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Lu Hua,1,2,&ast; Kaiyuan Sha,1,2,&ast; HongCheng Lu,1,2 Ying Han,1,2 Cehua Ou,1,2 Jiang-Lin Wang,1 Yue Zhang1,2 1Department of Pain Management, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou Southwest Medical University, Luzhou, Sichuan Province 646000 People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiang-Lin Wang; Yue Zhang, Department of Pain Management, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China, Email jianglin523@swmu.edu.cn; zhangyue0518@swmu.edu.cnPurpose: To explore the therapeutic effect of C2 dorsal root ganglion pulsed radiofrequency (PRF) combined with stellate ganglion block (SGB) in patients with cervicogenic headache (CEH).Patients and Methods: We retrospectively reviewed 90 patients diagnosed with CEH who were admitted to our hospital between May 2019 and May 2022. All patients were divided into three groups (n = 30 each) according to the actual treatment method used: ultrasound-guided SGB, ultrasound-guided C2 dorsal root ganglion PRF treatment, and ultrasound-guided C2 dorsal root ganglion PRF combined with SGB treatment. Patients’ pain intensity, sleep, and mood changes were assessed by statistically analyzing their pain visual analog scale (VAS), Pittsburgh Sleep Quality Inventory (PSQI), and short-form McGill Pain Questionnaire affective item scores before and after treatment.Results: The post-treatment VAS, PSQI, and McGill scores were significantly decreased in all patients (P < 0.05), and all three scores in ultrasound-guided C2 dorsal root ganglion PRF combined with SGB were lower than those in ultrasound-guided SGB alone and ultrasound-guided C2 dorsal root ganglion PRF alone (P < 0.05).Conclusion: The use of ultrasound-guided C2 dorsal root ganglion PRF combined with SGB in patients with CHE is effective in alleviating pain and improving sleep, and deserves to be replicated in the clinic.Keywords: cervicogenic headache, C2 dorsal root ganglion, pulsed radiofrequency, stellate ganglion block

Jun Cao,1,&ast; Lin Hua,2,&ast; Liang Dong,3 Zhouhuan Wu,4 Guohui Xue2 1Department of Biochemistry and Molecular Biology, School of Medicine, Jiujiang University, Jiujiang, People’s Republic of China; 2Department of Clinical Laboratory, Jiujiang NO.1 People’s Hospital, Jiujiang, People’s Republic of China; 3Department of Rheumatology, Jiujiang NO.1 People’s Hospital, Jiujiang, People’s Republic of China; 4Department of Pharmacology, School of Medicine, Jiujiang University, Jiujiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohui Xue, Email xueguohui0816@126.comBackground: Inflammatory responses and metabolic abnormalities play essential roles in the pathophysiology of osteoarthritis (OA). Our study aimed to evaluate the association between monocyte-to-high density lipoprotein-cholesterol ratio (MHR) and OA and compared it with other systemic inflammatory markers.Methods: This study recruited 323 OA cases and age- and sex-matched 283 control participants during the same period. Demographic, clinical, and imaging data and laboratory indicators were obtained from participants’ records. Systemic inflammatory markers were calculated for both cohorts. The diagnostic effectiveness of each index for distinguishing patients with OA was analyzed using receiver operating characteristic (ROC) curves. Spearman’s method and ordered logistic regression were used to analyze the association between each indicator and Kellgren and Lawrence (KL) grade.Results: MHR was significantly higher (0.38± 0.18 vs 0.25± 0.07, p < 0.0001) in OA patients than healthy controls. MHR had the largest area under the ROC curve for predicting OA. Analysis of ordered logistic regression indicated that MHR was a risk factor for OA radiological severity. Spearman correlation analysis indicated that MHR significantly correlates with the KL grade. Moreover, MHR was significantly higher in early stage patients than in healthy controls.Conclusion: These results suggest that an elevated MHR could reflect knee OA severity and might be a useful marker for diagnosis and monitoring of OA.Keywords: osteoarthritis, disease severity, monocyte to high-density lipoprotein cholesterol ratio, inflammation, biomarker

Jing Luo,1 Nuoyan Wang,1 Ling Hua,1 Fei Deng,1 Dan Liu,1 Jun Zhou,1 Yue Yuan,1 Fumin Ouyang,1 Xuemin Chen,1 Shujuan Long,1 Yasi Huang,1 Zhanxing Hu,2,3 Hong Zhou1 1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People’s Republic of China; 2State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, People’s Republic of China; 3The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, People’s Republic of ChinaCorrespondence: Hong Zhou, Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, People’s Republic of China, Tel +86-085128643451, Fax +86-085128642303, Email zhouh64@163.com Zhanxing Hu, State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, People’s Republic of China, Email huzhxi88@163.comBackground: The anti-inflammatory application of Guizhou ethnic medicine in the Karst area of China is mainly based on folk medicine experience, and there has been a lack of systematic research, leading to limited application of Guizhou ethnic medicine.Purpose: To evaluate the anti-inflammatory effects of compounds extracted from Guizhou ethnic medicine in the Karst area and investigate their molecular mechanisms.Methods and Results: Preliminarily, the anti-inflammatory effects of 181 compounds extracted from Guizhou ethnic medicine were screened in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and the 41 compounds with anti-inflammatory effects were selected. Then, these 41 compounds with anti-inflammatory effects were investigated for their druggability and 18 compounds were selected. Thirdly, compound Hx-150, named isocorydine, was selected as the candidate compound. In vitro and in vivo, isocorydine inhibited LPS-induced TNF-α and IL-6 release from LPS-treated mouse peritoneal macrophages. Isocorydine decreased TNF-α, IL-6, and IL-1β levels in the blood, lung, and spleen, and ameliorated lung tissue damage. Mechanistically, isocorydine had no effect on the mRNA expressions and protein levels of Tlr4, Myd88, and Traf6. Isocorydine also had no effect on the expression of RelA (encoding NFκB p65) mRNA, but inhibited phosphorylation of IκBα and NFκB p65 in the TLR4-mediated signaling pathway. Furthermore, isocorydine increased the cytoplasmic level of NFκB p65 and decreased its nuclear level in LPS-treated macrophages. Importantly, isocorydine upregulated Vdr mRNA (encoding the vitamin D receptor) expression and increased the nuclear VDR protein level.Conclusion: Many compounds from Guizhou ethnic medicine had potential anti-inflammatory activities. Among them, isocorydine has a strong anti-sepsis effect, which is tightly related to its upregulation of VDR expression and inhibition of NFκB p65 translocation into the nucleus, leading to reduced pro-inflammatory cytokines release and protection for LPS-challenged mice.Keywords: Guizhou ethnic medicine, LPS, Sepsis, Pro-inflammatory cytokines, NFκB, VDR

