ObjectiveTo investigate whether Anmei Dan （AMD） improves cognitive function and alleviates circadian rhythm disorders in an aged mouse model of sleep deprivation by inhibiting the erythropoietin-producing hepatocellular receptor A4 （EphA4）/Eph receptor-interacting protein A3 （EphrinA3） signaling pathway and its downstream Ras homolog family member A （RhoA）/Rho-associated coiled-coil containing protein kinase （ROCK） signaling， and to analyze its multi-target regulatory characteristics. MethodsAn aged C57 mouse model of sleep deprivation was established by the modified multiple platform water environment method. The mice were randomized into blank， model， rhynchophylline （Rhy， antagonist， 50 mg·kg^-1·d^-1）， and antagonist plus AMD （26.26 g·kg^-1·d^-1） groups. Spontaneous activity was assessed by the open field test， and circadian rhythm activity was monitored. Hematoxylin-eosin （HE） staining and Nissl staining were conducted to observe neuronal morphology in the hippocampal CA1/CA3 regions. Western blot and immunofluorescence assay were employed to determine the protein levels of EphA4， EphrinA3， Neuronal Nuclei Antigen （NEUN）， glial fibrillary acidic protein （GFAP）， phosphorylated （p）-EphA4， RhoA， Rho-associated coiled-coil containing protein kinase 1 （ROCK1）， Rho-associated coiled-coil containing protein kinase 2 （ROCK2）， brain-derived neurotrophic factor （BDNF）， synaptophysin （SYN）， postsynaptic density protein 95 （PSD95）， and growth-associated protein 43 （GAP43）. The mRNA levels of EphA4 and EphrinA3 were determined by real-time PCR. ResultsCompared with the blank group， the model group showed decreased spontaneous activity （P<0.01）， circadian rhythm disruption （P<0.01）， hippocampal neuron disarrangement and reduced Nissl bodies， upregulated protein levels of EphA4， EphrinA3， NEUN， p-EphA4， RhoA， ROCK1， ROCK2， and GFAP （P<0.01）， and downregulated protein levels of NEUN， BDNF， SYN， PSD95， and GAP43 （P<0.01）. Compared with the model group， both the antagonist group and the antagonist plus AMD group showed recovery in the above indicators （P<0.05， P<0.01）， with the combination group outperforming the antagonist group in behavioral， pathological， and molecular expression aspects （P<0.05， P<0.01）. ConclusionAMD can alleviate cognitive and rhythm disorders caused by sleep deprivation by inhibiting the EphA4/EphrinA3 signaling pathway and its downstream RhoA/ROCK signaling， and upregulating the expression of synapse-related proteins such as BDNF. Its combination with an EphA4 antagonist exhibits a synergistic effect， which suggests that the mechanism involves multi-link synergistic intervention.

Background::Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE. Methods::We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded.Results::Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to-4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group.Conclusion::Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.Trial Registration::https://clinicaltrials.gov; NCT02388737.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

The study of children who experienced with febrile seizures(FS) as a result of COVID-19 infection to gain insight into the clinical characteristics and prognosis of neurological damage, with the aim of improving prevention, diagnosis, and the treatment of neurological complications. This study investigated the clinical features of 53 children with FS who were admitted to Sanya Women and Children’s Hospital from December 1, 2022, to January 31, 2023. The results indicated that the duration of convulsion in the case and control group was 7.90±8.91 and 2.67±1.23 (minutes) respectively. The analysis reveals that convulsions occurred within 24 hours in 39 cases (95.12%) of the case group, and in 8 cases (66.7%) of the control group. The difference was statistically significant (P<0.05). Additionally, the case group presented lower counts of WBC and NEU compared to the control group (p<0.05). The findings indicate that convulsions manifest at earlier stages of COVID-19 in children and the last longer than in the control group. It is therefore crucial for healthcare workers to remain attentive to patients with COVID-19 who report fever within 24 hours, and act promptly to implement preventive measures, particularly in cases of prolonged fever. It is essential to integrate the clinical manifestation, particularly convulsions, and the continuous numerical changes of inflammatory factors to assess COVID-19 linked with febrile seizures. In addition, larger-scale multi-center and systematic research are necessary to aid clinicians in monitoring neuropathological signals and biological targets, enabling more equitable diagnosis and treatment plans.

