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Chenyao Lin,1 Hui Zhang,2 Qiaoping Wu,1 Xuedan Qiu,1 Qingcao Li,1 Guangliang Wu3 1Department of Clinical Laboratory, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Clinical Laboratory, Ninghai County Chengguan Hospital, Ningbo, People’s Republic of China; 3Department of Clinical Pharmacy, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Qingcao Li, Department of Clinical Laboratory, The Affiliated LiHuiLi Hospital of Ningbo University, 57 Xingning Road, Ningbo, Zhejiang, 315000, People’s Republic of China, Tel +86 139-8931-6035, Email lqc_lab@163.com Guangliang Wu, Department of Clinical Laboratory, The Affiliated LiHuiLi Hospital of Ningbo University, 57 Xingning Road, Ningbo, Zhejiang, 315000, People’s Republic of China, Tel +86 137-7709-1293, Email Lwuguang0313@163.comBackground: The emergence of multidrug-resistant bacteria limits antibiotic efficacy, making accurate antimicrobial susceptibility testing (AST) essential for clinical decisions. Broth microdilution (BMD) is the gold standard but is impractical for routine application. Current automated AST systems improve efficiency but face accuracy or operational challenges, highlighting the need for reliable and user-friendly solutions.Objective: This study aims to evaluate the performance of a novel automated AST system (AutoMic-i600) based on the BMD method for AST of common clinical bacteria.Methods: A total of 229 clinical isolates (150 Gram-negative and 79 Gram-positive) were prospectively collected from microbiology laboratory between June 2023 and August 2023. We reported the comparison of the AutoMic-i600 and Vitek 2 systems for routine antibiotics, and also validated the detection performance of AutoMic-i600 for novel antibiotics, based on the BMD method.Results: The overall essential agreement (EA) and categorical agreement (CA) between AutoMic-i600 and BMD were 93.2% and 93.5% for Gram-negative bacteria and 98.5% and 97.8% for Gram-positive bacteria, respectively. The overall EA and CA between Vitek 2 and BMD were 92.6% and 93.5% for Gram-negative bacteria and 97.9% and 97.4% for Gram-positive bacteria. Importantly, for drug-resistant bacteria, AutoMic-i600 demonstrated a higher overall agreement than Vitek 2 (EA: 98.1% vs 94.8%, CA: 97.5% vs 92.0%), especially in Gram-negative bacteria (EA: 97.7% vs 93.5%, CA: 97.7% vs 89.3%). The VME rate for Gram-negative bacteria using AutoMic-i600 was significantly lower than that of Vitek 2 (1.0% vs 2.9%). Novel antibiotics detected by AutoMic-i600 exhibited EA and CA rates exceeding 90.0%.Conclusion: Based on these findings, we recommend that the AutoMic-i600 system could be a new option for routine AST testing in a clinical setting. Particularly for drug-resistant bacteria and novel antibiotics, detection with AutoMic-i600 may be more reliable, which could further contribute to the prevention and treatment of drug-resistant bacteria.Keywords: antibiotic susceptibility testing, drug-resistant bacteria, AutoMic-i600 system, automate

Xiaoshan Yang,1– 3,* Yang Zhou,2,3,* Fuxing Zhou,4,* Lili Bao,2,3 Zhengyan Wang,5 Zihan Li,2,3 Feng Ding,2,3 Huijuan Kuang,6,7 Huan Liu,8 Shenglong Tan,1 Xinyuan Qiu,1 Huan Jing,9 Shiyu Liu,2,3 Dandan Ma1 1Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 3State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 4Department of Gynecology and Obstetrics, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 5Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, People’s Republic of China; 6Department of Orthopaedics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 7State Key Laboratory for Manufacturing System Engineering, Xi’an Jiaotong University, Xi’an, 710054, People’s Republic of China; 8Department of Otolaryngology Head and Neck Surgery, Peking University Third Hospital, Beijing, 100871, People’s Republic of China; 9Department of Endodontics, Guangdong Provincial High-level Clinical Key Specialty, Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dandan Ma, Stomatological Hospital, Southern Medical University, S366 Jiangnan Boulevard, Guangzhou, Guangdong, 510280, People’s Republic of China, Tel +86-20-34152996, Email mdd@smu.edu.cn Shiyu Liu, School of Stomatology, The Fourth Military Medical University, No. 145, West Changle Road, Xi’an, Shaanxi, 710032, People’s Republic of China, Tel +86-29-84772645, Email liushiyu@vip.163.comBackground: Osteoporosis is a major public health concern characterized by decreased bone density. Among various therapeutic strategies, apoptotic extracellular vesicles (ApoEVs) have emerged as promising agents in tissue regeneration. Specifically, T cell-derived ApoEVs have shown substantial potential in facilitating bone regeneration. However, it remains unclear whether ApoEVs can promote bone mass recovery through enzymatic activity mediated by membrane surface molecules. Therefore, this study aimed to investigate whether T cell-derived ApoEVs could promote bone mass recovery in osteoporosis mice and reveal the underlying mechanisms.Methods: ApoEVs were isolated through sequential centrifugation, and their proteomic profiles were identified via mass spectrometry. Western blot and immunogold staining confirmed the enrichment of CD39 and CD73 on ApoEVs. The role of CD39 and CD73 in hydrolyzing adenosine triphosphate (ATP) to adenosine was evaluated by quantifying the levels of ATP and adenosine. Inhibitors of CD39 and CD73, and an A2BR antagonist were used to explore the molecular mechanism of ApoEVs in promoting bone regeneration.Results: ApoEVs significantly reduced bone loss and promote the osteogenic differentiation of BMMSCs in ovariectomy (OVX) mice. We observed increased levels of extracellular ATP and a decrease in CD39 and CD73, key enzymes in ATP-to-adenosine conversion in bone marrow of OVX mice. We found that ApoEVs are enriched with CD39 and CD73 on their membranes, which enable the hydrolysis of extracellular ATP to adenosine both in vitro and in vivo. The adenosine generated by ApoEVs inhibits the inflammatory response and promotes osteogenesis through A2BR and downstream PKA signaling.Conclusion: T cell-derived ApoEVs are enriched with CD39 and CD73, enabling them to hydrolyze extracellular ATP to adenosine, thereby promoting bone regeneration via A2BR and PKA signaling pathway. Our data underscore the substantive role of T cell-derived ApoEVs to treat osteoporosis, thus providing new ideas for the development of ApoEVs-based therapies in tissue regeneration. Keywords: T cell apoptosis, apoptotic extracellular vesicles, CD39, CD73, adenosine, bone regeneration

Xiaoyang Qi,1,* Danxia Zheng,2,* Zhijie Lei,3,* Jianglin Yu,3 Xusheng Qiu,1,3 Yixin Chen2 1Department of Orthopedics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Orthopedics, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Orthopedics, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yixin Chen, Department of Orthopedics, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321, Zhongshan Road, Nanjing, Jiangsu Province, 210000, People’s Republic of China, Tel +86 15005149964, Email Chenyixin93@126.comPurpose: Minimally invasive percutaneous techniques offer a promising alternative to open surgical repair of the Achilles tendon. However, the possibilities of recurrent rupture and nerve complications remain. Hence, the present study was conducted to describe a modified repair technique for the Achilles tendon able to overcome these limitations.Patients and Methods: This retrospective study included 36 patients with acute closed Achilles tendon rupture treated at our institution between January 2020 and January 2022. All patients underwent surgery at our institution and were followed up for 12– 25 months. Functional evaluation was based on the American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale and the Achilles tendon total rupture score (ATRS), along with local complications.Results: None of the patients had sural nerve injury, infection or re-rupture at a minimum follow up of 12 months. At the final follow-up, the average AOFAS ankle-hindfoot score and ATRS were 95.5 and 90.0, respectively. The final magnetic resonance imaging showed continuity and thicker regeneration of the tendon.Conclusion: The modified percutaneous repair of the Achilles tendon is an effective procedure which yields good functional outcome with few complications, and it could be widely promoted in clinical practice.Keywords: Achilles tendon, acute rupture, percutaneous repair, minimally invasive technique, clinical outcome

Ziqing Yang,1,* Bingsong Li,2,3,* Dan Ma,1,4 Yitong Lv,1 Xinhui Qiu,5 Wenge Zhang,6 Jianye Wang,7 Yanlin Zhang,8 Chunming Xu,9 Yuxin Deng,9 Jinyang Li,10 Xuemei Zhen,2,3 Jun Zhang1 1Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, People’s Republic of China; 2Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 3NHC Key Laboratory of Health Economics and Policy Research (Shandong University), Jinan, Shandong, 250012, People’s Republic of China; 4Department of Orthodontics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 5The second Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 6School of Management, Shandong University, Jinan, Shandong, 250100, People’s Republic of China; 7Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 8School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 9Department of Pediatrics, Xinjiang Medical University, Urumqi, People’s Republic of China; 10Faculty of Nursing, Shihezi University, Shihezi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuemei Zhen; Jun Zhang, Email zhenxuemei@sdu.edu.cn; zhangj@sdu.edu.cnObjective: Existing research has yet to adequately examine the correlation between sleep time, body pain, and depressive symptoms. This study seeks to elucidate the interconnections between these three elements.Methods: The study used 2020 CHARLS data for analysis. To assess the intricate association among sleep time, body pain, and depressive symptoms, the study employed Spearman correlation analysis, multiple logistic regression, restricted cubic splines, and mediation effect analysis based on bootstrap testing.Results: Risk factors for depressive symptoms in middle-aged and elderly Chinese include physical pain and reduced sleep duration. Results from the RCS suggest that the lowest risk of depressive symptoms occurs when the sleep time for the middle-aged and elderly population is approximately 7.5 hours. Body pain accounts for a 19.05% mediating effect between sleep time and depressive symptoms, and even after controlling confounding factors, there remains a 7.5% mediating effect.Conclusion: The research findings indicate that there is a significant correlation among sleep time, body pain, and depressive symptoms. Insufficient sleep time and body pain can lead to depressive symptoms. Body pain plays a partial mediating role between sleep time and depressive symptoms.Keywords: middle-aged and elderly people, sleep time, body pain, depressive symptoms

