ObjectiveTo observe the effect of Huayu Mingmu prescription on retinal angiogenesis and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin （PI3K/Akt/mTOR）-hypoxia inducible factor-1α/vascular endothelial growth factor A （HIF-1α/VEGFA） signaling pathway in diabetic retinopathy （DR） rats. MethodsSixty-four SPF-grade male SD rats were used in the study. Eleven rats were randomly selected as the normal group， while the remaining 53 rats were fed a high-sugar， high-fat diet combined with low-dose streptozotocin （STZ） intraperitoneal injection to establish a type 2 diabetes mellitus （T2DM） rat model. DR model evaluation was performed after 12 weeks of diabetes. The rats were then divided into model， low-dose， medium-dose， and high-dose groups of Huayu Mingmu prescription （9.29， 18.57， 37.14 g·kg^-1）， and a calcium dobesilate group （0.16 g·kg^-1）， with 10 rats in each group. The rats were orally administered the corresponding doses of Huayu Mingmu prescription and calcium dobesilate. The normal and model groups received equal volumes of physiological saline via gavage for 8 consecutive weeks. Retinal vascular changes were observed through fundus photography， and pathological changes in retinal tissue were evaluated using hematoxylin-eosin （HE） staining. Retinal microvascular pathological changes were examined through retinal vascular network preparation and periodic acid-Schiff （PAS） staining. Immunofluorescence （IF） was used to detect the expression of VEGFA and angiopoietin-2 （Ang-2） in retinal tissue. Western blot was employed to detect the protein expression of PI3K， Akt， mTOR， HIF-1α， VEGFA， and VEGFR2 in retinal tissue. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to assess the mRNA expression of PI3K， Akt， mTOR， HIF-1α， VEGFA， and VEGFR2 in retinal tissue. ResultsCompared with the normal group， the model group exhibited significant pathological changes in retinal tissue， including the appearance of acellular capillaries， as well as significant endothelial cell （E） proliferation and pericyte （P） loss （P<0.01）. The E/P was significantly elevated （P<0.01）. Protein and mRNA expression levels of PI3K， Akt， mTOR， HIF-1α， VEGFA， and VEGFR2 in retinal tissue were significantly increased （P<0.01）， and the expression of Ang-2 protein was significantly elevated （P<0.01）. In contrast， retinal tissue in the treatment groups showed alleviated pathological changes， with reduced endothelial cell proliferation and pericyte loss （P<0.05， P<0.01）. Among the treatment groups， the high-dose Huayu Mingmu prescription and the calcium dobesilate group exhibited a decreased E/P （P<0.01）. Protein and mRNA expression levels of PI3K， Akt， mTOR， HIF-1α， VEGFA， and VEGFR2 in retinal tissue were significantly reduced （P<0.05， P<0.01）， and the expression of Ang-2 protein was significantly decreased （P<0.01）. ConclusionHuayu Mingmu prescription can intervene in retinal neovascularization in DR rats， delay the progression of DR， and its mechanism may be related to antagonizing the PI3K/Akt/mTOR-HIF-1α/VEGFA signaling pathway.

Objective:To evaluate the 10-year protective effect and immunogenicity of quadrivalent human papillomavirus (HPV) vaccine in Chinese women aged 20 to 45 years.Methods:From October 2019 to April 2020, a long-term follow-up study was conducted on the subjects of the Phase III clinical trial of the quadrivalent HPV vaccine (NCT00834106). Participants underwent a questionnaire survey, venous blood sampling, gynecological examination, cervical exfoliated cell pathology examination, and serum neutralizing antibody titers for HPV-6, 11, 16, and 18 were measured using a pseudovirus neutralization assay. The results of the cytological examination and the positive rate and titers of serum antibodies of different cervical exfoliated cells were compared.Results:A total of 889 subjects were followed up, including 240 in the control group, 453 in the vaccination group and 196 in the post-trial vaccination group. The age of the control group was (40±7) years old, which was higher than that of the supplementary vaccination group and the vaccination group [(38±4) and (38±6) years old, respectively] ( P<0.05). There were no statistically significant differences in condom use and sexual frequency among all groups (all P values>0.05). The abnormal proportion of cervical exfoliation cytopathology in the vaccination group was 3.7% (17/453), which was significantly lower than that in the control group [9.6% (23/240)] and post-trial vaccination group [5.6% (11/196)] ( P<0.05). There were two cases of cervical intraepithelial neoplasia (CIN) grade 1 in the vaccination group, two cases of CIN grade 1 and three cases of CIN grade 2 and above in the control group, and no CIN grade 1 and above cases in the post-trial vaccination group. The positive rate of HPV-18 antibody was 35.5% (161/453) in the vaccination group and 76.0% (149/196) in the post-trial vaccination group, which was significantly lower than that of other types ( P<0.05). The neutralizing antibody GMT ratio between the vaccination group and the control group ranged from 2.62 to 25.33 (9.05 to 83.08). Conclusion:Protective neutralizing antibodies are sustained in Chinese women aged 20 to 45 years after ten years of vaccination with quadrivalent HPV vaccine.