Xiao-nan Gao,1 Xu-yang Nie,1 Jing-lin Gao,1 Tian-fang Heng,2 Yu-qi Zhang,2 Li Hua,1 Ya-qi Sun,1 Zhang-ying Feng,1 Ming-xia Wang,1 Li Jia2 1Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Ming-xia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Tel +86 311-66696233, Email mxia_wang@163.com Li Jia, Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Email 281575038@qq.comPurpose: This study aimed to characterize the pharmacokinetics of nalbuphine in patients undergoing general anesthesia with varying degrees of liver dysfunction.Patients and Methods: Twenty-four patients were enrolled and divided into three cohorts based on liver function: normal liver function (n = 13), mild liver dysfunction (n = 5), and moderate/severe liver dysfunction (n = 6). During the induction of anesthesia, they received 15 mg of nalbuphine intravenously. Venous blood samples were collected from each patient. The plasma concentration of nalbuphine was determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of nalbuphine were calculated by non-compartmental analysis (NCA) using Phoenix WinNonlin software.Results: Compared with the normal liver function group, the plasma elimination half-life (T1/2) of nalbuphine was increased by approximately 33% in the moderate/severe liver dysfunction group (2.66 h vs 3.54 h, P< 0.05), and the volume of distribution (Vd) increased by approximately 85% (100.08 L vs 184.95 L, P< 0.05). Multivariate analysis revealed that weight and platelet were associated with clearance (CL); total bilirubin as an independent factor was associated with T1/2, and weight associated with area under the curve (AUC(0→∞)) independently.Conclusion: The T1/2, mean residence time, and Vd of nalbuphine in patients with moderate/severe liver dysfunction were prolonged or increased significantly compared with those in the normal liver function group. These data suggest that it may need to be used with caution when nalbuphine is administered to patients with moderate or severe liver dysfunction.Keywords: nalbuphine, intravenous, liver dysfunction, UPLC-MS/MS, pharmacokinetics

Dan Wang,1,&ast; Yanhong Zhou,2,&ast; Li Hua,2 Jiaxiang Li,2 Ni Zhu,2 Yifei Liu2 1School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, HuBei, People’s Republic of China; 2School of Stomatology and Ophthalmology, Xianning Medical College, Hubei University of Science and Technology, Xianning, HuBei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yifei Liu, School of Stomatology and Ophthalmology, Xianning Medical College, Hubei University of Science and Technology, Xianning, HuBei, People’s Republic of China, Tel +86-715-8266030, Email liuyifei@hbust.edu.cnIntroduction: In the cell cycle, cyclin-dependent kinases (CDKs) play a positive regulatory role, which is essential for normal cell growth, but the expression pattern and prognostic significance of the CDK family in colorectal cancer (CRC) have not been systematically investigated.Methods: In our study, we analyzed and visualized the expression of CDKs in CRC using TCGA, GEPIA, GSCALite, TIMER, HPA database, and R language CDKs risk model was constructed.Results: Overall, CDKs (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7 and CDK8) were differentially expressed between normal controls and colorectal cancer. Three CDKs genes (CDK3, CDK5 and CDK8) associated with prognosis were obtained by univariate and multivariate Cox and LASSO regression analysis. In CRC, CDK3, CDK5 and CDK8 are significantly associated with expression levels of recognized immune infiltrates.Conclusion: CDK3, CDK5 and CDK8 are potential diagnostic markers for CRC; meanwhile, CDK3, CDK5 and CDK8 are potential prognostic markers for CRC; studying the relationship between CDKs and tumor immunology may be helpful for immunotherapy of CRC, and more studies are needed to confirm these results.Keywords: colorectal cancer, cyclin-dependent kinases family, mRNA expression, prognosis, risk score model

Zhangying Feng, Jinglin Gao, Xiaonan Gao, Li Hua, Xuyang Nie, Yaqi Sun, Mingxia Wang Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Mingxia WangDepartment of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of ChinaTel +86311-66696233Email mxia_wang@163.comPurpose: A simple, rapid and reliable method to quantify methotrexate (MTX) in human plasma by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was established and validated in two laboratories.Patients and Methods: Sample separation was achieved on a Synergi Hydro-RP column (50 mm× 2.0 mm, 2.5 μm) with a gradient elution program in 3.5 min after a simple protein precipitation with methanol (MeOH) and acetonitrile (ACN) (1:1). About 5 mM ammonium formate aqueous solution with 0.2% formic acid and ACN were used as mobile phase with a flow rate of 0.5 mL/min at 40 °C. Mass spectrometry detection using AB Sciex Triple Quad 4500 mass spectrometer (4500 QQQ) and Qtrap 5500 mass spectrometer (5500 Q-trap) were both characterized by electrospray ionization (ESI) for positive ions in multiple reaction-monitoring (MRM) mode. Quantitative ion pairs were m/z 455.1→m/z 308.0 for MTX and m/z 248.1→m/z 121.0 for tinidazole (TNZ) used as internal standard (IS).Results: Linear calibration curves were generated over the range of 5– 1000 ng/mL (r2> 0.99) on both the 4500 QQQ and 5500 Q-trap, both of the intra- and inter-batch precision were less than 7.67% and accuracy ranged from 96.33% to 108.94%. The recovery and matrix effect were 82.20– 93.98% and 102.69– 105.28%, respectively.Conclusion: An analytical method transfer was achieved by re-verification in two laboratories to ensure stability and reproducibility and this method has been applied for therapeutic drug monitoring (TDM) successfully in children and adults with NHL, and during routine TDM, two delayed elimination of MTX cases were observed and analyzed.Keywords: methotrexate, therapeutic drug monitoring, non-Hodgkin lymphoma, children, adult