Yuchen Dai,1 Kaikai Shi,1 Qingren Liu,2 Changli Shen,3 Xinjian Lu,1 Xiaodong Qiu,1 Jie Sun1 1Department of Anesthesiology & Key Laboratory of Clinical Science and Research, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, Xishan People’s Hospital of Wuxi City, Wuxi, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, Xinxiang Central Hospital, Xinxiang, Henan, People’s Republic of ChinaCorrespondence: Jie Sun; Xiaodong Qiu, Department of Anesthesiology & Key Laboratory of Clinical Science and Research, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Nanjing City, 210009, Jiangsu Province, People’s Republic of China, Email dgsunjie@hotmail.com; qxdong@hotmail.comPurpose: This study aimed to investigate the relationship between intraoperative sleep spindle activity and postoperative sleep disturbance (PSD) in elderly orthopedic surgery patients.Patients and Methods: In this prospective observational cohort study, we collected intraoperative electroencephalography (EEG) data from 212 elderly patients undergoing orthopedic surgery from May 2023 to December 2023. We used the Athens Insomnia Scale to assess sleep quality on postoperative day (POD) 1 and POD 3 and analyzed the correlation between intraoperative sleep spindle activity and PSD through logistic regression.Results: The incidence of PSD was 65.6% on POD 1 and 41.9% on POD 3. On the first day, there were no significant differences in intraoperative sleep spindle characteristics between PSD and non-postoperative sleep disturbance (non-PSD) patients. However, by the third day, PSD patients showed lower sigma power compared to non-PSD patients, as well as lower spindle density in the bilateral frontopolar (Fp1/Fp2) and bilateral temporal (F7/F8) channels, with shorter average spindle duration (P < 0.05). Multivariate logistic regression analysis suggested that the average spindle density in F7/F8 channels (OR 0.543, 95% CI 0.375– 0.786; P = 0.001) was an independent risk factor for PSD on POD 3. Furthermore, Mini-Mental State Examination (MMSE) could independently predict PSD on POD 1 (OR 0.806, 95% CI 0.656– 0.991; P = 0.041) and POD 3 (OR 0.701, 95% CI 0.562– 0.875; P = 0.002). Pain on movement and at rest were independently associated with PSD on POD 1 (OR 1.480, 95% CI 1.200– 1.824; P < 0.001) and POD 3 (OR 1.848, 95% CI 1.166– 2.927; P = 0.009), respectively.Conclusion: Intraoperative mean spindle density in the F7/F8 channels was an independent risk factor for PSD on POD 3 in elderly patients undergoing orthopedic surgery. MMSE and postoperative pain also independently increased the risk of PSD.Keywords: postoperative sleep disturbance, sleep spindle, electroencephalography spectrum, elderly patients, orthopedic surgery

Qian Zhang,1,2,&ast; Xian Lu,3,&ast; Wen Zhang,4,&ast; Zhenyu Zhong,5,&ast; Lili Wang,4 Yuhan Qiao,4 Fei Ling,4 Xinyuan Qiu,4 Yueying Zhang1,2 1Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, People’s Republic of China; 3Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Xuzhou Medical University, Xuzhou, People’s Republic of China; 5Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yueying Zhang, Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China, Email zyy0218@126.comPurpose: To investigate the effect of continuous erector spinae plane block (ESPB) on postoperative sleep in patients undergoing thoracoscopic lung lobe resection surgery.Patients and Methods: Eighty-six patients were randomly assigned into two groups: ESPB group (Group E) or control group (Group P). Group E received ESPB before induction, followed by continuous ESPB analgesia, while Group P received postoperative intravenous controlled analgesia. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to assess postoperative sleep disturbance (PSD) on the postoperative day 3 (POD3). The St. Mary’s Hospital Sleep Questionnaire (SMH) evaluated sleep quality on the day of surgery and postoperative day 1 (POD1) and postoperative day 2 (POD2). The Identity Consequence Fatigue Scale-10 (ICFS-10) was utilized to evaluate postoperative fatigue status. Numeric Rating Scale (NRS) scores at resting and coughing were recorded at extubation, 6 h, 24 h, 48 h, 72 h after surgery. Consumption of propofol, remifentanil, and remedial analgesics (bucinazine), hospital duration, occurrence of postoperative adverse reactions were documented. Interleukin-6 (IL-6) and interleukin-10 (IL-10) serum levels were measured before surgery, 12 h, 24 h, 48 h after surgery.Results: The incidence of PSD in group E on POD3 was significantly lower than group P (75% vs 25%). Patients in group E had higher SMH scores than group P on the day of surgery and POD2. Compared with group P, the NRS scores of resting and coughing at all time points, remifentanil and bucinazine consumption, postoperative ICFS-10 scores, the incidence of nausea and vomiting, IL-6 serum levels in group E were significantly decreased. The IL-10 serum levels in group E were significantly higher than those in group P.Conclusion: The continuous ESPB can improve postoperative sleep quality, alleviate pain, fatigue and inflammation, and reduce the incidence of postoperative nausea and vomiting.Keywords: continuous erector spinae plane block, thoracoscopic, lung lobe resection, postoperative sleep disturbance

Xuan Qiu,1,&ast; Yanli Yao,1,&ast; Yulan Chen,1 Yu Li,2 Xiaojing Sun,3 Xiaoli Zhu4 1Department of Hypertension, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 2Second Department of Comprehensive Internal Medicine of Healthy Care Center for Cadres, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 3Department of Intensive Care Unit, the Seventh Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China; 4Department of Cardiovasology, the Traditional Chinese Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yulan Chen, Department of Hypertension, the First Affiliated Hospital of Xinjiang Medical University, 830011, People’s Republic of China, Tel +86-13999156752, Email sheliachen@sina.comPurpose: Intermittent hypoxia (IH), a defining feature of obstructive sleep apnea (OSA), is associated with heart damage and linked to transient receptor potential canonical channel 5 (TRPC5). Nonetheless, the function of TRPC5 in OSA-induced cardiac injury remains uncertain. For this research, we aimed to explore the role and potential mechanism of TRPC5 in cardiomyocyte injury induced by intermittent hypoxia.Methods: 30 patients with newly diagnosed OSA and 30 patients with primary snoring(PS) were included in this study. Participants were subjected to polysomnography (PSG) for OSA diagnosis. Echocardiography was used to evaluate the structure and function of the heart, while peripheral blood samples were obtained. Additionally, RT-qPCR was utilized to quantify the relative expression level of TRPC5 mRNA in peripheral blood. H9c2 cells experienced IH or normoxia. TRPC5 levels in H9c2 cells were determined via RT-qPCR and Western blotting (WB) methods. H9c2 cells overexpressing TRPC5 were subjected to either normoxic or intermittent hypoxia conditions. Cell viability was determined by CCK8, the apoptosis rate, reactive oxygen species(ROS) levels, and Ca2+ concentration were assessed by flow cytometry, and the protein levels of TRPC5, Bcl-2, Bax, and Caspase-3 were analyzed by WB. Mitochondrial membrane potential(MMP), mitochondrial membrane permeability transition pore(mPTP), and transmission electron microscopy(TEM) were employed to observe mitochondrial function and structure. After inhibiting ROS with N-acetylcysteine (NAC), apoptosis, mitochondrial function and structure, and the concentration of Ca2+ were further detected.Results: TRPC5 and left atrial diameter (LAD) were higher in OSA individuals, while the E/A ratio was lower(all P< 0.05). IH impaired cell viability, triggered cell apoptosis, and enhanced TRPC5 expression in H9c2 cells(all P< 0.05). The effects of IH on apoptosis, cell viability, mitochondrial function and structure damage, and oxidative stress (OxS) in H9c2 cells were accelerated by the overexpression of TRPC5(all P< 0.05). Furthermore, cell apoptosis and mitochondrial structural and functional damage caused by overexpression of TRPC5 were attenuated by ROS inhibition.Conclusion: TRPC5 is associated with structural and functional cardiac damage in patients with OSA, and TRPC5 promotes IH-induced apoptosis and mitochondrial damage in cardiomyocytes through OxS. TRPC5 may be a novel target for the diagnosis and treatment of OSA-induced myocardial injury.Keywords: TRPC5, oxidative stress, apoptosis, intermittent hypoxia, OSA