Objective:To evaluate the 10-year protective effect and immunogenicity of quadrivalent human papillomavirus (HPV) vaccine in Chinese women aged 20 to 45 years.Methods:From October 2019 to April 2020, a long-term follow-up study was conducted on the subjects of the Phase III clinical trial of the quadrivalent HPV vaccine (NCT00834106). Participants underwent a questionnaire survey, venous blood sampling, gynecological examination, cervical exfoliated cell pathology examination, and serum neutralizing antibody titers for HPV-6, 11, 16, and 18 were measured using a pseudovirus neutralization assay. The results of the cytological examination and the positive rate and titers of serum antibodies of different cervical exfoliated cells were compared.Results:A total of 889 subjects were followed up, including 240 in the control group, 453 in the vaccination group and 196 in the post-trial vaccination group. The age of the control group was (40±7) years old, which was higher than that of the supplementary vaccination group and the vaccination group [(38±4) and (38±6) years old, respectively] ( P<0.05). There were no statistically significant differences in condom use and sexual frequency among all groups (all P values>0.05). The abnormal proportion of cervical exfoliation cytopathology in the vaccination group was 3.7% (17/453), which was significantly lower than that in the control group [9.6% (23/240)] and post-trial vaccination group [5.6% (11/196)] ( P<0.05). There were two cases of cervical intraepithelial neoplasia (CIN) grade 1 in the vaccination group, two cases of CIN grade 1 and three cases of CIN grade 2 and above in the control group, and no CIN grade 1 and above cases in the post-trial vaccination group. The positive rate of HPV-18 antibody was 35.5% (161/453) in the vaccination group and 76.0% (149/196) in the post-trial vaccination group, which was significantly lower than that of other types ( P<0.05). The neutralizing antibody GMT ratio between the vaccination group and the control group ranged from 2.62 to 25.33 (9.05 to 83.08). Conclusion:Protective neutralizing antibodies are sustained in Chinese women aged 20 to 45 years after ten years of vaccination with quadrivalent HPV vaccine.

Objective:To investigate the characteristics of the sleep quality and health-related quality of life (HRQoL), and analyze the different effects of sleep quality on HRQoL among young and middle-aged people.Methods:A cross-sectional study recruited 1 976 participants.All participants completed a self-designed questionnaire for the adults' general condition, the Pittsburgh sleep quality index (PSQI) and Short-Form health survey (SF-36). All participants were divided into 3 age groups: 18-29-year-old group( n=1 148), 30-44-year-old group( n=586) and 45-59-year-old group ( n=242). SPSS 23.0 software was used for statistical analysis.Chi-square test was used to analyze the general characteristics of the three age groups.Non-parametric test was used to analyze the scores of the three age groups in different dimensions of sleep quality. One-way ANOVA was used to analyze the mean scores of the three age groups in different dimensions of HRQoL. Stepwise regression analysis was used to analyze the effect of sleep quality on HRQoL among the three groups after control the confounding factors such as marital status, education, smoking, drinking and exercise habits and past medical history. Results:In terms of sleep quality, the total PSQI scores of 18-29-year-old, 30-44-year-old and 45-59-year-old groups(4(2, 6), 4(2, 6), 4(2, 6)) showed statistically significant differences ( Z=10.951, P=0.004). In terms of HRQoL, there were statistically significant differences in physical component summary scores (18-29-year-old: 82.51±12.62, 30-44-year-old: 80.72±13.63, 45-59-year-old: 82.04±13.07, F=3.667, P=0.026) and mental component summary scores(18-29-year-old: 76.09±15.46, 30-44-year-old: 77.20±16.14, 45-59-year-old: 81.82±14.14, F=13.649, P<0.001) among young and middle-aged people in different age groups.Regression analysis found that daytime dysfunction was an independent influencing factor for HRQoL in young and middle-aged population ( β=-0.308--0.425, all P<0.01). Sleep disorders significantly decreased Physical Component Summary of HRQoL in young-aged people ( β=-0.127--0.215, all P<0.01). The use of hypnotic drugs significantly reduced the scores in the physiological field in the young adults aged 30-44 ( β=-0.076, P<0.05). The duration of sleep significantly decreased the scores in the mental domain of young adults aged 30-44 ( β=-0.112, P<0.01). Subjective sleep quality was an independent factor that significantly decreased HRQoL in young adults aged 18-29 and 30-44 years ( β=-0.089--0.169, all P<0.01). Conclusion:Sleep quality and HRQoL of young and middle-aged people in different age groups show different characteristics.The effect of sleep quality on HRQoL is different among people in different ages.Taking targeted interventions for people of different ages to improve the sleep quality may be an effective way to improve their HRQoL.