OBJECTIVE：To investigate the contents of 5 kinds of heavy metal as copper （Cu），arsenic（As），cadmium （Cd），mercury（Hg）and lead （Pb）in Yougui pills ，and to evaluate its safety risk. METHODS ：Using yttrium （89Y），indium （115In）and bismuth （209bi）as internal standard ，the contents of each element were determined by ICP-MS. ICP-MS condition included that atomization gas flow rate was 0.95 L/min，auxiliary gas flow rate was 1.2 L/min，plasma gas （argon）flow rate was 18 L/min，pump speed was 30 r/min. RF power of inductively coupled plasma was 1 200 W，the voltage in simulation stage was 1 750 V，the voltage in pulse stage was 1 300 V，the voltage of deflection device was －12 V，and the detector was in analog and pulse dual-mode. The determination methods of various elements were investigated ，and 45 batches of marketed Yougui pills were determined. Hazard index （HI）was used to analyze the non-carcinogenic risk of each element and calculate the maximum residual limit（MRL）of each element. RESULTS ：The linear range of Cu ，As，Cd，Hg and Pb ranged from 10-200，1-50，0.4-30，0.2-6 and 2-100 μg/L（all r＞0.999 0），respectively. The limits of quantitation were 0.67，0.23，0.20，0.07，0.27 μg/L. The limits of detection were 0.20，0.07，0.06，0.02，0.08 μg/L. RSDs of precision，stability and reproducibility tests were all lower than 3.5％ （n＝6 or n＝5）. Average recoveries were 92.96％-100.89％（RSD＝2.23％-3.62％，n＝3）. Average contents of Cu ，As，Cd，Hg and Pb in 45 batches of Yougui pills were 2.72，0.28，0.07，0.05，0.62 mg/kg，and superimposed HI of each element was less than 1. The contents of 5 kinds of heavy metals in Yougui pills were lower than the proposed MRL （MRL of Cu ，As，Cd，Hg and Pb were 20，2，1，0.2，5 mg/kg or 111.11，4.44，2.22，1.48，8.89 mg/kg respectively ）. CONCLUSIONS ：Established method can be used for the determination of content of 5 kinds of heavy metal in Yougui pills ；the heavy metal pollution rate of marketed Yougui pills is low and the safety risk is small.

Automobiles ; Hearing Loss, High-Frequency ; Hearing Loss, Noise-Induced/etiology* ; Humans ; Male ; Noise, Occupational/adverse effects* ; Occupational Diseases/epidemiology* ; Occupational Exposure

OBJECTIVE：To prepare Imperatorin ultradeformable liposomes gel （IMP-UDLs-Gel），and to evaluate its quality. METHODS：Based on single factor test ，using 12 h accumulative penetration amount （Q12h）as evaluation index ，the proportion of carbomer 940，glycerol and propyl glycol in formulation of IMP-UDLs-Gel were investigated by orthogonal test. The optimal formulation was screened. The quality of IMP-UDLs-Gel prepared with the optimal formulation was evaluated. RESULTS ：The optimal formulation of IMP-UDLs-Gel included carbomer 940 proportion of 1％，glycerol proportion of 15％ and propyl glycol proportion of 10％. Q12 h of IMP-UDLs-Gel was （11.543±0.241）μg/cm2；the appearance was milky white and translucent ；the particle size was （93.13±1.68）nm，PDI was 0.268±0.012，Zeta potential was （－24.96±1.99）mV；pH was 7.32±0.03； viscosity was （45.37±1.27）g·s；steady flow was （0.727±0.002）μg·h/cm2，lag time was （4.358±0.175）h，apparent permeability coefficient was 1.392×10－3 cm/h，and it has good physical and optical stability. CONCLUSIONS ：The preparation method is stable and feasible ，and the prepared IMP-UDLs-Gel has good adhesion ，stability and transdermal property.