Anbang Zhao,1,2,&ast; Bin Hao,1,2,&ast; Simin Liu,3,&ast; Xiaoyu Qiu,1,2,&ast; Xiaoping Ming,1,2 Xiuping Yang,1,2 Jie Cai,1,2 Zhen Li,4,5 Xiong Chen1,2 1Department of Otorhinolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Sleep Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Neurosurgery, Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 5Bariatric and Metabolic Disease Surgery Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiong Chen, Department of Otorhinolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China, Email zn_chenxiong@whu.edu.com Zhen Li, Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China, Email kamel_li@163.comPurpose: The diagnosis of severe OSA still relies on polysomnography, which causes a strong sense of restraint in patients with obesity. However, better prediction tools for severe OSA applicable to patients with obesity have not been developed.Patients and Methods: Relevant clinical data of 1008 patients with OSA who underwent bariatric surgery in our hospital were collected retrospectively. Patients were divided into training and test cohorts by machine learning. Univariate and multivariate logistic regression analysis was used to screen associations, including liver stiff measurement (LSM) and abdominal visceral tissue (aVAT), and to construct a severe OSA risk prediction nomogram. Then, we evaluated the effectiveness of our model and compared our model with the traditional Epworth Sleepiness Scale (ESS) model. Finally, our associations were used to explore the correlation with other indicators of OSA severity.Results: Our study revealed that age, biological sex, BMI, LSM, aVAT, and LDL were independent risk factors for severe OSA in patients with obesity. A severe OSA risk prediction nomogram constructed by six indicators possessed high AUC (0.845), accuracy (77.6%), and relatively balanced specificity and sensitivity (72.4%, 82.8%). The Hosmer-Lemeshow test (P=0.296, 0.785), calibration curves, and DCA of the training and test cohorts suggested better calibration and more net clinical benefit. Compared with the traditional ESS model, our model had higher AUC (0.829 vs 0.545), sensitivity (78.9% vs 12.2%), PPV (77.9% vs 53.3%), and accuracy (75.4% vs 55.2%). In addition, the associations in our model were independently correlated with other indicators reflecting OSA severity.Conclusion: We provided a simple, cheap, and non-invasive nomogram of severe OSA risk prediction for patients with obesity, which would be helpful for preventing further complications associated with severe OSA.Plain Language Summary: Question: Can we predict severe OSA in patients with obesity by their metabolic complications through some non-invasive examinations?Findings: Compared with traditional questionnaires, we developed and validated a new prediction model, including liver stiffness measurement and abdominal visceral adipose tissue, to screen severe OSA in bariatric surgery candidates through non-invasive examinations, which may contribute to perioperative safety and ultimate weight loss outcomes.Meaning: For patients with obesity who are in hospital because of metabolic disorders, it is necessary for them to be screened for possible severe OSA according to our new prediction nomogram, which is helpful for preventing further complications and perioperative risk associated with severe OSA.Keywords: obstructive sleep apnea, obesity, liver stiffness measurement, visceral adipose tissue, nomogram

Xin Qiu,1,2,&ast; Shuang Shen,1,&ast; Donghong Lu,2 Nizhen Jiang,3 Yifei Feng,3 Jindu Li,1 Chenglei Yang,1 Bangde Xiang1,4,5 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 4Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, People’s Republic of China; 5Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bangde Xiang; Chenglei Yang, Email xiangbangde@gxmu.edu.cn; chenglei2017yang@163.comBackground: Hepatocellular carcinoma (HCC) presents a significant global health challenge due to its poor prognosis and high recurrence rates post-surgery. This study examines the predictive efficacy of the Advanced Lung Cancer Inflammation Index (ALI) in assessing the post-hepatectomy prognosis of patients with HCC.Methods: A cohort comprising 1654 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital from 2013 to 2019 was enrolled. Patients were stratified into two groups according to the median ALI level, and then subjected to propensity score matching (PSM) in a 1:1 ratio. Kaplan-Meier survival curves, the traditional Cox proportional hazards (CPH) model, and machine learning (ML) models were employed to analyze and evaluate ALI’s prognostic significance. Furthermore, ALI’s prognostic value in digestive system tumors was validated via analysis of the National Health and Nutrition Examination Survey (NHANES) database.Results: After applying PSM, a final cohort of 1284 patients, categorized into high and low ALI groups, revealed a significantly reduced survival time in the low ALI cohort. Univariate and multivariate Cox analyses identified ALI, BCLC stage, CK19, Hepatitis B virus (HBV) DNA, lymph node metastasis, and microvascular invasion (MVI) as independent predictors of prognosis. Both traditional CPH and ML models incorporating ALI demonstrated excellent predictive accuracy, validated through calibration curves, time-dependent ROC curves, and decision curve analysis. Furthermore, the prognostic value of ALI in digestive tumors was confirmed in the NHANES database.Conclusion: The ALI exhibits potential as a prognostic predictor in patients with HCC following hepatectomy, providing valuable insights into postoperative survival.Keywords: advanced lung cancer inflammatory index, ALI, hepatocellular carcinoma, HCC, prognosis, Cox regression, machine learning, ML

Hongyan Tan, Bin Zhang, Xiawei Kang, Lvyao Wang, Xiao Qiu, Xiangyu Hu Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400011, People’s Republic of ChinaCorrespondence: Xiangyu Hu, Email 369930758@qq.comPurpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris.Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects.Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α.Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.Keywords: pityriasis rubra pilaris, JAK inhibitors, tofacitinib, secukinumab, ustekinumab

Yongxiong Huang,1,2,&ast; Xianshuai Qiu,3,&ast; Jinlian Liu,4 Jiangtao Wan,5 Cheng Yu,1 Chun Liu,1 Yang Duan,1 Chong Chen,2 Jingxing Dai,6 Jun Ouyang,6 Ming Liu,3 Shaoxiong Min,1,5 Sujun Qiu1 1Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Spine Surgery, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, 510000, People’s Republic of China; 3Department of Orthopedics and Sports Medicine Center, Heyou Hospital, Foshan, 528333, People’s Republic of China; 4Department of Pathophysiology, Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 5Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Medical Biomechanics & National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sujun Qiu, Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China, Email qiusjspine@126.com Shaoxiong Min, Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China, Email msxbear24@163.comBackground: Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). The mechanism of IDD development and progression is not fully understood. Peripheral biomarkers are increasingly vital non-radioactive methods in early detection and diagnosis for IDD. Nevertheless, less attention has been paid to the role of mitophagy genes in the progress of IDD. This study aimed to identify the mitophagy disease-causing genes in the process of IDD and mitophagy diagnostic biomarkers for IDD.Methods: Mitophagy-related differentially expressed genes (MRDEGs) related to IDD were investigated by analyzing the microarray datasets of IDD cases from GEO, PathCards and Molecular Signatures Databases. We used R software, WGCNA, PPI, mRNA-miRNA, mRNA-TF, GO, KEGG, GSEA, GSVA and Cytoscape to analyze and visualize the data. We further used ssGSEA for immunoinfiltration analysis to obtain different immune cell infiltration. LASSO model was developed to screen for genes that met the diagnostic gene model requirements. Finally, qRT-PCR, Western blotting and HE were used to verify hub genes and their expression from clinical IDD samples.Results: We identified 14 MRDEGs and 12 hub genes. GO, KEGG, GSEA and GSVA analyses demonstrated that hub genes were critical for the development of IDD. LASSO diagnostic model consisted of six hub genes, among which SQSTM1, ATG7 and OPTN were significantly different between the two IDD disease subtypes. At the same time, SQSTM1 also had a high correlation with immune characteristic subtypes. The results of qRT-PCR and Western blotting also indicated that these genes were significantly differentially expressed in nucleus pulposus cells (NPCs) of the IDD group.Conclusion: We explored an association between MRDEGs-associated signature in IDD and validated that hub genes like SQSTM1 might serve as biomarkers for diagnostic and therapeutic targets for IDD. Meanwhile, this study can provide new insights into the functional characteristics and mechanism of mitophagy in the development of IDD. Keywords: intervertebral disc degeneration, mitophagy-related differentially expressed genes, immune infiltration, diagnostic model, SQSTM1, nucleus pulposus cells

Min Jiang,1,&ast; Hui Zhang,2,&ast; Wenjun Lu,3 Xuedan Qiu,1 Chenyao Lin,1 Rongqing Zhao,1 Qingcao Li,1 Qiaoping Wu1 1Clinical Laboratory, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China; 2Clinical Laboratory, Ninghai County Chengguan Hospital, Ningbo, Zhejiang Province, People’s Republic of China; 3Intensive Care Units, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingcao Li; Qiaoping Wu, The Affiliated LiHuiLi Hospital of Ningbo University, 1111 Jiangnan Road, Ningbo, Zhejiang Province, 315040, People’s Republic of China, Tel +86-574-55835786, Fax +86-574-55835781, Email lqc_lab@163.com; lhlyywqp@163.comBackground: Klebsiella pneumoniae (KP) is a common nosocomial pathogen. Capsules are an important component of KP’s virulence, among which the K1, K2, K5, K20, K54, and K57 serotypes are predominant and exhibit varying degrees of virulence.Methods: The capsule and virulence genes of 150 carbapenem-resistant Klebsiella pneumoniae (CRKP) and 213 carbapenem-sensitive Klebsiella pneumoniae (CSKP) isolates were examined by polymerase chain reaction (PCR). The isolates were tested for hypermucoviscosity by string tests. Phylogenetic relationships between KP isolates were analyzed using multilocus sequence typing (MLST) and a Galleria mellonella infection model confirmed the differences in virulence.Results: A total of 111 of 363 isolates of KP were detected, the highest detected serotypes were K1, K5, and K2, and CSKP was detected more frequently than CRKP. There was a greater prevalence of K1 and K2 serotypes in CSKP, while in CRKP, K5 serotypes were more prevalent. K1 isolates had the highest detection rates for hypermucoviscosity Klebsiella pneumoniae (hmKP) and hypervirulent Klebsiella pneumoniae (hvKP), and carried the most virulence genes. K54 isolates had the lowest detection rate of hmKP while K5 isolates had the lowest detection rate of hvKP and carried the fewest virulence genes. MLST results for serotypes K1, K20, and K57 showed significant homogeneity, while those for serotypes K2, K5, and K54 showed diversity. The Galleria mellonella infection model showed that the K1 serotype was the most virulent and the K54 serotype was the weakest.Conclusion: CSKP isolates were detected more frequently than CRKP isolates for capsular serotype detection. K1 isolates had the most virulence gene and strongest virulence, K5 isolates carried the fewest virulence genes, and K54 isolates had the weakest virulence. Furthermore, significant homogeneity was observed among K1, K20, and K57 isolates.Keywords: Klebsiella pneumoniae, capsular serotypes, virulence, MLST