Yi Ren, Tiehua Zheng, Lei Hua, Fuzhou Zhang, Yangwei Ma, Jianmin Zhang Department of Anesthesiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of ChinaCorrespondence: Jianmin ZhangDepartment of Anesthesiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56, South Lishi Road, Beijing, 100045, People’s Republic of ChinaTel +861059616415Fax +861059616429Email zjm_bch@163.comPurpose: The Nuss procedure is a recognized treatment for adolescent pectus excavatum that results in severe postoperative pain. Erector spinae plane block (ESPB) is a novel technique that provides postoperative analgesia and reduces opioid consumption. Our aim is to explore whether ESPB produces analgesia similar to thoracic epidural anaesthesia (TEA) in paediatric patients undergoing Nuss procedure.Study Design and Methods: This randomized, controlled, non-inferiority trial will enrol 300 paediatric patients undergoing Nuss surgery. Participants will be randomly assigned 1:1 to receive ESPB or TEA preoperatively. The primary, joint endpoint is the average numeric rating scale (NRS) score and cumulative sufentanil consumption. The secondary endpoints are pain scores and sufentanil consumption at different time points after surgery, analgesia-related side effects, and other postoperative complications. Data will be analysed by the intention-to-treat principle.Discussion: This study investigates the effect of ESPB on postoperative opioid consumption and pain scores and intend to provide a new strategy of analgesia management for Nuss procedure in paediatric patients.Keywords: postoperative pain, erector spinae plane block, pectus excavatum, Nuss procedure, opiates

Zhaoxian Yan,1 Yahui Chen,2 Xin Zhang,3 Lin Hua,3 Lifa Huang3 1First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China; 2Department of Rheumatology, Ningbo No.6 Hospital, Ningbo, 315040, Zhejiang, People’s Republic of China; 3Department of Neurosurgery, Zhejiang Provincial Hospital of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, Zhejiang, People’s Republic of ChinaCorrespondence: Lifa HuangDepartment of Neurosurgery, Zhejiang Provincial Hospital of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, No. 54 Youdian Road, Shangcheng District, Hangzhou, 310006, Zhejiang, People’s Republic of ChinaEmail eaybig@163.comBackground: Tumor necrosis factor-α (TNF-α)-induced protein 3-interacting protein 2 (TNIP2) has been well demonstrated to act as a principal contributor to the development of inflammatory diseases; however, the role of TNIP2 in cerebral ischemic/reperfusion injury has never been studied.Methods: Gene expression was examined by using quantitative real-time polymerase chain reaction and Western blot. The functional role of TNIP2 in oxygen and glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury was evaluated using cell counting kit-8, terminal deoxynucleotidyl transferase dutp nick end labeling assay and enzyme-linked immunosorbent assay. Commercial kits were applied to evaluate the activity of NF-kappa-B (NF-κB) and caspase-3, as well as the release of lactate dehydrogenase release (LDH).Results: TNIP2 expression was substantially declined in HT22 cells following OGD/R stimulation. TNIP2 overexpression attenuated ODG/R-induced inflammation in HT22 cells, as evidenced by reduced levels of TNF-α, interleukin (IL)-1β, and intercellular cell adhesion molecule-1 (ICAM-1), and increased levels of IL-10. TNIP2 overexpression also reduced activity of NF-κB under ODG/R condition. Meanwhile, OGD/R treatment caused a reduction of cell viability and an elevation of cell apoptosis in HT22 cells, as indicated by the increase in LDH and caspase-3 activity. Whereas, OGD/R-induced HT22 cell injury was mitigated by TNIP2 overexpression in HT22 cells. Besides, we found the involvement of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/NF-κB pathway in the neuroprotective effect of TNIP2 on OGD/R-induced HT22 cell damage.Conclusion: TNIP2 overexpression mitigates OGD/R-induced inflammatory response and apoptosis. Moreover, TLR4/MyD88/NF-κB pathway participates in the protective effect of TNIP2 on OGD/R-induced neuronal damage.Keywords: TNF-α-induced protein 3-interacting protein 2, ischemic reperfusion injury, inflammation, apoptosis, toll-like receptor 4/myeloid differentiation factor 88/NF-kappa-B signaling

