Objective To introduce the concepts and principles of the win ratio method and to analyze it in the context of a case study of a clinical trial in cerebrovascular disease.Methods Based on the study of clopidogrel with aspirin in high risk patients with acute non disabling cerebrovascular events 2,and key prognostic factors,the outcome events were defined sequentially as ① time to death within 90 d,② time to recurrence of ischemic stroke within 90 d,③ time to moderate-to-severe hemorrhage within 90 d.Using clopidogrel combined with aspirin as the reference group,the winning ratio(Rw)of ticagrelor combined with aspirin was analyzed by the win ratio method,and the 95% confidence interval(CI)of Rw was estimated by the Bootstrap method and compared with the hazard ratio(HR)calculated by the competing risk model.Results When only fatal events were considered,the win ratio method suggested that the ticagrelor group was significantly better than the clopidogrel group,Rw=2.00(95% CI:1.52-2.47),and after stepwise inclusion of ischemic stroke and moderate-to-severe hemorrhage recurrence,the win ratio method yielded a value of 1.29(95% CI:1.25-1.57),and the HR value from Fine and Gray competing risk regression was 0.78(95% CI:0.65-0.95),both of which indicated that the efficacy of the ticagrelor group was superior to that of the clopidogrel group.Conclusion The win ratio method can be used to analyze clinical trials with composite endpoints after prioritizing multiple outcome variables,showing the advantages of win ratio and its promising application in cerebrovascular disease research.

Objective To introduce the concepts and principles of the win ratio method and to analyze it in the context of a case study of a clinical trial in cerebrovascular disease.Methods Based on the study of clopidogrel with aspirin in high risk patients with acute non disabling cerebrovascular events 2,and key prognostic factors,the outcome events were defined sequentially as ① time to death within 90 d,② time to recurrence of ischemic stroke within 90 d,③ time to moderate-to-severe hemorrhage within 90 d.Using clopidogrel combined with aspirin as the reference group,the winning ratio(Rw)of ticagrelor combined with aspirin was analyzed by the win ratio method,and the 95% confidence interval(CI)of Rw was estimated by the Bootstrap method and compared with the hazard ratio(HR)calculated by the competing risk model.Results When only fatal events were considered,the win ratio method suggested that the ticagrelor group was significantly better than the clopidogrel group,Rw=2.00(95% CI:1.52-2.47),and after stepwise inclusion of ischemic stroke and moderate-to-severe hemorrhage recurrence,the win ratio method yielded a value of 1.29(95% CI:1.25-1.57),and the HR value from Fine and Gray competing risk regression was 0.78(95% CI:0.65-0.95),both of which indicated that the efficacy of the ticagrelor group was superior to that of the clopidogrel group.Conclusion The win ratio method can be used to analyze clinical trials with composite endpoints after prioritizing multiple outcome variables,showing the advantages of win ratio and its promising application in cerebrovascular disease research.

Objective:To investigate the value of fetal heart quantification (fetal HQ) in assessing ventricular function of fetuses with small-for-gestational-age (SGA) and fetal growth restriction (FGR).Methods:A total of 152 singleton pregnancies with estimated fetal weight (EFW) or abdominal circumference less than the 10th percentile in the Third Affiliated Hospital of Zhengzhou University were prospectively selected from August 2022 to September 2023, where fetal EFW or abdominal circumference were in the 3rd to 9th percentile with normal Doppler findings were classified as the SGA group ( n=79), and the rest as the FGR group ( n=73). In the same period, 161 cases of normal single fetuses were matched as the control group.Based on the gestational week in which FGR occurred, the FGR group were categorized into the early-onset group (<32 weeks, n=46) and the late-onset group (≥32 weeks, n=27), and fetuses in the FGR group with absent end-diastolic velocity of the umbilical artery were defined as severe FGR ( n=11), and the rest as mild FGR ( n=62). Fetal ventricular fractional area change (FAC), global longitudinal strain (GLS), longitudinal fractional shortening (LFS) and 24-segment fractional shortening (FS) were obtained by fetal HQ. The cardiac systolic function between groups were compared, the correlations between each parameter and gestational week were analyzed, the inter-observer and intra-observer repeatability tests were performed. Results:Compared with the control group, ventricular FAC, LFS, and GLS were lower in the SGA and the FGR group, right ventricular FS of segments 9-24 were reduced in the SGA group, and left ventricular FS of segments 10-19, 21-24 and right ventricular FS of segments 18-24 were reduced in the FGR group, the differences were statistically significant (all P<0.05). Left ventricular GLS, LFS and right ventricular FAC, GLS, LFS, FS of segments 1-14 were lower in the severe FGR group than in the mild FGR group, the differences were statistically significant (all P<0.05). The values of left ventricular GLS and LFS were higher in the early-onset FGR group than in the late-onset FGR group, the differences were statistically significant (all P<0.05). The ROC showed that the ventricular systolic function parameters predicted adverse perinatal outcomes with an AUC>0.6 (all P<0.05). Left ventricular GLS and right ventricular partial-segments FS were no correlations with gestational week in the FGR group (-0.3< rs<0.3, all P<0.05). There was no correlation between the parameters and gestational week in the SGA group (all P>0.05). The inter-observer and intra-observer intraclass correlation coefficients (ICC) were >0.75, with good reproducibility. Conclusions:Fetal HQ can quantitatively assess the changes of ventricular function in SGA and FGR fetuses, and the ventricular overall, longitudinal and localized contractile function in SGA and FGR fetuses are reduced, and abnormal ventricular systolic function is associated with adverse perinatal outcomes.