Yuanfeng Wang,1,&ast; Xu Qiu,1,&ast; Jiao Liu,1,&ast; Xuanyi Liu,1 Jialu Pan,2 Jiayi Cai,2 Xiaodong Liu,1,3 Shugen Qu1,3 1College of Public Health and Management, Zhejiang Provincial Key Laboratory of Watershed Science and Health, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The First Clinical Medical College, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3South Zhejiang Institute of Radiation Medicine and Nuclear Technology, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this work.These authors contributed equally to this workCorrespondence: Xiaodong Liu; Shugen Qu, Email forget45@wmu.edu.cn; shugenju@wmu.edu.cnIntroduction: Sepsis is a worldwide epidemic, with high morbidity and mortality. Cuproptosis is a form of cell death that is associated with a wide range of diseases. This study aimed to explore genes associated with cuproptosis in sepsis, construct predictive models and screen for potential targets.Methods: The LASSO algorithm and SVM-RFE model has been analysed the expression of cuproptosis-related genes in sepsis and immune infiltration characteristics and identified the marker genes under a diagnostic model. Gene-drug networks, mRNA-miRNA networks and PPI networks were constructed to screen for potential biological targets. The expression of marker genes was validated based on the GSE57065 dataset. Consensus clustering method was used to classify sepsis samples.Results: We found 381 genes associated with the development of sepsis and discovered significantly differentially expressed cuproptosis-related genes of 16 cell types in sepsis and immune infiltration with CD8/CD4 T cells being lower. NFE2L2, NLRP3, SLC31A1, DLD, DLAT, PDHB, MTF1, CDKN2A and DLST were identified as marker genes by the LASSO algorithm and the SVM-RFE model. AUC > 0.9 was constructed for PDHB and MTF1 alone respectively. The validation group data for PDHB (P=0.00099) and MTF1 (P=7.2e-14) were statistically significant. Consistent clustering analysis confirmed two subtypes. The C1 subtype may be more relevant to cellular metabolism and the C2 subtype has some relevance to immune molecules.The results of animal experiments showed that the gene expression was consistent with the bioinformatics analysis.Discussion: Our study systematically explored the relationship between sepsis and cuproptosis and constructed a diagnostic model. And, several cuproptosis-related genes may interfere with the progression of sepsis through immune cell infiltration.Keywords: machine learning, cuproptosis, immune infiltration, sepsis, diagnostic model

Xun Qiu,1,2,&ast; Libin Dong,1,2,&ast; Kai Wang,1,2 Xinyang Zhong,1,2 Hanzhi Xu,1,2 Shengjun Xu,2 Haijun Guo,2 Xuyong Wei,1,2 Wei Chen,2,3 Xiao Xu1,2 1Department of Surgery, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China; 2Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China; 3Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Chen; Xiao Xu, Email jackweichen@zju.edu.cn; zjxu@zju.edu.cnBackground: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Accumulating evidence indicates that hypoxia and lactate metabolism play critical roles in tumor progression and therapeutic efficacy. This study aimed to construct a hypoxia- and lactate metabolism-related prognostic model (HLPM) to evaluate survival and treatment responses for HCC patients and develop a nomogram integrated with HLPM and clinical characteristics for prognosis prediction in HCC.Methods: Expression profile and clinical data of HCC were obtained from TCGA and ICGC databases. The univariate, LASSO and stepwise multivariate Cox analyses were used to identify the hypoxia- and lactate metabolism-related biomarkers, whose expression levels were then validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Kaplan–Meier survival curves were utilized to assess the prognostic values of biomarkers or models. Analyses of ImmuCellAI, TIDE and drug sensitivity were conducted to evaluate the therapeutic responses of patients. Furthermore, the nomogram integrated with hypoxic and lactate metabolic characteristics was established through univariate and multivariate Cox analyses. ROC curves, C-index, and calibration curves were depicted to evaluate the performance of the nomogram.Results: Five hypoxia- and lactate metabolism-related biomarkers (KIF20A, IRAK1, ADM, PPARGC1A and EPO) were used to construct HLPM. The expression of five prognostic biomarkers was validated in 14 pairs tissue samples and single-cell RNA sequencing dataset. Analyses of ImmuCellAI, TIDE and drug sensitivity implied that patients with low-risk score were more sensitive to immunotherapy and major chemotherapeutic agents. The nomogram that contained age, histological grade and risk score of HLPM was developed and exhibited a better capacity in prognosis prediction than HLPM only.Conclusion: A novel nomogram integrated with hypoxic and lactate metabolic characteristics was developed and validated for prognosis prediction in HCC, providing insight into personalized decision-making in clinical management.Keywords: hepatocellular carcinoma, nomogram, prognosis, lactate metabolism, hypoxia, immunotherapy

Rehua Wang,1,2,&ast; Yongjun Lin,3,&ast; Mao Chen,4 Wei Wang,5 Yongli Chen,6 Xiaoxia Qiu,7 Xing Miao1,2 1Department of Cardiology, Fujian Provincial Hospital, Fuzhou, 350001, People’s Republic of China; 2Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 3Department of General Medicine, the First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, 362000, People’s Republic of China; 4Department of Scientific Research, Fujian Provincial Hospital, Fuzhou, 350001, People’s Republic of China; 5Department of Psychiatry, Fuzhou Neuro-Psychiatric Hospital Affiliated to Fujian Medical University, Fuzhou, 350008, People’s Republic of China; 6Department of Cardiology, Fujian Provincial Hospital South Branch, Fuzhou, 350028, People’s Republic of China; 7Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xing Miao, Department of Cardiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, No. 134 East Street, Gulou District, Fuzhou, 350001, People’s Republic of China, Tel +86 13763810443, Email miaoxingph@outlook.comPurpose: Temperature changes unfavorably impact on cardiovascular disease. However, the association between temperature changes and coronary artery disease (CAD) is not well documented. This study aimed to explore the association between daily mean temperature and daily CAD hospital admissions on the southeast coast of China (Fuzhou City).Methods: A total of 1883 CAD patients who underwent percutaneous coronary intervention between 2017 and 2019 were obtained. The severity of CAD was evaluated by the Gensini score. Distributed lag non-linear model (DLNM) combined with a quasi-Poisson regression model was used to examine the delayed effect between daily mean temperature and daily CAD hospital admissions. Stratified analyses were performed by Gensini score and severity of lesions. The relative risk (RR) with a 95% confidence interval (CI) was used to assess the relationship.Results: Extreme cold (8°C) (RR=0.49, 95% CI: 0.25– 0.99) and moderate cold (10°C) (RR=0.56, 95% CI: 0.31– 0.99) daily mean temperature with a lag of 0– 20 days were correlated with lower risk of daily CAD hospital admissions. Moderate heat (30°C) (RR=1.80, 95% CI: 1.01– 3.20) and extreme heat (32°C) (RR=2.02, 95% CI: 1.01– 4.04) daily mean temperature with a lag of 0– 20 days related to a higher risk of daily CAD hospital admissions. Similar results were observed for daily mean temperature with a lag of 0– 25 days. Stratified analysis showed the lagged effect of daily mean temperature (lag 0, 0– 5, 0– 15, 0– 20, and 0– 25 days) on the daily CAD hospital admissions was observed only in patients with a Gensini score ≤ 39 (tertile 1).Conclusion: Cold temperatures may have a protective effect on daily CAD hospital admissions in the Fuzhou area, whereas hot temperatures can have an adverse effect.Keywords: temperature, coronary artery disease, gensini score, daily admissions, lag effect

Guimei Fan,1 Mo Yi,2 Xiangmin Qiu,1 Jinfang Zhao1 1Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2School of Nursing, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Jinfang Zhao, Shandong Provincial Hospital Affiliated to Shandong First Medical University, &num;324 Jingwuweiqi Road, Huaiyin District, Jinan City, Shandong Province, 250021, People’s Republic of China, Email zjfcqt@qq.comPurpose: This study aims to explore the complicated decision-making dilemma and challenges confronted by parents of children suffering from severe asthma within the Pediatric Intensive Care Unit (PICU) when participating in the development of their children’s discharge care plans.Patients and Methods: Employing a phenomenological methodology, a purposive sampling was performed to engage with 17 parents who participated in in-depth and semi-structured interviews between October 2022 and February 2023. The transcripts of these interviews were transcribed into textual data, which was then subjected to Colaizzi’s seven-step analysis for meticulous coding and comprehensive thematic elucidation.Results: The comprehensive analysis of the factors involved in the intricate decision-making dilemmas faced by parents of children with severe asthma during the process of crafting discharge care plans in the PICU revealed five themes and eight sub-themes: 1) Complexity of asthma-related information; 2) Insufficient provision of comprehensive decision-making support; 3) Encountering negative emotions and wavering confidence; 4) Navigating realistic constraints impacting both parents and HCPs; 5) Balancing the advantages and disadvantages of various plans.Conclusion: Parents of children with severe asthma in the PICU encounter intricate and multifaceted decision-making dilemmas while engaging in the formulation of discharge care plans. These complexities significantly dampen their decision-making enthusiasm and introduce potential risks to the children’s prognosis and recovery. In the future, it is imperative to leverage the guidance provided by healthcare professionals (HCPs) in the decision-making process, develop tailored decision support tools specifically designed for the formulation of discharge care plans for children with severe asthma in the PICU.Keywords: severe asthma, parents, discharge care plan, decision-making dilemma, phenomenological study

Xiaoqin Qiu,1 Yuechou Nong2 1Department of Nursing, The Guangxi Hospital of the First Affiliated Hospital of Sun Yat-sen University, Nanning, Guangxi, 530021, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Guangxi Academy of Medical Sciences, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Yuechou Nong, Email yuechou_gx@163.com

Wang H, Zhou C, Su Y, Gou K, Geng X, Qiu X. Drug Des Devel Ther. 2021;15:4865–4873. The authors have informed the journal that ripretinib was used in this study, not erdafitinib as indicated in parts of the paper. Namely, on page 4865, Abstract, Results section; page 4868, Animal Experiments and Pharmacokinetics Study sections; page 4872, Pharmacokinetics Effects and Conclusions sections. The authors have also advised on page 4867, Materials and Methods, Chemicals Materials section, third line from the bottom, the text “Itraconazole” should read “voriconazole”. The authors apologize for any confusion this may have caused.