Yanping Su,1 Meirong Huo,1 Lin Hua,2 Yuan Zhang,1 Jiawen Yi,1 Shu Zhang,1 Jie Li,1 Yuhui Zhang1 1Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing, People’s Republic of China; 2School of Biomedical Engineering, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Yuhui ZhangDepartment of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, 8 Gongtinan Road, Chaoyang District, Beijing, People’s Republic of ChinaTel +86 13520208369Email zhangyhcy@163.comPurpose: To explore the relationship between venous thromboembolism (VTE) and early mortality (within six months) in Chinese patients with newly diagnosed metastatic non-small cell lung cancer (NSCLC) after entering the era of precision treatment.Methods: A cohort of 706 consecutive subjects with newly diagnosed metastatic NSCLC were prospectively observed. Clinical and survival data were recorded over a six-month follow-up period. The predictive factors for the occurrence of VTE and the relationship with early mortality were evaluated through univariate and multivariate analyses.Results: During the six-month follow-up period, VTE events occurred in 12.2% (86/706) of the enrolled patients. In the multivariate analyses for VTE, an age older than 70 years (vs < 70: sub-distribution hazard radio [SHR], 1.678; 95% confidence interval (CI), 1.073– 2.600; P=0.022), an Eastern Cooperative Oncology Group performance status ≥ 2 (vs 0/1: SHR, 1.946; 95% CI, 1.277– 2.970; P=0.002), and having an ALK rearrangement (vs non-rearrangement: SHR, 2.377; 95% CI, 1.186– 4.760; P=0.015) were significantly associated with the occurrence of VTE. Within six months, 116 subjects (16.4%) died, and the occurrence of VTE (vs no VTE: adjusted HR: 1.863; 95% CI: 1.178– 2.947, P=0.008) was remarkably associated with early mortality. Further analysis showed 98 patients (13.9%) with early mortality had EGFR/ALK wild-type genes, with a risk of early mortality 5.935-fold higher than that of patients with an EGFR mutation/ALK rearrangement. Finally, subgroup analyses showed that VTE occurrence was a significant factor for predicting early mortality in patients with EGFR/ALK wild-type genes (adjusted HR: 1.682; 95% CI: 1.023– 2.768, P=0.041).Conclusion: Patients with an EGFR mutation/ALK rearrangement had a significantly decreased risk of early mortality in the era of targeted therapy; however, VTE occurrence remained an important predictor for early mortality in metastatic NSCLC patients, especially in patients with EGFR/ALK wild-type genes.Keywords: venous thromboembolism, non-small cell lung cancer, early mortality

Hongliang Zhou, 1 Lingling Hua, 1 Haiteng Jiang, 2 Zongpeng Dai, 2 Yinglin Han, 1 Pinhua Lin, 1 Haofei Wang, 1 Qing Lu, 2, 3 Zhijian Yao 1, 4 1Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210096, People’s Republic of China; 3Child Development and Learning Science, Key Laboratory of Ministry of Education, Nanjing 210096, People’s Republic of China; 4Nanjing Brain Hospital, Medical School of Nanjing University, Nanjing 210093, People’s Republic of ChinaCorrespondence: Zhijian YaoDepartment of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of ChinaTel +8625 8229600Fax +8625 82296000Email zjyao@njmu.edu.cnQing LuSchool of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210096, People’s Republic of ChinaTel/Fax +8625 83792349Email luq@seu.edu.cnObjective: To investigate the mechanism of interactions between autonomic nervous system (ANS) and cognitive function in Major depression (MD) with Magnetoencephalography (MEG) measurements.Methods: Participants with MD (n = 20), and Health controls (HCs, n = 18) were completed MEG measurements during the performance of a go/no-go task. Heart rate variability (HRV) indices (SDANN, and RMSSD) were derived from the raw MEG data. The correlation analysis of the HRV and functional connectivities in different brain regions was conducted by Pearson’s r in two groups.Results: The go/no-go task performances of HCs were better than MD patients; HRV indices were lower in the MD group. Under the no-go task, a brain MEG functional connectivity analysis based on the seed regions of the orbitofrontal cortex (OFC) displayed increased functional inter-region connectivity networks of OFC in MD group. HRV indices were correlated with different functional inter-region connectivity networks of OFC in two groups, respectively.Conclusion: ANS is related to inhibitory and control function through functional inter-region connectivity networks of OFC in MD. These findings have important implications for the understanding pathophysiology of MD, and MEG may provide an image-guided tool for interventions.Keywords: major depression, magnetoencephalography, heart rate variability, functional connectivity, the orbitofrontal cortex

Lingyang Hua,1 Fengchun Hua,2 Hongda Zhu,1 Jiaojiao Deng,1 Daijun Wang,1 Shihai Luan,1 Hailiang Tang,1 Yihui Guan,2 Qing Xie,1 Ye Gong1,3 1Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, People’s Republic of China; 2Department of Nuclear Medicine and PET Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, People’s Republic of China; 3Department of Critical Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, People’s Republic of ChinaCorrespondence: Ye GongDepartment of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai 200040, People’s Republic of ChinaTel +86 138 1793 9896Email drgongye@163.com Qing XieDepartment of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai 200040, People’s Republic of ChinaTel +86 21 5288 7030Fax +86 21 5288 7218Email neurosurgeon.qing@gmail.comObjective: This study aims to evaluate the potential role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in detecting high-grade meningiomas and predicting the prognosis of patients after meningioma surgery.Patients and methods: A total of 124 patients met the final inclusion criterion. Tumor to gray ratio (TGR) was compared with Ki-67 labeling index, and its correlations with pre-operative neurological function and treatment status were also evaluated. Receiver-operating characteristic (ROC) curve was drawn to determine a cut-off value which could discriminate meningioma of different grades. Prognostic factors including TGR were analyzed using Kaplan-Meier survival curve and cox proportional model.Results: The TGR of higher World Health Organization (WHO) grade meningioma was significantly higher than that in lower grade (p < 0.001), and it was correlated with the Ki-67 labeling index (p < 0.001, r = 0.1545). The TGR of 1.30 was the best cutoff value for the detection of high grade (WHO grade II&III) meningioma from low grade (WHO grade I) according to ROC analysis, with a sensitivity of 61.5%, the specificity of 86.7%, and accuracy of 81.5%. The TGR (p < 0.001), treatment status (p = 0.035), tumor grade (p < 0.001) and Ki-67 labeling index (p < 0.001) were significantly associated with progression-free survival (PFS). Cox proportional hazards model demonstrated that TGR (p = 0.013) was an independent prognostic factor for PFS.Conclusion: A high uptake of FDG was correlated with a more proliferative biological behavior and is a risk factor for tumor recurrence.Keywords: meningioma, 18F-FDG PET, molecular imaging, clinical characteristic, prognosis

