.cn; suxinhui@zju.edu.cnBackground: Recurrence and metastasis are important causes of postoperative death in most HCC patients. Conventional imaging modalities such as 18F-FDG PET/CT and enhanced MRI are still unsatisfactory in evaluating these patients in the clinical setting. PET/CT imaging with a radiolabeled fibroblast activation protein inhibitor (FAPI) has emerged as a new imaging technique for the diagnosis and radiotherapy of malignant tumors. While many studies have focused on the diagnostic accuracy of intrahepatic primary HCC, the evaluation of recurrent and metastatic HCC remains only poorly investigated.Case Presentation: A 71-year-old man with a five-year history of HCC after radical resection underwent 18F-FDG PET/CT due to further surgery for tumor recurrence, which revealed two iso-metabolic lesions in the right peritoneum and a hypo-metabolic lesion in the right liver. 18F-FAPI PET/CT was performed to further complement 18F-FDG PET/CT in the detection of these suspected metastatic lesions. Importantly, multiple diffuse intense radioactivity was shown in the hepatic capsule, suggesting metastatic lesions, but a wedge-shaped elevated 18F-FAPI uptake disorder around the FDG-unavid necrotic lesion after radiofrequency ablation (RFA) demonstrated benign stromal fibrosis.Conclusion: This case suggested that 18F-FAPI may have an advantage over 18F-FDG in detecting peritoneal metastasis even in tiny or early hepatic capsules of HCC, but its false positives due to postoperative stromal fibrosis should be noted. Wedge- or strip-shaped FAPI-avid lesions with sharp edges may be post-treatment stromal fibrosis.Keywords: 18F-FAPI, 18F-FDG, PET/CT, magnetic resonance imaging, hepatocellular carcinoma, false-positive, stromal fibrosis

Yalan Bi,1 Xiaohua Shi,2 Dian Chen,1 Yi Zhao1 1Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Yi Zhao, Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, People’s Republic of China, Tel/Fax +86 010 56119127, Email zhaoyimd@tsinghua.edu.cnPurpose: To investigate the clinical value of CD133 and CD44 as putative cancer stem cell markers in distinguishing between basal cell carcinoma (BCC) and trichoblastomas (TB).Patients and Methods: Tumor samples from 24 BCC and 23 TB patients were retrospectively retrieved for immunohistochemical staining of CD133 and CD44. The results were interpreted using a semiquantitative scoring system (H score). A receiver operating characteristic (ROC) curve was developed to identify an optimal cutoff value for differentiating between BCC and TB.Results: Expression of CD133 was significantly higher in BCC patients than in TB patients (median H score: 30 [IQR: 12.5– 56.3] vs 0 [IQR: 0– 2], P < 0.001). However, there was no significant difference in CD44 expression between the two groups (median H score: 105 [IQR: 63.8– 155.0] vs 60 [IQR: 30– 120], P = 0.095). The ROC analysis of CD133 immunostaining yielded an area under the curve (AUC) of 0.881 (95% CI: 0.756– 1.000) for differentiating between BCC and TB by using a H score of 7 as the cut-off value (98.5% sensitivity and 87.0% specificity). By contrast, immunostaining of CD44 showed a lower diagnostic value, with an AUC of 0.642 (95% CI: 0.476– 0.808) at the optimal cut-off value of 85 (62.5% sensitivity and 73.9% specificity). The positive and negative predictive values were 88.5% and 95.2% for CD133 and 71.4% and 65.4% for CD44, respectively. Additionally, CD133 expression was significantly associated with mitotic activity in BCC patients (r = 0.549, P = 0.005).Conclusion: Our study expanded upon previous studies of CD133 and CD44 expressions in skin tumors, suggesting that CD133, but not CD44, may serve as a novel biomarker for differential diagnosis of BCC, although future studies using a larger number of patients are needed to justify it further.Keywords: basal cell carcinoma, BCC, trichoblastomas, TB, differential diagnosis, CD133, CD44, immunohistochemistry, receiver operating characteristic, ROC

Lihong Chen,1 Yunyi Gao,2 Yan Li,1 Chun Wang,1 Dawei Chen,1 Yun Gao,1 Xingwu Ran1 1Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Medical Affairs, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xingwu Ran, Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu, 610041, People’s Republic of China, Tel +86 028-85422046, Email ranxingwu@163.comBackground: Obstructive sleep apnea is prevalent in patients with diabetic foot ulcers, while the effect of intermittent hypoxia on wound healing is unclear. The objective of this study was to investigate the effect of severe intermittent hypoxia on wound healing.Methods: C57BL/6 mice were exposed to 5 weeks of severe intermittent hypoxia or normoxia. The wound healing rate were assessed. The gene expression of CD206 and HIF-2α was tested in vivo and in vitro. Inflammatory factors in RAW264.7 macrophages were measured to investigate the effect of intermittent hypoxia on macrophage polarization. The proliferation of HUVECs and HaCaT cells was also assessed after exposure to intermittent hypoxia.Results: Severe intermittent hypoxia decreased wound healing at day 3. The expression of CD206 and HIF-2α was significantly decreased after exposure to severe intermittent hypoxia. In vitro, severe intermittent hypoxia significantly promoted M1 phenotype polarization of RAW264.7 macrophages and increased the expression of proinflammatory factors (IL-1β and TNF-α). Severe intermittent hypoxia also decreased the proliferation of HUVECs cultured in endothelial cell medium and HaCaT cells cultured in high glucose DMEM.Conclusion: Severe intermittent hypoxia could lead to M1 but not M2 macrophage polarization through downregulation of HIF-2α, and then lead to impaired wound healing.Keywords: wound and injuries, intermittent hypoxia, wound healing, inflammation, hypoxia inducible factor