Yan Lan, Chensheng Pan, Xiuli Qiu, Jinfeng Miao, Wenzhe Sun, Guo Li, Xin Zhao, Zhou Zhu, Suiqiang Zhu Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Zhou Zhu; Suiqiang Zhu, Tel +86-18171081029 ; +86-13035101141, Email zhouzhu@hust.edu.cn; zhusuiqiang@163.comPurpose: Previous studies have shown that persistent post-stroke depression (PSD) was associated with unfavorable prognosis. The aim of this multicenter prospective study was to investigate the predictors associated with persistent PSD, develop a nomogram and validate its clinical usefulness by decision curve analysis (DCA).Patients and Methods: A total of 875 acute ischemic stroke patients from four hospitals were consecutively recruited and completed 1-year follow-ups. Sociodemographic indicators, vascular risk factors, clinical information, serum biochemical indicators and cytokines were collected on admission. The functional outcome was assessed at 1 year after stroke. Persistent depression was defined as having a presentation of depression at each follow-up points and the depressive symptoms occurring persistently since the diagnosis of depression.Results: There were 513 patients who experienced PSD during the 1-year follow-up, the cumulative incidence of PSD within 1 year was 58.6%. Persistent PSD was recorded in 289 patients, of which 59 (20.4%) result in unfavorable outcomes. The risk factors of persistent PSD in 1 year after stroke were the Hamilton Depression Scale-17 items (HAMD-17) score at admission, serum direct bilirubin and free serum thyroxine (FT4) level and activated partial thromboplastin time (APTT). Nomogram conducted based on these factors has a C-index (± standard deviation) of 0.655 ± 0.039, and the DCA demonstrated that the nomogram had a favorable clinical utility.Conclusion: We found that persistent depression after stroke in the first-year time course after stroke was associated with HAMD-17 score at admission, lower serum direct bilirubin and FT4 level, and APTT. A nomogram was developed with advisable clinical usefulness in our study.Keywords: persistent post-stroke depression, nomogram, decision curve analysis

Siqi Gao,&ast; Yifeng Yu,&ast; Zheng Wang, Yifan Wu, Xingan Qiu, Chao Jian, Aixi Yu Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Chao Jian, Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China, Tel +86-27-6781-3120 ; +86-27-6781-3120, Email yuaixi@whu.edu.cn; chaojian@whu.edu.cnPurpose: Currently, skin avulsion–injury reconstruction is mainly based on subjective evaluation of traditional clinical signs. It frequently results in unnecessary tissue loss and incomplete debridement-related infection. This pilot study aimed to develop a novel near-infrared (NIR) II fluorescence imaging method to assess avulsed skin–perfusion status and thus predict its outcome early.Methods: Skin avulsion–injury models were established by avulsing 10× 4 cm pedicled flaps on porcine hindlimbs. A clinically available improved NIR-&Igr;/II multispectral imaging system was applied for NIR imaging using indocyanine green (ICG) fluorescence. Continuous NIR-wavelength filters and dynamic imaging were used to investigate optimal imaging conditions and time window. NIR-&Igr;/II imaging was synchronously conducted for quality comparison of the two methods. Visual inspection and histological studies were used for assessing the final outcome of avulsed skin.Results: NIR-II fluorescence imaging with a 1,100 nm filter obtained satisfactory performance and reached maximum fluorescence intensity at 1 minute after ICG injection. NIR-II imaging clearly visualized the microvascular network in vascularized avulsed skin and revealed “dark areas” in nonvascularized avulsed skin in a real-time fashion. NIR-II fluorescence imaging demonstrated higher resolution than NIR-I imaging, as indicated by ae higher signal-to-background ratio (2.11) and lower full width at half maximum (6.50614). The dark area of avulsed skin on imaging finally developed to necroses that were confirmed by histology.Conclusion: NIR-II real-time fluorescence imaging clearly maps the microvascular network and shows the perfusion status of avulsed skin at higher resolution than traditional NIR-I imaging, and thus precisely predicts the outcome of avulsed skin early.Keywords: ICG, near-infrared fluorescence imaging, skin avulsion-injury, swine model

Chen Wang,1,&ast; Chunyan Peng,2,&ast; Leping Ning,3,&ast; Xueping Qiu,1 Kaisong Wu,4 Na Yang,1 Bingyu Jin,1 Yue Zhao,1 Fang Zheng1 1Center for Gene Diagnosis, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Laboratory Medicine, Taihe hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China; 3Department of Laboratory Medicine, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 4Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Zheng, Center for Gene Diagnosis & Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, People’s Republic of China, Tel +86-27-67813233, Fax +86 27 67813497, Email zhengfang@whu.edu.cnPurpose: SARS-CoV-2 is extremely infectious, and the incidence of nosocomial infection is conceivably high. We aimed to develop and validate a nomogram to assist monitoring nosocomial SARS-CoV-2 infection in hospitalized patients.Patients and Methods: There were 437 COVID-19 hospitalized cases and 420 negative inpatients enrolled from two hospitals in Hubei province, China. We compared the demographic and clinical characteristics of participants between the two groups. Then, LASSO regression and logistic regression were applied to build a nomogram for SARS-CoV-2 infection prediction in the development cohort. Our nomogram was assessed by area under the curve (AUC), calibration curve, decision curve (DCA) and clinical impact curve analysis (CICA).Results: After LASSO regression filtration, eleven laboratory indicators were correlated with SARS-CoV-2 infection. Then, we integrated these features and constructed a nomogram, which showed a high AUC 0.863 (95% CI: 0.834– 0.892) in the development cohort with a sensitivity of 80.41% and specificity of 77.38% and 0.813 (95% CI: 0.760– 0.866) in validation cohort with a sensitivity of 82.98% and specificity of 70.43%. The calibration plot displayed that the predicted outcomes were in good concordance with the actual observations. DCA and CICA further showed a larger clinical net benefit.Conclusion: We constructed and validated a nomogram that integrated eleven laboratory indexes to assist monitoring of nosocomial SARS-CoV-2 infection in hospitalized patients. Our nomogram is remarkably informative for clinical practice, which will be helpful for preventing SARS-CoV-2 further transmission in hospital and avoiding nosocomial infection.Graphical Abstract: Keywords: COVID-19, nomogram, nosocomial SARS-CoV-2 infection, machine learning

Jia-Xin Cai,1– 3,&ast; Ji-Hua Liu,1– 3,&ast; Jun-Yong Wu,1– 3 Yong-Jiang Li,1– 3 Xiao-Han Qiu,1– 3 Wen-Jie Xu,1– 3 Ping Xu,1,2 Da-Xiong Xiang1– 3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drug, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Xu; Da-Xiong Xiang, Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China, Email xuping1109@csu.edu.cn; xiangdaxiong@csu.edu.cnPurpose: In order to prepare a biomimetic nano-carrier which has inflammatory chemotaxis, homologous targeting and reduce immune clearance, for targeted chemotherapy of osteosarcoma, we fabricated the paclitaxel-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles coated with 143B-RAW hybrid membrane (PTX-PLGA@[143B-RAW] NPs) and evaluate its anti-cancer efficacy in vitro and vivo.Methods: PTX-PLGA@[143B-RAW] NPs were prepared by the ultrasonic method and were characterized by size, zeta potential, polymer dispersion index (PDI), Coomassie bright blue staining, transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC). Cellular uptake, cell viability assay, flow cytometry and chemotactic effect of PTX-PLGA@[143B-RAW] NPs were evaluated in vitro. Biodistribution, anti-cancer therapeutic efficacy and safety of PTX-PLGA@[143B-RAW] NPs were evaluated in 143B osteosarcoma xenograft mice.Results: The hybrid membrane successfully coated onto the surface of PLGA nanoparticles. PTX-PLGA@[143B-RAW] NPs had a drug loading capacity of 4.24 ± 0.02% and showed targeting ability to osteosarcoma. PTX-PLGA@[143B-RAW] NPs showed high cellular uptake and improved anti-cancer efficacy against 143B cells. More importantly, PTX-PLGA@[143B-RAW] NPs treatment suppressed tumor growth in tumor-bearing mice with minimal damage to normal tissues.Conclusion: PTX-PLGA@[143B-RAW] NPs could be used for targeted drug delivery and osteosarcoma therapy.Keywords: biomimetic nano-drug delivery system, osteosarcoma, paclitaxel, targeted therapy