Yu Xia, Yi Chen, Liang Hua, Mingqi Zhao, Tiantian Xu, Changbing Wang, Yinghua Li, Bing Zhu Virus Laboratory, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China Background: Selenium nanoparticles (SeNPs) loaded with chemotherapeutic drugs provided a novel perspective for cancer therapy.Materials and methods: Here, SeNPs were modified with cyclic peptide (Arg–Gly–Asp–D-Phe–Cys [RGDfC]) to fabricate tumor-targeting delivery carrier RGDfC-SeNPs and, then, doxorubicin (DOX) was loaded to the surface of RGDfC-SeNPs for improving the antitumor efficacy of DOX in non-small-cell lung carcinoma therapy.Results: The chemical structure characterization of RGDfC-Se@DOX showed that DOX was successfully loaded to the surface of RGDfC-SeNPs to prepare functionalized antitumor drug delivery system RGDfC-Se@DOX. RGDfC-Se@DOX exhibited effective cellular uptake in A549 cells and entered A549 cells mainly by clathrin-mediated endocytosis pathway. Compared to free DOX or Se@DOX at the equivalent dose of DOX, RGDfC-Se@DOX showed greater activity to inhibit A549 cells’ proliferation and migration/invasion and induce A549 cells’ apoptosis. More importantly, compared with passive targeting delivery system Se@DOX, active targeting delivery system RGDfC-Se@DOX exhibited more significant antitumor efficacy in vivo.Conclusion: Taken together, RGDfC-Se@DOX may be a novel promising drug candidate for the lung carcinoma therapy. Keywords: nanoscale drug carrier, antitumor, chemotherapy, RGDfC peptide, apoptosis

Zhengfang Lin,1,* Yinghua Li,1,* Guifang Gong,2 Yu Xia,1 Changbing Wang,1 Yi Chen,1 Liang Hua,1 Jiayu Zhong,1 Ying Tang,1 Xiaomin Liu,1 Bing Zhu1 1Department of Center Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Obstetrics Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Introduction: Ribavirin (RBV) is a broad-spectrum antiviral drug. Selenium nanoparticles (SeNPs) attract much attention in the biomedical field and are used as carriers of drugs in current research studies. In this study, SeNPs were decorated by RBV, and the novel nanoparticle system was well characterized. Madin-Darby Canine Kidney cells were infected with H1N1 influenza virus before treatment with RBV, SeNPs, and SeNPs loaded with RBV (Se@RBV). Methods and results: MTT assay showed that Se@RBV nanoparticles protect cells during H1N1 infection in vitro. Se@RBV depressed virus titer in the culture supernatant. Intracellular localization detection revealed that Se@RBV accumulated in lysosome and escaped to cytoplasm as time elapsed. Furthermore, activation of caspase-3 was resisted by Se@RBV. Expressions of proteins related to caspase-3, including cleaved poly-ADP-ribose polymerase, caspase-8, and Bax, were downregulated evidently after treatment with Se@RBV compared with the untreated infection group. In addition, phosphorylations of phosphorylated 38 (p38), JNK, and phosphorylated 53 (p53) were inhibited as well. In vivo experiments indicated that Se@RBV was found to prevent lung injury in H1N1-infected mice through hematoxylin and eosin staining. Tunel test of lung tissues present that DNA damage reached a high level but reduced substantially when treated with Se@RBV. Immunohistochemical test revealed an identical result with the in vitro experiment that activations of caspase-3 and proteins on the apoptosis pathway were restrained by Se@RBV treatment. Conclusion: Taken together, this study elaborates that Se@RBV is a novel promising agent against H1N1 influenza virus infection. Keywords: nanomaterials, H1N1 influenza virus, rivabirin, apoptosis, caspase-3

Hai Zhuang,1–3 Shoushan Bu,1 Lei Hua,1 Mohammad A Darabi,2,3 Xiaojian Cao,4 Malcolm Xing2,3 1Department of Stomatology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Mechanical Engineering, Biochemistry & Medical Genetics, 3Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada; 4Department of Orthopedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China Abstract: In this study, we fabricated glial cell-line derived neurotrophic factor (GDNF)-loaded microspheres, then seeded the microspheres in gelatin-methacrylamide hydrogel, which was finally integrated with the commercial bilayer collagen membrane (Bio-Gide®). The novel composite of nerve conduit was employed to bridge a 10 mm long sciatic nerve defect in a rat. GDNF-loaded gelatin microspheres had a smooth surface with an average diameter of 3.9±1.8 µm. Scanning electron microscopy showed that microspheres were uniformly distributed in both the GelMA gel and the layered structure. Using enzyme-linked immunosorbent assay, in vitro release studies (pH 7.4) of GDNF from microspheres exhibited an initial burst release during the first 3 days (18.0%±1.3%), and then, a prolonged-release profile extended to 32 days. However, in an acidic condition (pH 2.5), the initial release percentage of GDNF was up to 91.2%±0.9% within 4 hours and the cumulative release percentage of GDNF was 99.2%±0.2% at 48 hours. Then the composite conduct was implanted in a 10 mm critical defect gap of sciatic nerve in a rat. We found that the nerve was regenerated in both conduit and autograft (AG) groups. A combination of electrophysiological assessment and histomorphometry analysis of regenerated nerves showed that axonal regeneration and functional recovery in collagen tube filled with GDNF-loaded microspheres (GM + CT) group were similar to AG group (P>0.05). Most myelinated nerves were matured and arranged densely with a uniform structure of myelin in a neat pattern along the long axis in the AG and GM + CT groups, however, regenerated nerve was absent in the BLANK group, left the 10 mm gap empty after resection, and the nerve fiber exhibited a disordered arrangement in the collagen tube group. These results indicated that the hybrid system of bilayer collagen conduit and GDNF-loaded gelatin microspheres combined with gelatin-methacrylamide hydrogels could serve as a new biodegradable artificial nerve guide for nerve tissue engineering. Keywords: controlled release of GDNF, gelatin microspheres, biodegradable nerve conduit, gelatin-methacrylamide hydrogel, sciatic nerve regeneration