Zhouzhou Feng, Lu Zhang, Haichuan Yu, Xiaojie Su, Tiankui Shuai, Lei Zhu, De Chen, Jian Liu The First Clinical Medical College, Lanzhou University, Lanzhou City, Gansu Province, People’s Republic of ChinaCorrespondence: Jian Liu, The first clinical medical college, Lanzhou University, Lanzhou City, Gansu Province, People’s Republic of China, Email medecinliu@sina.comObjective: To evaluate the clinical efficacy of high-flow nasal oxygen therapy (HFNC) and non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) after extubation.Research Methods: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: reintubation rate, mortality, complication rate, and ICU length of stay.Results: Eight studies were included, with a total of 612 subjects, including 297 in the HFNC group and 315 in the NIV group. The effect of HFNC and NIV on the reintubation rate of AECOPD patients after extubation, RR (1.49 [95% CI,0.95 to 2.33], P = 0.082). Subgroup analysis with or without hypercapnia according to the included AECOPD population, with hypercapnia, RR (0.69 [95% CI,0.33 to 1.44], P=0.317), without hypercapnia, RR (2.61 [95% CI,1.41 to 4.83], P=0.002). Mortality, RR (0.92 [95% CI,0.56 to 1.52], P = 0.752). ICU length of stay, MD (− 0.44 [95% CI,-1.01 to 0.13], P = 0.132). Complication rate, RR (0.22 [95% CI,0.13 to 0.39], P = 0.000). After subgroup analysis, the reintubation rate of HFNC and NIV has no statistical difference in patients with hypercapnia, but NIV can significantly reduce the reintubation rate in patients without hypercapnia. In the outcome measures of complication rate, HFNC significantly reduced complication rate compared with NIV. In mortality and ICU length of stay, analysis results showed that HFNC and NIV were not statistically different.Conclusion: According to the available evidence, the application of HFNC can be used as an alternative treatment for NIV after extubation in AECOPD patients with hypercapnia, but in the patients without hypercapnia, HFNC is less effective than NIV.Keywords: nasal high-flow oxygen therapy, acute exacerbation of chronic obstructive pulmonary disease, non-invasive ventilation, meta-analysis

Yanran Yang,1 Daiyun Chen,2 Yilin Li,1 Jinghua Zou,1 Ruiqi Han,1 Hongkun Li,1 Jun Zhang1 1Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Orthodontics, School of Stomatology, Shandong First Medical University, Jinan, People’s Republic of ChinaCorrespondence: Jun Zhang, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China, Tel +86 13953109816, Fax +86 53188382923, Email zhangj@sdu.edu.cnPurpose: Puerarin (C21H20O10) is a phytoestrogen that possesses various pharmacological effect, and several researches have revealed the relationship between puerarin and bone metabolism. This study was aimed to evaluate the potential influence of puerarin on the proliferation and osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMSCs) as well as on new bone formation following rapid maxillary expansion (RME) model in rats.Methods: Rat BMSCs were adopted, and the cell proliferation was detected by cell-counting kit-8 (CCK-8) assay in vitro experiments. Alkaline phosphatase (ALP) activity and alizarin red staining were analyzed quantitatively to show extracellular matrix mineralization. The mRNA and protein expression levels were used to detect osteogenic differentiation of BMSCs. In vivo bone regeneration was analyzed in a rat RME model. Eighteen 6-week-old male Wistar rats were divided into 3 groups: group 1 without any treatment, group 2 received RME and saline solution (15mg/kg), group 3 received RME and puerarin solution (15mg/kg). After 2 weeks, micro-computed tomography (Micro-CT), hematoxylin and eosin (HE) staining, and Masson staining were used to detect the new bone formation and morphological changes. Besides, ALP and bone morphogenetic protein 2 (BMP2) expression levels in mid-palatal suture were evaluated by immunohistochemical staining.Results: The results showed that puerarin upregulates cell proliferation dose-dependently. ALP activity and mineralized matrix generation were clearly enhanced at certain specific concentrations (10− 5 and 10− 6 mol/L); the expression levels of the osteoblast-related genes and proteins were increased. The measurement of micro-CT imaging revealed that puerarin significantly promoted new bone formation. Concomitantly, the histological examinations showed that puerarin solution enhanced osteogenesis in mid-palatal suture.Conclusion: Those works indicated that puerarin regulates osteogenesis in vitro and exerts a beneficial impact on bone regeneration in vivo, revealing that puerarin treatment may become one of the potential keys for improving the stability and preventing relapse of RME.Keywords: bone marrow-derived mesenchymal stem cells, bone regeneration, micro-CT, rapid maxillary expansion