Xiangyuan Qiu,1 Xinying Li,1 Yuanliang Yan,2 Yuan Cai,3 Qiuju Liang,2 Bi Peng,3 Zhijie Xu,3– 5 Muzhang Xiao,6 Fada Xia,1 Jinwu Peng3,4 1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 4Department of Pathology, Xiangya Changde Hospital, Changde, 415000, Hunan, People’s Republic of China; 5National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 6Department of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaCorrespondence: Muzhang XiaoDepartment of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xmzsir@sina.comFada XiaDepartment of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of ChinaEmail xiafada@csu.edu.cnBackground: N6-methyladenosine (m6A) is most common internal RNA modification in eukaryotic cells. Existing evidence shows that m6A is closely related to pathogenesis and progression in breast cancer (BRCA). Therefore, it is critical to investigate the key role of m6A target genes in BRCA.Methods: M6A target genes in BRCA are acquired using RMVar online database. The differentially expressed genes (DEGs) from three microarray datasets (GSE5764, GSE22358, GSE9014) is processed by GEO2R. Oncomine, GEPIA, UALCAN and TNMplot were applied to validate the expression of DST. Survival analyses were performed via DRUGSURV and Kaplan–Meier Plotter database. Univariable survival and multivariate Cox analysis were completed to assess the prognostic value of DST and receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of DST. We also investigated the correlation between DST and cancer immune infiltration via using CIBERSORT, TIMER and TISIDB.Results: DST and COL11A1 were significantly expressed in both DEGs and m6A target genes set. COL11A1 show no significance on the patients’ survival. However, high expression of DST was related to the favorable prognosis. Multivariate analysis revealed that the DST dysregulation is an independent prognostic factor and ROC indicated that the great diagnostic value of DST with AUC of 0.948. Subsequently, immunological analyses showed that DST was significantly associated with various immune infiltration cells, including NK cells, T helper cells and Mast cells. Furthermore, DST was also related with multiple immune checkpoints and chemokines, including LAG3, LMTK3 CD24, CXCL12, KDR and CX3CR1. These results indicated the potential roles of DST in the development of BRCA via altering the immune response.Conclusion: DST can influence the development and progression of BRCA by altering the immune microenvironment.Keywords: breast cancer, DST, N6-methyladenosine, immune microenvironment, immune infiltration

Guo Li,1 Jinfeng Miao,1 Chensheng Pan,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Yanyan Wang,1 Zhou Zhu,1 Suiqiang Zhu,1 Lifei Lian1 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of ChinaCorrespondence: Lifei Lian Tel +86-151 7150 7263Email 47009189@qq.comPurpose: Post-stroke depression (PSD) is one of the most common and severe psychological sequelae after stroke, negatively affecting the patient’s functional outcome and quality of life. Rapidly measurable biomarkers to predict PSD are pivotal for the optimized care and allocation of healthcare resources. Lactic dehydrogenase (LDH) levels are increased in patients with central nervous system (CNS) disorders such as cerebral infarction and hypoxic–ischemic encephalopathy, which may be related to the occurrence of PSD in acute ischemic stroke (AIS) patients. This study aimed to investigate whether LDH levels on admission are associated with PSD at discharge.Patients and Methods: A multicenter prospective cohort study was conducted, including all consecutive AIS patients within 7 days after symptom onset from May 2018 to October 2019. According to the distribution of LDH and the number of patients, patients were divided into equal tertiles. PSD was evaluated by DSM-V criteria and the 17-item Hamilton Rating Scale for Depression (HRSD-17) at discharge.Results: A total of 518 AIS patients were included. The optimal cut-off points of LDH were: lowest tertile (T1) 102– 159/L, middle tertile (T2) 160– 189 U/L, and upper tertile (T3) 190– 520 U/L. A total of 249 patients (48.07%) were diagnosed with PSD at discharge. After adjusting for potential confounding factors, the odds ratio of T3 PSD was 1.698 (95% CI, 1.070– 2.694, P=0.025), compared with T1.Conclusion: In summary, LDH serum levels on admission are associated with PSD at discharge. Clinicians should pay more attention to the baseline LDH level in screening for PSD at discharge.Keywords: post-stroke depression, lactic dehydrogenase, screen, cohort study

Hui-jun Wang,1 Chun-yan Zhou,1 Yan-ding Su,1 Kai-feng Gou,1 Xiao-nan Geng,1 Xiang-jun Qiu1,2 1Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China; 2Functional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuFunctional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied.Methods: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→ 416.85 and 499.1→ 482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated.Results: Ripretinib had a good linear relationship in the range of 1– 1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h.Conclusion: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.Keywords: itraconazole, voriconazole, ripretinib, UPLC-MS/MS, pharmacokinetics, beagle dog

Xingan Qiu,&ast; Yifan Wu,&ast; Dong Zhang, Hao Zhang, Aixi Yu, Zonghuan Li Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Zonghuan LiDepartment of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of ChinaTel +86-27-67813120; +86-134 76041532Email yuaixi@whu.edu.cn; lizonghuan@whu.edu.cnBackground: Negative-pressure wound therapy (NPWT) is an effective way to promote wound healing. However, its mechanisms have not been investigated thoroughly. Growing evidence suggests that oxidative stress and Raftlin levels play important roles in wound healing. However, whether NPWT promotes wound healing through this mechanism remains unclear.Purpose: Our study focuses on the different levels of oxidative stress and antioxidant response between wounds treated by NPWT and routine dressing change. The objective of this study was to measure the differences in Raftlin levels between the two groups, which is a new biomarker related to wound healing.Methods: We divided 48 male Sprague-Dawley rats with identical full-thickness skin defects into two groups. At specific times (0, 3, 5, 7, 9, 11, and 13 days after surgery), wound tissue samples were obtained for immunohistochemistry and biochemical analysis. The expression of Raftlin and levels of oxidative stress, including malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured by biochemical analysis. Wound-healing times were also compared.Results: In the NPWT group, MDA levels were significantly decreased on days 3, 5, and 7. Furthermore, the expressions of SOD and CAT were significantly reduced on days 3 and 5. Our data also revealed that Raftlin was significantly upregulated across the whole period of wound healing. Moreover, wound healing in the NPWT group was significantly more rapid (16 days on average) than in the control group (24 days on average). On day 13 post surgery, the wound-healing percentage in the NPWT group was 91%, while that in the control group was 48%.Conclusion: NPWT may promote wound healing by upregulating Raftlin and inhibiting oxidative stress levels.Keywords: SOD, CAT, MDA, Raftlin, negative-pressure wound therapy

Zeyu Zhang,1 Xiangyuan Qiu,1 Yuanliang Yan,2 Qiujiu Liang,2 Yuan Cai,3 Bi Peng,3 Zhijie Xu,3,4 Fada Xia1 1Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Zhijie XuDepartment of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaEmail xzj1322007@csu.edu.cnFada XiaDepartment of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaEmail xiafada@csu.edu.cnBackground: Ferroptosis is the latest-discovered, iron-dependent form of regulated cell death. It has been increasingly recognized that ferroptosis-related genes participate in oncogenesis and development of cancers, including breast cancer (BRCA). Thus, It is important to explore the biofunctions of ferroptosis-related genes in BRCA.Methods: Transcriptome microarray datasets (GSE22358, GSE9014 and GSE8977, GSE2990 and GSE2034) and TCGA-BRCA were retrieved for analyses. And a variety of computational tools were used to identify the roles and associated biological functions in BRCA.Results: Two ferroptosis-related genes (AKR1C1 and AKR1C3) were significantly expressed in GSE22358, GSE9014 and GSE8977. Higher expression of AKR1C1 was related with favorable prognosis. TCGA-BRCA further confirmed the expression of AKR1C1 and the prognostic value of AKR1C1. Co-expression analyses showed the most enriched GO term and KEGG pathways were termination of DNA-templated transcription and Fanconi anemia pathway. Subsequently, immunological analyses showed AKR1C1 was significantly associated with various immune infiltration cells; among these, dendritic cells, neutrophils, macrophages were the top three infiltrating cells. Furthermore, AKR1C1 was also associated with multiple immunostimulatory molecules and chemokines, including PD-1, PD-L1, CTLA4, B7-H3, VSIR, IL-6, BTLA, CXCL2, and CCR7. These results indicated the potential roles of AKR1C1 in the immune reaction during the pathogenesis of breast cancer.Conclusion: This study firstly demonstrated that ferroptosis-related gene, AKR1C1, could be associated with immune microenvironment, thereby influencing the development and prognosis of patient with breast cancer.Keywords: breast cancer, AKR1C1, ferroptosis, immune microenvironment, immune infiltration

Jialing Wu,&ast; Kaiyun You,&ast; Xingsheng Qiu,&ast; Ting Shen, Juanjuan Song, Changlong Chen, Yanhui Jiang, Yimin Liu Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yimin Liu; Yanhui JiangDepartment of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Yuexiu District, Guangzhou City, Guangdong Province, People’s Republic of ChinaTel +86 18922182513Email liuyimin@mail.sysu.edu.cn; jiangyh26@mail.sysu.edu.cnPurpose: Local failure after endoscopic laryngeal surgery (ELS) for early glottic cancer mounts a challenge to researchers to investigate risk factors of recurrence. The present study was therefore designed to explore the prognostic factors in patients who underwent ELS for early glottic cancer.Patients and Methods: We reviewed 328 patients with T1-2N0 glottic cancer who were treated with either ELS or open surgery between 2007 and 2018 at our institution. Survival, univariate and multivariate analyses were performed in different groups (ELS vs open surgery; < 65 vs ≥ 65 years).Results: Age was discovered to be the independent prognostic factor of DFS for patients treated with ELS (HR = 3.673, p = 0.003), but not for patients who underwent open surgery. Survival analysis performed on young patients (< 65 years) showed that survival outcomes between different surgery modalities were significantly different (ELS vs open surgery: five-year DFS: 72.5 vs 84.7%, p = 0.034). Univariate and multivariate analyses further confirmed the finding, whereas these results did not appear in old patients (≥ 65 years).Conclusion: Young patients (< 65 years) treated with ELS had less favorable oncologic outcomes than those treated with open surgery. Young patients (< 65 years) are advised to consider open surgery over ELS.Keywords: early glottic cancer, age, recurrence, prognostic factor, surgery