{L-End}Objective To establish the norm of Core Occupational Stress Scale (COSS) for electronic manufacturing industry workers in China. {L-End}Methods A total of 3 049 workers from five electronic manufacturing enterprises in four prefecture-level cities concentrated distribution of the electronics manufacturing industry in China were selected as research subjects using a stratified sampling method. COSS was used to investigate occupational stress levels, and the mean norm, percentile norm and threshold norms were established. {L-End}Results The average score of COSS for the electronic manufacturing industry workers in China was (43.5±7.4) points, and the average scores of social support, organization and reward, demand and effort, and autonomy dimensions were (9.5±3.1), (15.1±3.9), (13.1±3.0), and (5.7±2.0) points, respectively. A total score of 0.0-<47.0 points was determined as no occupational stress, 47.0-<51.0 points as mild occupational stress, 51.0-≤54.0 points as moderate occupational stress, and >54.0 points as severe occupational stress. {L-End}Conclusion The norm of COSS for workers in China's electronics manufacturing industry has been established, which can provide a reference for the evaluation and intervention of their occupational stress levels.

Objective:To evaluate the systolic function of 24 segments in dichorionic diamniotic (DCDA) twin pregnancy by fetal heart qualification (fetal HQ) analysis, and to compare the difference with singleton pregnancies.Methods:Thirty-one cases of DCDA twin pregnancy (observation group) and 100 cases of singleton pregnancy (control group) matched in gestational age were enrolled. They underwent perinatal health care in the Third Affiliated Hospital of Zhengzhou University from February 2022 to February 2023.Fetal HQ was applied to track endocardial motion trajectories and automatically calculate the global strain (GS), fractional area change (FAC) and fractional shortening (FS) of 24 segments of left and right ventricles in order to compare the difference between DCDA fetuses and singleton fetuses. One case of twins with growth discordance were selected to demonstrate the utility of this technique.Results:①There were no statistically significant differences in GS, FAC and 24-segments FS of left and right ventricles between the two fetuses in the observation group (all P>0.05). ②The LV-FS of segments 1-10 were higher in the observation group than the control group, and the differences were statistically significant (all P<0.05). However, there were no statistically significant differences in GS and FAC of left and right ventricles, LV-FS of segments 11-24 and RV-FS of segments 1-24 between the observation group and the control group (all P>0.05). The intraclass correlation coefficient(ICC) was greater than 0.75, indicating good repeatability. ③Two fetuses with discordant growth in dichorionic diamniotic twins had abnormal FS in some segments of the left and right ventricles. Conclusions:Fetal HQ technology could easily and reliably evaluate fetal heart function in DCDA pregnancy with good repeatability. The changes of fetal cardiac function in twin pregnancy did not always follow the same pattern as in singleton pregnancy. The related data of singleton pregnancy should not be blindly used in the clinical management and scientific research of twin pregnancy.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.

OBJECTIVE: To evaluate the diagnostic ability of toxicity pathology in patho-toxicological testing institutions in China. METHODS: The institutions participated in the 2018 Interlaboratory Comparison Activity of Toxicity Pathology Testing(hereinafter referred to as reference unit) were selected as the research subjects. The heart, spleen, skin, soft tissue, liver and mammary gland of SD rats of different groups in the 2-year carcinogenesis test were selected. The femur, knee joint and nose of Beagle dogs in the 4-week toxicity test and a total of 10 pathological tissues were selected as the comparison samples. The pathological diagnosis was carried out by the pathological diagnostic personnel of the reference unit, and the diagnostic results were reported. The expert appointed by the Toxicology and Pathology Committee of Chinese Toxicology Association compared the diagnostic results with the appointed value. RESULTS: A total of 167 pathological diagnostic personnel from 75 reference units in 24 provinces and municipalities participated in the comparison activity. The reference units were mainly distributed in East China, South China and North China, accounting for 77.3%(58/75). Totally 75 reference units fed back 750 effective diagnostic results. The qualified rates of diagnosis on heart, spleen, skin, soft tissue and breast samples were higher than 60.0%. The qualified rates of diagnosis on femur and knee joint, and nose samples were low(30.7% and 6.7%, respectively). There were 1(1.3%), 46(61.4%) and 28(37.3%) reference units rated as unqualified, qualified and excellent, respectively. CONCLUSION: Most of the testing institutions in China have a high level of patho-toxicological diagnostic ability, that can provide reliable diagnostic results for toxicology safety evaluation tests.

