"Toxicity Testing in the 21st Century—A Vision and Strategy"proposed by the National Research Council of US has brought innovative directives and objectives for toxicity evaluation and risk assessment,pushing forward the next generation of toxicity testing and risk assessment.In this initiative,the concept of adverse outcome pathways(AOPs)has emerged as a prominent methodology,capturing the attention of toxicologists and researchers due to its promising applications in recent years.The quantitative AOP(qAOP)is an extension of the adverse outcome pathway,which is built upon the foundational qualitative adverse outcome pathway model and leverages mathematical frame-works to depict dose-response and/or response-response relationships.This article reviews the princi-ples and advancement surrounding qAOP,introduceds two prevalent methodologies for constructing qAOP,Bayesian network models and regression models,and demonstrates diverse applications of qAOP.Actual cases are used to underscore the transformative role of qAOP in contemporary toxicology and risk assessment practices.

Objective:To evaluate the effect of exogenous interleukin-18 (IL-18) binding protein (IL-18BP) on sepsis-associated lung injury and the role of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in rats.Methods:This study was performed in two parts. Experiment Ⅰ Thirty-six SPF-grade healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 200 g, were allocated into 3 groups ( n=12 each) using a random number table method: sham operation group (S group), sepsis-associated lung injury group (SLI group), and sepsis-associated lung injury+ IL-18BP group (SI group). The rat model of sepsis-associated lung injury was developed using cecal ligation and puncture. The rats in group S underwent laparotomy without the subsequent ligation and puncture procedures. IL-18BP 1.5 mg/kg was intraperitoneally injected immediately after surgery in group SI. Experiment Ⅱ The aforementioned 36 rats were allocated into 3 groups ( n=12 each) using a random number table method: sepsis-associated lung injury + IL-18BP + vehicle group (SIV group), sepsis-associated lung injury + IL-18BP + MCC950 group (SIM group), and sepsis-associated lung injury + IL-18BP + nigericin group (SIN group). In SIV group, SIM group and SIN group, solvent, MCC950 (NLRP3 inhibitor, 5 mg/kg) and nigerin (NLRP3 agonist, 2 mg/kg) were intraperitoneally injected at 30 min before surgery respectively, and IL-18BP 1.5 mg/kg was intraperitoneally injected after operation. HE staining was used to observe the lung injury at 24 h after operation. The left lung tissues were obtained for calculation of the wet/dry weight (W/D) ratio. The concentrations of IL-18 and IL-18BP in broncho-alveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay. The percentage of NLRP3 positive cells in lung tissues was detected by immunofluorescence. The expression of IL-18, IL-18BP, cl-caspase-1 and gasdermin D (GSDMD) in lung tissues was detected by Western blot. Results:Experiment Ⅰ Compared with group S, the injury score of lung tissues, W/D ratio, concentrations of IL-18 and IL-18BP in BALF, and percentage of NLRP3 positive cells were significantly increased, and the expression of IL-18, IL-18BP, cl-caspase-1 and N-GSDMD was up-regulated in group SLI ( P<0.05). Compared with group SLI, the injury score of lung tissues, W/D ratio, concentrations of IL-18 and IL-18BP in BALF, and percentage of NLRP3 positive cells were significantly decreased, the expression of IL-18, cl-caspase-1 and N-GSDMD was down-regulated, and the expression of IL-18BP was up-regulated in group SI ( P<0.05). Experiment Ⅱ Compared with group SIV, the injury score of lung tissues, W/D ratio, concentrations of IL-18 in BALF, and percentage of NLRP3 positive cells were significantly decreased, and the expression of IL-18, cl-caspase-1 and N-GSDMD was down-regulated in group SIM, and the injury score of lung tissues, W/D ratio, concentrations of IL-18 in BALF, and percentage of NLRP3 positive cells were significantly increased, and the expression of IL-18, cl-caspase-1 and N-GSDMD was up-regulated in group SIN ( P<0.05). Conclusions:Exogenous IL-18BP can reduce sepsis-associated lung injury, and the mechanism is related to inhibition of activation of NLRP3 inflammasomes in rats.

Objective To investigate the distribution of cell membrane tension in a gradient fluid shear stress(FSS)field.Methods A gradient plate flow chamber model was constructed.Fluid-solid coupling numerical simulations were conducted to analyze the distribution of membrane tension with different FSS gradients and FSS amplitudes under varying hydrostatic pressures.Results With an increase in the flow rate at the inlet of the flow chamber,the FSS gradient exhibited a proportionally positive increase.Under the gradient FSS field,the cell membrane tension initially decreased and then increased from the bottom to the top of the cell.Under normal blood pressure,higher hydrostatic pressure was correlated with increased membrane tension.Larger FSS amplitudes result ed in higher membrane tension.When the FSS amplitude was constant,the average difference in membrane tension between the high-and low-FSS regions increased with the FSS gradient.Similarly,with a constant FSS gradient,the average difference in membrane tension between the high-and low-FSS regions increased with the FSS amplitude.Conclusions Local variation in cell membrane tension induced by gradient FSS is a crucial factor influencing the directional migration of osteoclast precursors in a gradient FSS field.