Guo Li,1 Ping Jing,2 Guohua Chen,3 Junhua Mei,3 Jinfeng Miao,1 Wenzhe Sun,1 Yan Lan,1 Xin Zhao,1 Xiuli Qiu,1 Zhou Zhu,1,&ast; Suiqiang Zhu1,&ast; 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Department of Neurology, Wuhan Central Hospital, Wuhan, Hubei, 430014, People’s Republic of China; 3Department of Neurology, Wuhan First Hospital, Wuhan, Hubei, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhou Zhu Tel +86-18171081029Email zhouzhu@hust.edu.cnSuiqiang Zhu Tel +86-13035101141Email zhusuiqiang@163.comPurpose: The early detection of major post-stroke depression (PSD) is essential to optimize patient care. A major PSD prediction tool needs to be developed and validated for early screening of major PSD patients.Patients and Methods: A total of 639 acute ischemic stroke (AIS) patients from three hospitals were consecutively recruited and completed a 3-month follow-up. Sociodemographic, clinical and laboratory test data were collected on admission. With major depression criteria being met in the DSM-V, 17-item Hamilton Rating Scale For Depression (HRSD) score ≥ 17 at 3 months after stroke onset was regarded as the primary endpoint. Multiple imputation was used to substitute the missing values and multivariable logistic regression model was fitted to determine associated factors with a bootstrap backward selection process. The nomogram was constructed based on the regression coefficients of the associated factors. Performance of the nomogram was assessed by discrimination (C-statistics) and calibration curve.Results: A total of 7.04% (45/639) of patients were diagnosed with major PSD at 3 months. The final logistic regression model included age, baseline NIHSS and mRS scores, educational level, calcium–phosphorus product, history of hypertension and atrial fibrillation. The model had acceptable discrimination, based on a C-statistic of 0.81 (95% CI, 0.791– 0.829), with 71.1% sensitivity and 78.6% specificity. We also transformed the model to a nomogram, an easy-to-use clinical tool which could be used to facilitate the early screening of major PSD patients at 3 months.Conclusion: We identified several associated factors of major PSD at 3 months and constructed a convenient nomogram to guide follow-up and aid accurate prognostic assessment.Keywords: major post-stroke depression, nomogram, calcium–phosphorus product, C-statistic

Chen-jian Zhou,1 Hui-jun Wang,2 Chun-yan Zhou,2 Chao-fan Li,2 Ming-Jia Zhu,2 Xiang-jun Qiu2 1Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, 325027, People’s Republic of China; 2School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A method for the determination of selinexor by UPLC-MS/MS was established to study the effect of posaconazole on the pharmacokinetics of selinexor in rats.Methods: The experiment rats were divided into group A (0.5% CMC-Na) and group B (posaconazole, 20 mg/kg), 6 rats in each group. 30 minutes after administration of 0.5% CMC-Na or posaconazole, all the rats were given selinexor (8 mg/kg), and plasma samples were collected. The plasma samples underwent acetonitrile protein precipitation, and were separated by UPLC on an Acquity UPLC BEH C18 column with gradient elution. Acetonitrile and 0.1% formic acid were used as the mobile phases. The analyte detection was used a Xevo TQ-S triple quadrupole tandem mass spectrometer and multiple reaction monitoring (MRM) for analyte monitoring. We use acetonitrile for protein precipitation.Results: Selinexor had good linearity (1.0– 1000 ng/mL, r2= 0.996 2), and the accuracy and precision, recovery rate and matrix effects(ME) were also met the FDA approval guidelines. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 60.33%, 48.28% and 48.27%, and Tmax increased by 53.92%, CLz/F reduced by 32.08%.Conclusion: This bioanalysis method had been applied to the study of drug interactions in rats. It was found that posaconazole significantly increased the concentration of selinexor in rats. Therefore, when selinexor and posaconazole are combined, we should pay attention to the possible drug–drug interactions to reduce adverse reactions.Keywords: UPLC-MS/MS, selinexor, posaconazole, pharmacokinetics, DDIs, rats

Arun Venkataraman,1 Yuchuan Zhuang,2 Jennifer Marsella,3 Madalina E Tivarus,4,5 Xing Qiu,6 Lu Wang,6 Jianhui Zhong,1,4 Giovanni Schifitto3,4 1Department of Physics and Astronomy, University of Rochester, Rochester, NY, USA; 2Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA; 3Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA; 4Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, USA; 5Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA; 6Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, USACorrespondence: Arun Venkataraman Email Arun_Venkataraman@urmc.rochester.eduObjective: To examine resting-state functional MRI (rs-fMRI) networks related to sleep in the context of HIV infection.Methods: rs-fMRI data were collected in 40 HIV-infected (HIV+) individuals at baseline (treatment-naive), 12 week (post-treatment) and one year timepoints. A group of 50 age-matched HIV-negative (HIV-) individuals were also imaged at baseline and one year timepoints. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was administered at all timepoints. Using group independent component analysis (ICA), maps of functional networks were generated from fMRI data; from these, sleep-related networks were selected. A generalized linear model (GLM) was used to analyze if these networks were significantly associated with the PSQI score, and if this relationship was influenced by HIV status/treatment or timepoint.Results: HIV+ individuals had significantly lower PSQI score after treatment (p=0.022). Networks extracted from group ICA analysis included the anterior and posterior default mode network (DMN), central executive network (CEN), bilateral frontoparietal networks (FPNs), and the anterior cingulate cortex salience network (ACC SN). We found the posterior DMN, right FPN, and ACC SN GLMs showed significantly higher goodness-of-fit after incorporating PSQI data (p = 0.0204, 0.044, 0.044, respectively). Furthermore, the correlation between ACC SN and posterior DMN connectivity was significantly decreased in the HIV+ cohort.Conclusion: Functional networks such as the DMN, FPN, CEN, and ACC SN are altered in poor sleep, as measured by the PSQI score. Furthermore, the relationship between these networks and PSQI is different in the HIV+ and HIV- populations.Keywords: HIV, fMRI, sleep quality, functional connectivity

Wenyi Lv,1 Jin Feng,1 Li Chen,1 Shuai Liu,1,2 Xiaoguang Qiu1,2 1Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of China; 2Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, People’s Republic of ChinaCorrespondence: Xiaoguang Qiu; Shuai LiuBeijing Neurosurgical Institute, Capital Medical University, No. 119, South 4th Ring West Road, Fengtai District, Beijing 100070, People’s Republic of ChinaTel/Fax +86 1059975266; +86 1059975580Email qiuxiaoguang@bjtth.org; s.liu@bjtth.orgPurpose: Basal ganglia intracranial germ cell tumors (iGCTs) can specifically destroy the basal ganglia network, leading to several cognitive, learning, behavioral, and social impairments. This study aimed to investigate the behavior and social disorders of patients with basal ganglia iGCTs.Patients and Methods: We recruited 30 newly diagnosed iGCTs patients (and their parents) for the current study. The Child Behavior Checklist/6– 18 was used to evaluate emotional and behavioral problems. The Conner’s Parent Rating Scales was used to assess symptoms of hyperactivity/impulsivity and conduct problems. The health-related quality of life (HRQoL) was assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scale. Performance status was assessed using the Lansky play-performance scale and Karnofsky performance scale. The effects of basal ganglia lesions on these scores were examined.Results: Patients with basal ganglia iGCTs (n = 10) had more behavioral problems (attention problems, aggressive behavior, learning problems, hyperactivity index), social function impairment, anxiety/depression, and poorer HRQoL compared to patients with non-basal ganglia iGCTs (n = 20). There was no significant difference in the Lansky play-performance/Karnofsky performance scale scores.Conclusion: This study demonstrates the effects of basal ganglia lesions on behavioral and emotional outcomes, social functions, and HRQoL of patients with iGCTs. The results may help to understand the function of basal ganglia and provide evidence for the benefit of early psychological intervention to improve the treatment for this rare disease.Keywords: intracranial germ cell tumors, pediatrics, The Child Behaviour Checklist, The Conner’s Parent Rating Scales, health-related quality of life

Wei Zhou,1,2 Shuang-long Li,3 Ti Zhao,3 Le Li,3 Wen-bin Xing,3 Xiang-jun Qiu,3 Wei Zhang1 1The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Nanyang City Central Hospital, Nanyang 473009, People’s Republic of China; 3School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Wei ZhangThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaEmail zhangw571012@126.comXiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaEmail lyxiangjun@126.comObjective: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles.Materials and Methods: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 μg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 μg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg.Results: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements.Conclusion: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.Keywords: dexmedetomidine, dezocine, midazolam, 1-hydroxymidazolam, pharmacokinetics, drug–drug interactions