Background: Tea (Camellia sinensis) has a rich history and is widely consumed across many countries, and is categorized into green tea, white tea, oolong tea, yellow tea, black tea, and dark tea based on the level of fermentation. Based on a review of previous literature, the commonly recognized bioactive substances in tea include tea polyphenols, amino acids, polysaccharides, alkaloids, terpenoids, macro minerals, trace elements, and vitamins, which have been known to have various potential health benefits, such as anticancer, antioxidant, anti-inflammatory, anti-diabetes, and anti-obesity properties, cardiovascular protection, immune regulation, and control of the intestinal microbiota. Most studies have only pointed out the characteristics of tea’s bioactivities, so a comprehensive summary of the pharmacological characteristics and mechanisms of tea’s bioactivities and their use risks are vital. Aim of Review: This paper aims to summarize tea's bioactive substances of tea and their pharmacological characteristics and mechanisms, providing a scientific basis for the application of bioactive substances in tea and outlining future research directions for the study of bioactive substances in tea. Key Scientific Concepts of Review: This review summarizes the main biologically active substances, pharmacological effects, and mechanisms and discusses the potential risks. It may help researchers grasp more comprehensive progress in the study of tea bioactive substances to further promote the application of tea as a natural bioactive substance in the medical field.

Abstract Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

Abstract This study aimed to explore the potential association between Endothelin type A receptor (EDNRA) genetic polymorphisms and susceptibility to large artery atherosclerotic stroke (LAA), as well as the involvement of inflammation mechanisms. We recruited Han Chinese patients with LAA and age- and sex-matched controls. The distribution of alleles and genotypes for 16 single nucleotide polymorphisms (SNPs) in EDNRA was analyzed using dominant, recessive, and co-dominant genetic models between cases and controls. We quantified the mRNA and protein levels of EDNRA and NLRP3 genes, and concentrations of inflammatory factors (TNFα, IL-1β, IL-6, IL-8, IL-10, IL-18, and CCL18) in peripheral blood samples randomly selected from cases and controls. We also investigated the relationship between these SNPs, gene expression patterns and inflammatory factor levels. A total of 428 LAA cases and 434 controls were enrolled in this study. The results showed that rs5343 TT genotype of EDNRA was significantly associated with an increased risk of LAA (OR = 3.243, 95%CI = 1.608–6.542, P = 0.001). It also demonstrated a significant upregulation level of NLRP3 as well as higher concentrations of IL-10, IL-18, and CCL-18 in cases compared to controls. Besides, we discovered that the EDNRA polymorphisms were linked to NLRP3, IL-6, IL-10, and IL-18 levels in cases. There existed a positive correlation between EDNRA transcription levels and both NLRP3 transcript levels (r = 0.437, p

Abstract Background Malaria-associated acute lung injury/acute respiratory distress syndrome (MA-ALI/ARDS) is a fatal complication of Plasmodium falciparum infection that is partially triggered by macrophage recruitment and polarization. As reported, copper exposure increases the risk of malaria infection, and copper accumulation-induced cuproptosis triggers M1 macrophage polarization. It is thus hypothesized that cuproptosis could act as a critical mediator in the pathogenesis of MA-ALI/ARDS, but its underlying mechanism remains unclear. The present study aimed to explore the role of cuproptosis in the severity of murine MA-ALI/ARDS. Methods We utilized an experimental model of MA-ALI/ARDS using female C57BL/6 mice with P. berghei ANKA infection, and treated these animals with the potent copper ion carrier disulfiram (DSF) or copper ion chelator tetrathiomolybdate (TTM). The RAW 264.7 macrophages, which were stimulated with infected red blood cells (iRBCs) in vitro, were also targeted with DSF-CuCl2 or TTM-CuCl2 to further investigate the underlying mechanism. Results Our findings showed a dramatic elevation in the amount of copper and the expression of SLC31A1 (a copper influx transporter) and FDX1 (a key positive regulator of cuproptosis) but displayed a notable reduction in the expression of ATP7A (a copper efflux transporter) in the lung tissue of experimental MA-ALI/ARDS mice. Compared to the P. berghei ANKA-infected control group, mice that were administered DSF exhibited a remarkable increase in parasitemia/lung parasite burden, total protein concentrations in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio, vascular leakage, and pathological changes in lung tissue. Strikingly, the experimental MA-ALI/ARDS mice with DSF treatment also demonstrated dramatically elevated copper levels, expression of SLC31A1 and FDX1, numbers of CD86+, CD68+, SLC31A1+-CD68+, and FDX1+-CD68+ macrophages, and messenger RNA (mRNA) levels of pro-inflammatory cytokines (tumor necrosis factor [TNF-α] and inducible nitric oxide synthase [iNOS]) in lung tissue, but showed a remarkable decrease in body weight, survival time, expression of ATP7A, number of CD206+ macrophages, and mRNA levels of anti-inflammatory cytokines (transforming growth factor beta [TGF-β] and interleukin 10 [IL-10]). In contrast, TTM treatment reversed these changes in the infected mice. Similarly, the in vitro experiment showed a notable elevation in the mRNA levels of SLC31A1, FDX1, CD86, TNF-α, and iNOS in iRBC-stimulated RAW 264.7 cells targeted with DSF-CuCl2, but triggered a remarkable decline in the mRNA levels of ATP7A, CD206, TGF-β, and IL-10. In contrast, TTM-CuCl2 treatment also reversed these trends in the iRBC-stimulated RAW 264.7 cells. Conclusions Our data demonstrate that the activation of cuproptosis with DSF aggravated the severity of MA-ALI/ARDS by partially inducing M1 polarization of pulmonary macrophages, while inhibition of cuproptosis with TTM contrarily ameliorated the severity of MA-ALI/ARDS by promoting macrophage M2 polarization. Our findings suggest that blockage of cuproptosis could be a potential therapeutic strategy for treatment of MA-ALI/ARDS. Graphical Abstract