Objective: To explore the most economically feasible cervical cancer screening strategies in urban China. Methods: A series of Markov models were constructed to evaluate health and economic outcomes of different screening strategies. There were 24 screening strategies including four screening methods: liquid-based cytology (LBC), human papillomavirus (HPV) DNA genotyping, HPV DNA genotyping with LBC triage (HPV DNA+ LBC), HPV DNA genotyping and LBC co-testing (HPV DNA-LBC), along with three intervals (every 1, 3 or 5 years) and two starting age for screening (30 or 35 years old) were compared. Models parameters were obtained from a cervical cancer screening study in urban China and literature reviews. Results: The cumulative incidence and mortality risk of cervical cancer declined over 69% and 82% respectively for each screening strategy as compared with the no screening scenario. LBC every five years starting from 35 years old strategy cost the least (RMB 690 per capita) and could save life years compared with no screening. The cost effectiveness ratios of 24 strategies ranged from -10 903 to 117 992 RMB per life year saved. All strategies were cost-effective compared to no screening. In the incremental cost-effectiveness analysis, LBC every 5 years starting from 30 strategy, HPV DNA genotyping every 3 years starting from 30 strategy, LBC every 3 years starting from 30 strategy and LBC every year starting from 30 strategy were dominant strategies. Conclusions Screening can effectively prevent cervical cancer. In urban Chinese areas with insufficient socioeconomic resources, LBC every 5 years from 35 years old strategy is recommended. In relatively more affluent areas, LBC every 5 years from 30 years old strategy, LBC every 3 years from 30 years old strategy, HPV DNA genotyping every 3 years from 30 years old strategy, and LBC every year from 30 years old strategy are recommended successively.

Objective To evaluate the feasible cervical cancer screening strategies in rural China. Methods The study was based on the health industry scientific research project of National Health Commission in 2015, cervical cancer screening technology and demonstration research suitable for rural areas in China, we collected health economics and epidemiological parameters and established the unscreening model and screening model with Treeage Pro 2011 software. Combining with the data acquired from site investigation, including population screening, treatment-related clinical materials and cost data, we simulated the occurrence and the development of cervical cancer of rural women in China under different screening and intervention programs and predicted the screening effects [cumulative incidence, cumulative risk of disease, life years and quality adjusted life years (QALY), gains] and costs after 20 years, and using health economic evaluation analysis (cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis). Screening programs included five screening strategies [visual inspection with acetic acid/lugol's iodine (VIA/VILI), careHPV, ThinPrep cytology test (TCT), careHPV+TCT, careHPV+VIA/VILI] and three screening intervals (1-year, 3-year, 5-year), a total of fifteen screening programs. Results Compared with no screening, fifteen screening programs reduced the cumulative incidence by 22.65%-51.76%. Compared with TCT or VIA/VILI, for the same screening interval, the reduced cumulative incidence, the amounts of life-year saved and QALY and benefits gained of careHPV were the highest. The cost-effectiveness ratios of these screening programs ranged (0.44-3.24)×104 Yuan per life-year saved, cost-utility ratios ranged (0.15-1.01)×104 Yuan per QALY, benefit-cost ratios ranged 7.73-59.10. The results of incremental cost-effectiveness ratios showed that VIA/VILI every five years, VIA/VILI every three years, careHPV every five years, careHPV every three years and careHPV every year were dominant programs. Conclusions VIA/VILI screening is cost-effective, careHPV is slightly more expensive but more effective. In rural China, careHPV screening every five years could be recommended. This study provides a basis for the determination of cervical cancer screening methods feasible for rural areas in China.