Shuang-long Li, Yong-liang Zhu, Chun-yang Zhu, Shao-bin Li, Zi-heng Li, Xiang-jun Qiu Medical College of Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuMedical College of Henan University of Science and Technology 471023, People’s Republic of ChinaTel +86 13698882699 Fax + 86 379-64830346 Email lyxiangjun@126.comAbstract: A method for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagle plasma by UPLC-MS/MS was developed and validated. After the plasma was extracted by acetonitrile precipitation, the analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using acetonitrile-formic acid as the mobile phase in gradient mode. The analytes were monitored by multiple reaction monitoring (MRM) in electrospray negative ion mode. The mass transfer pairs were m/z 368.97→ 119.01 for parecoxib, m/z 312.89→ 118.02 for valdecoxib, and m/z 379.98→ 316.02 for celecoxib (internal standard, IS). The correlation coefficients of parecoxib and valdecoxib ranged from 5 to 4000 ng/mL were greater than 0.9998. The recovery of parecoxib and valdecoxib was greater than 82.54%. The inter- and intra-day precision RSD values were 1.36∼ 3.65% and 2.28∼ 5.91%, respectively. The accuracy of RE values were − 1.38%∼ 1.96%. Finally, the matrix effect (ME) and stability were also within acceptable criteria. This method had been successfully applied to the pharmacokinetics of parecoxib and valdecoxib in beagle plasma after injection of parecoxib (1.33 mg/kg, intramuscular injection).Keywords: parecoxib, valdecoxib, UPLC-MS/MS, pharmacokinetics

Lili Cao,*,1,2 Xiaofang Che,*,1,2 Xueshan Qiu,3 Zhi Li1,2 Bowen Yang1,2 Shuo Wang1,2 Kezuo Hou1,2 Yibo Fan1,2 Xiujuan Qu1,2 Yunpeng Liu1,21Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 3Department of Pathology, College of Basic Medical Sciences of China Medical University, Shenyang 110001, People’s Republic of China*These authors contributed equally to this workBackground: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC.Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients.Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P

Qianmeng Lin,1,2,* Saili Xie,1,* Xiangjun Qiu,3 Jingjing Chen,1 Ren-Ai Xu11The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325000, People’s Republic of China; 3Medical College of Henan University of Science and Technology, Luoyang 471003, People’s Republic of China*These authors contributed equally to this work Background: In clinical practice, common problem polypharmacy could result in the increased risks of drug–drug interactions (DDIs). Co-administered imatinib (IMA) and voriconazole (VOR) as one treatment protocol in cancer patients with fungal infections are common.Purpose: The aim of the present study was to assess the potential DDIs associated with the concurrent use of IMA and VOR in rat liver microsomes (RLMs) and in rats.Methods and results: The concentration levels of IMA, VOR, and their metabolites N-desmethyl IMA (CGP74588) and N-oxide voriconazole (N-oxide VOR) were determined by ultra performance liquid chromatography-tandem mass spectrometry. In vitro study of RLMs, VOR inhibited the IMA metabolism with the half-maximal inhibitory concentration (IC50) of 105.20 μM, while IC50 for IMA against VOR was 61.30 μM. After co-administered IMA and VOR in rats, the Cmax of IMA was increased significantly, while the AUC0→t, AUC0→∞, and Cmax of CGP74588 were decreased significantly. In addition, similar results were also found that the main pharmacokinetic parameters (AUC0→t, AUC0→∞, MRT0→∞, Tmax, and Cmax) of VOR were increased significantly, while the AUC0→t, AUC0→∞, and Cmax of N-oxide VOR were decreased significantly. Incorporation of all the results indicated that both drugs had a inhibitory effect on each other’s metabolism in vitro and in vivo.Conclusion: Thus, it is of great value to monitor the concomitant use of IMA and VOR in the clinic to reduce the risks of unexpected clinical outcomes.Keywords: drug–drug interaction, imatinib, voriconazole, rat liver microsome, metabolism

Qian Chen,1 Xiaoyun Zeng,2 Dongping Huang,2 Xiaoqiang Qiu2 1Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China; 2Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China Background and aim: Previous studies have suggested that lymph node metastasis (LNM) in early-stage cervical cancer (CESC) may affect the prognosis of patients and the outcomes of subsequent adjuvant therapy. However, research focused on miRNA expression in early-stage CESC patients with LNM remains limited. Therefore, it is necessary to identify prognostic miRNAs and determine their molecular mechanisms.Methods: We evaluated the differentially expressed genes in early-stage CESC patients with LNM compared to patients without LNM and evaluated the prognostic significance of these differentially expressed genes by analyzing a public dataset from The Cancer Genome Atlas. Potential molecular mechanisms were investigated by gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction network analyses.Results: According to the The Cancer Genome Atlas data, hsa-miR-508, hsa-miR-509-2, and hsa-miR-526b expression levels were significantly lower in early-stage CESC patients with LNM than in patients without LNM. A multivariate analysis suggested that three miRNAs were prognostic factors for CESC (P

Xuefeng Qiu,1,2,* Kai Cao,1,2,* Tingsheng Lin,1,2 Wei Chen,1 Ahu Yuan,2 Jinhui Wu,2 Yiqiao Hu,2 Hongqian Guo1 1Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, China; 2State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China *These authors contributed equally to this work Abstract: Intravesical instillation of antitumor agents following transurethral resection of bladder tumors is the standard strategy for the treatment of superficial bladder cancers. However, the efficacy of current intravesical instillation is limited partly due to the poor permeability of the urothelium. We therefore aimed to develop a high-penetrating, target-releasing drug delivery system to improve the efficacy of intravesical instillation. PAMAM, a dendrimer, were conjugated with polyethylene glycol (PEG) to form PEG-PAMAM complex as a nanocarrier. Doxorubicin (DOX) was then encapsulated into PEG-PAMAM to generate DOX-loaded PEG-PAMAM nanoparticles (PEG-PAMAM-DOX). Our results indicated that the PEG-PAMAM was a stable nanocarrier with small size and great biosafety. The release of DOX from PEG-PAMAM-DOX was sluggish but could be effectively triggered in an acid microenvironment (pH =5.0). As a drug carrier, PEG-PAMAM could penetrate mice bladder urothelium effectively and increase the amount of DOX within the bladder wall after intravesical instillation. The antitumor effect of PEG-PAMAM-DOX was evaluated using an orthotopic bladder cancer model in mice. Compared to free DOX, PEG-PAMAM-DOX showed significantly improved efficacy of DOX for intravesical instillation with limited side effects. In conclusion, we successfully developed a PEG-PAMAM-based drug delivery system to enhance the antitumor effect of intravesical instillation. Keywords: bladder cancer, intravesical instillation, chemotherapy, dendrimer, PAMAM, penetration, acid microenvironment, target-releasing

Bo Cheng,1,2 Xiaofu Qiu,1 Huanhui Li,1 Guosheng Yang1 1Department of Urology, Southern Medical University affiliated Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China Purpose: Laser therapy provides an alternative option for treating non-muscle-invasive bladder cancer (NMIBC). However, the clinical evidence for potassium-titanyl-phosphate (KTP) laser en bloc resection is still limited. Here, we investigated the efficacy and safety of the 120-W front-firing KTP laser for the treatment of NMIBC.Methods: A total of 64 patients with NMIBC treated with either a 120-W front-firing KTP-photoselective vapo-enucleation of the bladder tumor (PVEBT, n=34) or transurethral resection of the bladder tumor (TURBT, n=30) were included. En bloc resection was applied to the patients in PVEBT group.Results: There was no significant difference in rinsing time (P=0.292), indwelling catheter (P=0.080), pathologic type, and T stage (P=0.870) between the two groups. Compared with the TURBT group, patients treated with PVEBT had a shorter hospitalization stay (P=0.044), a shorter operation time (P=0.008), and a lower muscle miss rate (P=0.044). PVEBT is superior to TURBT in terms of the rate of 1-year recurrence (P=0.015) and tumor grade progression rate (P=0.019).Conclusion: The 120-W front-firing KTP laser en bloc enucleation technique is a safe and feasible procedure for treating patients with NMIBC. Further external validation in larger cohorts with a long follow-up period is warranted. Keywords: bladder cancer, transurethral resection, en bloc, laser surgery, recurrence

Julio C Fernandes,1 Xingping Qiu,2 Francoise M Winnik,2 Mohamed Benderdour,1 Xiaoling Zhang,3 Kerong Dai,3 Qin Shi11Orthopaedics Research Laboratory, Research Centre, Sacré-Coeur Hospital, 2Department of Physical Chemistry and Polymer Science, Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada; 3Orthopaedic Cellular and Molecular Biology Laboratories, Institute of Health Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaAbstract: The low transfection efficiency of chitosan is one of its drawbacks as a gene delivery carrier. Low molecular weight chitosan may help to form small-sized polymer-DNA or small interfering RNA (siRNA) complexes. Folate conjugation may improve gene transfection efficiency because of the promoted uptake of folate receptor-bearing cells. In the present study, chitosan was conjugated with folate and investigated for its efficacy as a delivery vector for siRNA in vitro. We demonstrate that the molecular weight of chitosan has a major influence on its biological and physicochemical properties, and very low molecular weight chitosan (below 10 kDa) has difficulty in forming stable complexes with siRNA. In this study, chitosan 25 kDa and 50 kDa completely absorbed siRNA and formed nanoparticles (≤220 nm) at a chitosan to siRNA weight ratio of 50:1. The introduction of a folate ligand onto chitosan decreased nanoparticle toxicity. Compared with chitosan-siRNA, folate-chitosan-siRNA nanoparticles improved gene silencing transfection efficiency. Therefore, folate-chitosan shows potential as a viable candidate vector for safe and efficient siRNA delivery.Keywords: nonviral vector, chitosan, gene delivery, folate-targeted, siRNA