Abstract Background Exposure of the hepatic artery is a fundamental step in many surgeries, during which iatrogenic hepatic artery injury may occur. Although the incidence of hepatic artery haemorrhage is low, its occurrence can lead to life-threatening haemorrhage. It is difficult and dangerous to accumulate clinical experience in laparoscopic hepatic artery repair in actual patients, and simulation training models for laparoscopic hepatic artery repair are currently lacking. In this study, a 3D printed model was designed to simulate the training curriculum for sudden hepatic artery haemorrhage, but whether training with the 3D printed model could yield superior skill improvement for surgeons remained to be determined. Methods A new 3D printed model was designed for this study. Surgeons from the General Surgery Department of Sir Run Run Shaw Hospital participated in this simulation training. The surgical performance of each model was compared, and the authenticity of the model was evaluated and mechanically tested. Results Experienced surgeons performed better on the 3D printed model. After repeated training, inexperienced surgeons showed significant improvement of their laparoscopic hepatic artery repair skills. The authenticity of the model was generally satisfactory, but shortcomings persisted in the mechanical testing of artery wall tearing, necessitating further improvement. Conclusions Few studies have investigated laparoscopic simulation training for sudden hepatic artery haemorrhage. This simulation model distinguishes surgeons with different levels of experience and allows those with less experience to improve their laparoscopic hepatic artery repair skills through training on the model.

Abstract Cardiovascular disease (CVD) is a major chronic disease worldwide and its risk factors have long been investigating in epidemiological studies. Our study aims to develop a body composition-based risk score and integrate it into the Framingham Risk Score (FRS) to improve CVD prediction among well-functioning older adults. We included 1882 older adults from the Health, Aging and Body Composition (Health ABC) study to screen body composition variables obtained from the Dual-energy X-ray absorptiometry (DXA). Three models were developed and compared: the 4-DXA model, the refit FRS, and the refit FRS plus 4-DXA model. C-statistics were 0.62 (95% CI: 0.59, 0.65) for the refit FRS, 0.58 (95% CI: 0.55, 0.61) for the 4-DXA model, and 0.63 (95% CI: 0.60, 0.66) for the refit FRS plus 4-DXA model. Compared to the refit FRS, the refit FRS plus 4-DXA model slightly improved CVD outcome prediction as the discrimination slope, net reclassification index, and the integrated discrimination index were 0.053 (95% CI: 0.041, 0.066), 0.098 (95% CI = – 0.0033, 0.20) and 0.013 (95% CI: 0.0069–0.019). This study provides a model for more accurate risk stratification and draws more attention on DXA-based indices in the clinical setting. It also encourages further research in validating the developed risk score in more diverse population and in investigating a broader range of CVD risk factors.

Abstract Background Fish gut microbiota undergo dynamic changes under the influence of many factors and play an important role in the nutrition, immunity and development in fish. Although common carp (Cyprinus carpio L.) is an economically important freshwater fish, there are few reports on its gut microbiota changes at different early developmental stages. In the present study, the gut microbiota of common carp during the early developmental stages and its correlation with the feed and pond water flora were studied using the Illumina MiSeq sequencing platform. Results The results showed that the gut microbiota of common carp underwent continuous and mild changes over the development process, and the pond water environment might provide bacterial resources and have a certain influence on the changes in the gut microbiota of common carp. However, host selection pressure played a more important role in shaping the gut microbiota. Although the gut microbiota was affected by many factors, the presence of core microbiota indicated that some bacterial species adapt to the gut microenvironment of common carp and played a role in its growth process. Conclusions The dynamic changes of gut microbiota of carp in early development stage were related to the feed, water environment and host selection. The results of this study provide a theoretical basis for healthy farming and disease prevention of common carp.

Abstract Background Patellar tendinopathy (PT) is a common sport injury prone to recurrence. Heavy Slow Resistance Training (HSR) and High-Dose Therapeutic Ultrasound (TUS) are frequently used interventions for PT. However, the combined effectiveness of these therapies remains unclear. This study investigated the impact of combination therapy on functional outcomes in patients with PT. Methods Fifty-one college students aged 18–25, diagnosed with PT via musculoskeletal ultrasound, were randomly assigned to one of three groups (n = 17 per group): combined HSR and high-dose TUS, HSR training alone, or high-dose TUS alone. The eight-week intervention included assessments using the Victorian Institute of Sport Assessment-Patella (VISA-P), Visual Analogue Scale (VAS), Y-balance Test (YBT), Modified Thomas Test (MTT), Horizontal Jumping Distance, Maximum Isometric Muscle Strength Test, and musculoskeletal ultrasound for patellar tendon thickness and blood flow. Assessments were conducted at baseline and post-intervention, with a follow-up VISA-P assessment at week 16. This randomized, single-blind controlled trial was registered on ISRCTN11447397 ( www.ISRCTN.com ) on February 17, 2024 (retrospectively registered). Results All groups demonstrated significant improvements in VISA-P scores at the end of the intervention compared to baseline (p

Purpose: The aim of this systematic review and meta-analysis is to explore the effect of topical vancomycin powder (VP) in surgical site infection (SSI) prevention and adverse events after joint arthroplasty and to provide a specific theoretical basis for clinical treatment. Methods: The review process was conducted according to the PRISMA guidelines. Two independent researchers meticulously screened the literature based on predefined inclusion and exclusion criteria, evaluated the quality of the selected studies, and extracted relevant data. Data analysis was conducted using RevMan 5.4 software. Results: This meta-analysis included 24 studies encompassing a total of 34 811 patients. The pooled analysis showed that the topical administration of VP significantly reduced the incidence of SSI. Subgroup analyses by doses, type of joint (hip and knee), and type of surgery (primary and revision) confirmed that vancomycin consistently lowered SSI rates. Moreover, the incidence of SSI caused by gram-negative germs and gram-positive germs decreased following the use of VP, although the reduction was not significant for infections caused by MRSA. However, the use of VP was associated with a significant increase in sterile complications at the incision site and delayed incision healing. Conclusion: The topical application of VP is effective in reducing the incidence of infections following joint arthroplasty. Despite an increased risk of complications such as delayed healing of incisions, the pros and cons should be weighed in clinical decision-making. However, it should not be discarded due to side effects.