Objective To determine whether local gradient fluid shear stress(FSS)causes a specific distribution of intracellular calcium ion concentration,which ultimately determines the direction of cell migration.Methods Numerical simulations were performed using COMSOL software.The method of staining intracellular calcium ion for RAW264.7 osteoclast precursors was established.After applying gradient FSS on the cells,the distribution and dynamic changes of intracellular calcium ion concentration and cell migration parameters were analyzed.Results Osteoclast precursors tended to migrate towards regions with lower FSS,and oscillatory flow regulated the distribution of intracellular calcium ions along the direction of cell migration.After blocking phospholipase C(PLC),mechanosensitive cation-selective channels(MSCC),endoplasmic reticulum(ER),and removing extracellular calcium,the migration speed of cells towards the low FSS direction was significantly reduced,but the migration speed along the liquid flow direction was significantly enhanced.Meanwhile,the calcium ion distribution along the liquid flow direction was significantly increased.Conclusions Osteoclast precursors can sense the FSS gradient,resulting in a specific distribution of intracellular calcium ions along the direction of migration.This ultimately leads to the migration of osteoclast precursors towards regions with lower FSS.This study provides important basic data for ultimately elucidating the cellular and molecular mechanisms of bone tissue remodeling under dynamic external forces.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Objective To study the clinical manifestations and histopathological characteristics of acute ocular injuries caused by the unsymmetrical dimethylhydrazine propellant in rabbits,and to investigate the mechanism of ocular injuries caused by unsymmetrical dimethylhydrazine.Methods A rabbit eye tainting model was established by placing propellant-grade liquid on the corneal surface.The rabbit eyes were divided into the normal control group and the 2 h,1 d,3 d and 7 d post-toxicity groups.The corneal clouding in each group was scored,the integrity of the corneal epithelium was observed,the percentage of corneal epithelial defects was calculated,fundus photographs were taken of the rabbits in each group,and the changes in the posterior segment of the retina of the rabbits were observed.Histopathological slides of rabbit eyes were prepared at each time point.Pathological sections were taken from the rabbit eyes at each time point to observe the histo-pathological changes of the cornea,lens,iris,ciliary body and retina.Immunohistochemistry was used to analyze the expres-sions of CD31,TNF-α and MMP-2 in the tissues of eyes of each group.Results The score of corneal opacity degree in each group was 0,but was 2.00(1.25,2.50),3.00(2.75,3.00),2.00(2.00,2.50),1.00(0.75,1.00)after exposure,so the difference was statistically significant(P<0.001).The percentage of the size of the epithelial defect was(100.00±0.00)%2 hours after exposure to the toxin,but was subsequently(99.17±6.36)%,(17.38±5.66)%,and(9.71±3.00)%,respectively.The difference between the groups was statistically significant(P<0.001).Rabbits in each groups had normal fundi.Histopathological examination found that the corneal injury to the rabbits after exposure to the poison was manifested as loss of epithelia,edema and thickening of the stroma layer,cystic degeneration of epithelial cells,vasodilation and congestion of the iris and ciliary body,mild edema of the stroma layer,swelling of muscle fibers,all of which recovered within 3 days.The lens structure of the rabbits in each group remained unchanged.The expressions of MMP-2 in the cytoplasm of the corneal stroma,roots of theiris and ciliary body,and in endothelial cells in the corneal limbus vascular wall were significantly enhanced 1 day after exposure,so was the expression of CD31 in the corneal stroma and limbus.No positive expression of TNF-αwas found in anyeye tissuein these groups.Conclusion The unsymmetrical dimethylhydra-zine propellant can damage eye tissues under a simulated working environment,but the damage is limited.The damage of unsymmetrical dimethylhydrazine to the cornea is superficial and confined to the corneal epithelium.The damage to the anterior segment is mild,and inflammation has a quick onset and recovery.The damage to the cornea,iris and ciliary body tends to recover on its own.

Osteoporotic thoracolumbar fracture in the elderly will seriously reduce their quality of life and life expectancy. For osteoporotic thoracolumbar fracture in the elderly, spinal reconstruction is necessary, which should comprehensively consider factors such as the physical condition, fracture type, clinical characteristics and osteoporosis degree. While there lacks relevant clinical norms or guidelines on selection of spinal reconstruction strategies. In order to standardize the concept of spinal reconstruction for osteoporotic thoracolumbar fracture in the elderly, based on the principles of scientificity, practicality and progressiveness, the authors formulated the Clinical guideline for spinal reconstruction of osteoporotic thoracolumbar fracture in elderly patients ( version 2022), in which suggestions based on evidence of evidence-based medicine were put forward upon 10 important issues related to the fracture classification, non-operative treatment strategies and surgical treatment strategies in spinal reconstruction after osteoporosis thoracolumbar fracture in the elderly, hoping to provide a reference for clinical treatment.