Objective: To explore the effect of BMI and waist circumference on diabetes of adults. Methods: After excluding participants with heart disease, stroke, cancer and diabetes at baseline study, 53 916 people aged 30-79 in the China Kadoorie Biobank (CKB) study from Tongxiang city of Zhejiang province were recruited. Cox regression model was used to estimate the hazards ratios (HR) for the associations of baseline BMI and waist circumference with incident diabetes. Results: Among 391 512 person-years of the follow-up program between 2004 and 2013 (median 7.26 years), a total of 944 men and 1 643 women were diagnosed as having diabetes. Compared to those with normal weight, after adjusting for known or potential factors, HR of both overweight and obesity in men for incident diabetes appeared as 2.72 (95%CI: 2.47-2.99) and 6.27 (95%CI: 5.33-7.36), respectively. The corresponding figures in women were 2.19 (95%CI: 2.04-2.36) and 3.78 (95%CI: 3.36-4.26). Compared to those with normal waist circumference, after adjusting for known or potential factors, HR of Ⅰgrade andⅡgrade in men for diabetes were 2.56 (95%CI: 2.22-2.95) and 4.66 (95%CI: 4.14-5.24), respectively. The corresponding figures in women were 1.99 (95%CI: 1.80-2.21) and 3.16 (95%CI: 2.90-3.44), respectively. Conclusions: Overweight, obesity and central obesity were all associated with the increased incident of diabetes. Strategies on diabetes prevention should include not only losing weight, but reducing waist circumference as well.
Adult ; Aged ; Body Mass Index ; China/epidemiology* ; Diabetes Mellitus/ethnology* ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Obesity/epidemiology* ; Obesity, Abdominal/epidemiology* ; Overweight/epidemiology* ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; Waist Circumference

Objective: To prospectively explore the association between tea drinking and incidence of stroke of adults of Zhejiang province. Methods: After excluding participants with heart disease, stroke, cancer and diabetes at baseline study, 53 916 participants aged 30-79 years in the China Kadoorie Biobank (CKB) study from Tongxiang were included for final analysis. Cox regression model was used to estimate the hazard ratio (HR) for the association of tea drinking with incident stroke. Results: The main type of drinking tea was black tea (79.78%), followed by green tea (20.08%). Of the 53 916 participants, the proportion of participants who drank tea at least once per week was 31.27%. The corresponding proportions for men and women were 60.24% and 10.30%, respectively. Among 391 512 person-years of the follow-up program (median 7.26 years), a total of 1 487 men and 1 769 women were diagnosed with stroke. After adjusting for socio-demographic status, lifestyle, BMI, waist circumference, and systolic blood pressure, HR for incident stroke decreased with the increase of daily average tea consumption amount (P=0.000 6). Compared with participants who did not drink tea weekly, the HRs for incident stroke in those consuming tea 0.1-, 3.0- and ≥5.0 g/d were 0.93 (95%CI: 0.85-1.00), 0.88 (95%CI: 0.77-0.99) and 0.79 (95%CI: 0.69-0.89), respectively. The HRs for incident stroke in smokers and non-smokers who consumed tea ≥5.0 g/d were 0.71 (95%CI: 0.59-0.86) and 0.97 (95%CI: 0.77-1.21), respectively, compared with current smokers and non-smokers who did not drink tea weekly (P=0.040 0). The corresponding HRs for alcohol drinkers and non-drinkers were 0.96 (95%CI: 0.76-1.22) and 0.70 (95%CI: 0.58-0.84), respectively (P=0.040 0). The corresponding HRs for central obese persons and non-central obese persons were 0.60 (95%CI: 0.44-0.81) and 0.86 (95%CI: 0.73-1.01), respectively (P=0.040 0). Conclusion: Tea drinking had an effect on reducing the possibility of incident stroke, especially among those who were current smokers, non-alcohol drinkers and central obese.
Adult ; Aged ; China/epidemiology* ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Risk Assessment/methods* ; Risk Factors ; Stroke/ethnology* ; Tea/adverse effects*