Abstract Background The contribution of interspecies interactions between coinfecting pathogens to chronic refractory infection by affecting pathogenicity is well established. However, little is known about the impact of intraspecific interactions on infection relapse, despite the cross-talk of different strains within one species is more common in clinical infection. We reported a case of chronic refractory pulmonary infection relapse, caused by two methicillin-sensitive S. aureus (MSSA) strains (SA01 and SA02) and revealed a novel strategy for relapse via intraspecific cooperation. Methods The hemolytic ability, growth curve, biofilm formation, virulence genes and response of G. mellonella larvae to S. aureus infection were analysed to confirm this hypothesis. Results SA02 hemolytic activity was inhibited by SA01, along with the expression of hemolysin genes and the virulence factor Hla. Additionally, SA01 significantly enhanced the biofilm formation of SA02. AIP-RNAIII may be a possible pathway for this interaction. Compared with mono-infection, a worse outcome (decreased larval survival and increased microbial burden) of the two MSSA strains coinfected with G. mellonella confirmed that intraspecific interactions indeed enhanced bacterial survival in vivo. Conclusion The intraspecific interaction of S. aureus could lead to chronic refractory infection via pathogenicity changes.

Abstract Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder associated with alterations in structural and functional coupling in gray matter. However, despite the detectability and modulation of brain signals in white matter, the structure-function coupling in white matter in autism remains less explored. Methods In this study, we investigated structural-functional coupling in white matter (WM) regions, by integrating diffusion tensor data that contain fiber orientation information from WM tracts, with functional connectivity tensor data that reflect local functional anisotropy information. Using functional and diffusion magnetic resonance images, we analyzed a cohort of 89 ASD and 63 typically developing (TD) individuals from the Autism Brain Imaging Data Exchange II (ABIDE-II). Subsequently, the associations between structural-functional coupling in WM regions and ASD severity symptoms assessed by Autism Diagnostic Observation Schedule-2 were examined via supervised machine learning in an independent test cohort of 29 ASD individuals. Furthermore, we also compared the performance of multi-model features (i.e. structural-functional coupling) with single-model features (i.e. functional or structural models alone). Results In the discovery cohort (ABIDE-II), individuals with ASD exhibited widespread reductions in structural-functional coupling in WM regions compared to TD individuals, particularly in commissural tracts (e.g. corpus callosum), association tracts (sagittal stratum), and projection tracts (e.g. internal capsule). Notably, supervised machine learning analysis in the independent test cohort revealed a significant correlation between these alterations in structural-functional coupling and ASD severity scores. Furthermore, compared to single-model features, the integration of multi-model features (i.e., structural-functional coupling) performed best in predicting ASD severity scores. Conclusion This work provides novel evidence for atypical structural-functional coupling in ASD in white matter regions, further refining our understanding of the critical role of WM networks in the pathophysiology of ASD.

In order to achieve sustainable development that balances economic growth, environmental protection, and social well-being and ensures a sustainable future, strict environmental regulations and sustainable nuclear energy production may play a vital role. Empirical works are insufficient when measuring the effects of strict environmental policies and nuclear energy production on sustainable development. This research aims to close this gap by examining how environmental policy stringency and nuclear energy production contribute to sustainable development in the top 17 nuclear energy-generating countries between 1995 and 2021. The research uses the linear and nonlinear CS-ARDL and PMG-ARDL models to achieve this goal. The linear model suggests that environmental policy stringency and nuclear energy production contribute to long-term sustainable development. In the nonlinear model, a positive change in environmental policy stringency and nuclear energy production causes long-run sustainable development to grow, while a negative change in environmental policy stringency and nuclear energy production hinders long-run sustainable development. Furthermore, environmental technologies, human capital, financial development, trade liberalization, and research and development expenditures are crucial for fostering long-run sustainable development. In contrast, the natural resource rents hurt sustainable development. These findings suggest that policymakers should consider combining strict environmental regulations and nuclear energy in devising policies for sustainable development.

Abstract We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Abstract Background We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. Results Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Summary Background Tuberculosis (TB) remains a persistent threat to global public health and traditional treatment monitoring approaches are limited by their potential for contamination and need for timely evaluation. Therefore, new biomarkers are urgently required for monitoring the treatment efficacy of TB. Methods This study aimed to elucidate the levels of CXCL10 and CXCL9 in pulmonary TB patients who underwent anti-TB treatment. The data was acquired from five databases, including PubMed, Ovid, Web of Science, Embase, and the Cochrane Library. A meta-analysis of CXCL10 data from all time points was conducted. Furthermore, a trend meta-analysis of temporal data of CXCL10 and CXCL9 from multiple time points was also performed. Results It was revealed that patients who responded poorly to anti-TB treatment had higher serum levels relative to those who responded well (SMD: 1.23, 95% CI: -0.37–2.84) at the end of intensive treatment (2 months). Furthermore, heterogeneity was observed in these results, which might be because patients with a prior history of TB and different treatment monitoring methods than those selected in this study were also included. The analysis of alterations in CXCL10 and CXCL9 levels since the last collection time points indicated that their levels reduced with time. Conclusion In summary, the study revealed that reductions in CXCL10 levels during the first two months of anti-TB treatment are correlated with treatment responses. Furthermore, decreasing levels of CXCL9 during the treatment suggest that it may also serve as a biomarker with a similar value to CXCL10. Future in-depth studies are thus warranted to further probe the relevance of CXCL10 and CXCL9 in monitoring the treatment efficacy of TB.