OBJECTIVE: To investigate the chronic toxicity and carcinogenicity of kresoxim-methyl in rats. METHODS: Specific pathogen free SD rats were randomly divided into control group and low-, medium-and high-dose groups according to the body weight of rats, 120 rats in each group with half male and half female rats. The chronic toxicity and carcinogenesis was induced in rats for 104 weeks by oral feeding. The dose of kresoxim-methyl in feed of male and female rats was 0, 75, 300 and 1 200 mg/kg. During the process of experiment, the body weight of rats was weighed. The blood biochemistry, organ coefficient and histopathology were examined at the end of the exposure, and the tumor incidence was calculated. RESULTS: There was no significant difference in mortality of the female or male rats in the four groups(P>0.05). At the 32 nd, 48 th and 56 th week after exposure, the body mass of female rats in the high dose group was lower than that in control group(P<0.05); at the 8 th, 16 th, 24 th and 32 nd week, the body mass of male rats in the high dose group was lower than that in the control group(P<0.05). The organ coefficients of heart and adrenal gland of female rats in the high dose group were higher than those in the control group and the low dose group(P<0.05). The organ coefficient of liver of male rats in the high dose group was lower than that in the control group(P<0.05). The alkaline phosphatase of male rats in the three dose groups was lower than that in the control group(P<0.05). The blood glucose of male rats in the high dose group was higher than that in the control group(P<0.05). The aspartate aminotransferase of male rats in the high dose group was lower than that in the control group(P<0.05). There was no significant difference among the three indexes in female rats(P>0.05). The tumor incidence of the control group and the low, medium and high dose groups were 68.3%, 75.0%, 75.0% and 78.8%, respectively, with no significant difference(P>0.05). The tumor incidence of the female rats was higher than that of the male rats(87.0% vs 61.5%,P<0.01).The tumor multiplicity of the above four groups were 38.3%, 35.8%, 35.0%, 39.8%, respectively, with no significant difference(P>0.05). The tumor multiplicity in female rats was higher than that in male rats(56.9% vs 17.6%,P<0.01). CONCLUSION: The no observed adverse effect level of kresoxim-methyl to female and male SD rats was 24.726 and 20.002 mg/(kg·d), respectively. No carcinogenicity of kresoxim-methyl to SD rats was observed.

OBJECTIVE: To observe the pathological changes of rat silicosis model at different time points. METHODS: The specific pathogen free SD rats were randomly divided into control group and 7, 15, 21, 30, 45, 60, 75 and 90 day model groups based on their body weight, with 5 rats in each group. Non-exposed endotracheal intubation was performed. Silicosis rat model was established by intratracheal instillation of 250 g/L silica suspension in each rat, and 0.9% sodium chloride solution was perfused into the trachea of rats in the control group. The rats in the control group were sacrificed on the 90 th day after exposure, and the model rats in the other 8 groups were sacrificed on the 7 th, 15 th, 21 st, 30 th, 45 th, 60 th, 75 th and 90 th days after the end of exposure. The gross appearance of the lung tissue of rats was observed. The rat lung tissues were stained with hematoxylin-eosin and Masson staining to observe the pathological changes, and Ashcroft score was evaluated. RESULTS: The gross observation showed that the lungs of rats in the model groups had varying degree of gray changes, hardened texture, and spots and nodules on the surface of the lobes. These changes were aggravated with the increase of time after dust exposure. The results of histopathological examination of the lungs showed that the rats developed acute alveolar inflammation, and a large number of macrophages and neutrophils were seen in the lung tissues in the 7 th and 15 th day model groups. Cellular nodules appeared in the lung tissue, and fibrosis appeared in the center of the nodule in the rats of 21 st, 30 th, and the 45 th day model groups; the silicosis nodules appeared in the lung tissues of rats in the 60 th, 75 th, and 90 th day model groups, and the small nodules gradually merged into larger ones. Simultaneously, with the increase of time after dust exposure, the lung tissue of rats gradually showed severe pulmonary fibrosis. The lung organ coefficient and Aschcroft score of rats increased with the increase of time after dust exposure(P<0.01). CONCLUSION: The rat lung changes after dust exposure. Acute alveolar inflammation occurs on the 7 th to 15 th day after dust exposure; cellular nodules develop on the 21 st to 45 th day after dust exposure; silicosis nodules develop on the 60 th to 90 th day after dust exposure. The severity of lung fibrosis after dust exposure showed a time-effect relationship in rats.