Objective: To evaluate the feasible cervical cancer screening strategies in rural China. Methods: The study was based on the health industry scientific research project of National Health Commission in 2015, cervical cancer screening technology and demonstration research suitable for rural areas in China, we collected health economics and epidemiological parameters and established the unscreening model and screening model with Treeage Pro 2011 software. Combining with the data acquired from site investigation, including population screening, treatment-related clinical materials and cost data, we simulated the occurrence and the development of cervical cancer of rural women in China under different screening and intervention programs and predicted the screening effects [cumulative incidence, cumulative risk of disease, life years and quality adjusted life years (QALY) , gains] and costs after 20 years, and using health economic evaluation analysis (cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis). Screening programs included five screening strategies [visual inspection with acetic acid/lugol's iodine (VIA/VILI), careHPV, ThinPrep cytology test (TCT), careHPV+TCT, careHPV+VIA/VILI] and three screening intervals (1-year, 3-year, 5-year), a total of fifteen screening programs. Results: Compared with no screening, fifteen screening programs reduced the cumulative incidence by 22.65%-51.76%. Compared with TCT or VIA/VILI, for the same screening interval, the reduced cumulative incidence, the amounts of life-year saved and QALY and benefits gained of careHPV were the highest. The cost-effectiveness ratios of these screening programs ranged (0.44-3.24)×10⁴ Yuan per life-year saved, cost-utility ratios ranged (0.15- 1.01)×10⁴ Yuan per QALY, benefit-cost ratios ranged 7.73-59.10. The results of incremental costeffectiveness ratios showed that VIA/VILI every five years, VIA/VILI every three years, careHPV every five years, careHPV every three years and careHPV every year were dominant programs. Conclusions VIA/VILI screening is cost-effective, careHPV is slightly more expensive but more effective. In rural China, careHPV screening every five years could be recommended. This study provides a basis for the determination of cervical cancer screening methods feasible for rural areas in China.

Objective: To account the direct cost of uterine cervix carcinoma treatment in China and to explore the related factors which influence the direct financial burden of the disease. Methods: Data was collected through the medical record system and telephone interviews in 14 county-level hospitals and 9 provincial and municipal hospitals from 14 provinces/municipalities enrolled in the Chinese National Health Industry Research Project in 2015. The direct financial burden of uterine cervix carcinoma treatment consisted of the direct medical cost and the direct non-medical cost of treatment in different pathological cervical cancer stages and precancerous lesions. Multiple liner regression method was used to analyze the factors affecting the costs. Results: The age of the 3 246 patients was (46.40±10.43) years, including 2 423 patients from provincial and municipal hospitals and 823 patients from county-level hospitals. The direct financial burden for one patient of pathological uterine cervix carcinoma stage or precancerous lesion ranged from 10 156.3 yuan to 75 716.4 yuan in provincial and municipal hospitals, and for patients from county-level hospitals, the cost was between 4 927.9 yuan and 47 524.8 yuan per person. There was a wide gap between the direct financial burden of patients in different disease stages. The direct financial burden of patients with precancerous lesions ranged from 4 927.9 yuan per person to 11 243.0 yuan per person, as for patients of pathological uterine cervix carcinoma stages, the direct financial burden was between 29 274.6 yuan and 75 716.4 yuan per person. The factors which influence direct financial burden would include: the levels of the hospital, pathological period, medicare reimbursement, days of treatment, and the methods of treatment (P<0.001). Conclusion The direct financial burden of diseases in patients with pathological uterine cervix carcinoma stage or precancerous lesion differed in different levels of hospital and pathological periods. In addition, medicare reimbursement, days of treatment, and the methods of treatment all had impact on it.

Objective To evaluate the 15 years changing trends of prevalence of high risk HPV (HR?HPV) infection and the risks of cervical cancer and precancerous lesions (CIN2+) among a Chinese rural population. Methods The screening cohort with 1 997 women aged 35 to 45 years old was built in 1999 in Xiangyuan County, Shanxi province ( SPOCCS?I) and followed up by cytology and HR?HPV testing in the years of 2005, 2010, and 2014. The changes of HR?HPV prevalence and the risks of cervical precancerous lesions with CIN2+ as the endpoints were analyzed during the past 15 years. Results The detection rates of HPV infection and CIN2+ were 15.7%?22.3% and 1.1%?4.3% for the baseline visit and the other 3 follow?ups, respectively. The cumulative risk of CIN2+ in HR?HPV positive women at baseline was significantly higher than HR?HPV negative women ( P<0.01) during the 15?year follow?up. The risk of CIN2+ in the four?times HPV positive group was 40. 0%, while the group with four?times negative HPV results was 0.6% (Adjusted RR = 55.0, 95% CI: 11.3 to 268.4). Conclusions The prevalence of HR?HPV infection and CIN2+ lesions were high in Xiangyuan county during the 15 years. HR?HPV positivity elevated the risk of CIN2+ compared to women whose HR?HPV test was negative. The risks of CIN2+incidence in 6 years were low among women with negative HR?HPV test. The risk of CIN2+ increased with the numbers of HPV infection events. The screening interval could be extended to 5?6 years.

Objective To evaluate the 15 years changing trends of prevalence of high risk HPV (HR?HPV) infection and the risks of cervical cancer and precancerous lesions (CIN2+) among a Chinese rural population. Methods The screening cohort with 1 997 women aged 35 to 45 years old was built in 1999 in Xiangyuan County, Shanxi province ( SPOCCS?I) and followed up by cytology and HR?HPV testing in the years of 2005, 2010, and 2014. The changes of HR?HPV prevalence and the risks of cervical precancerous lesions with CIN2+ as the endpoints were analyzed during the past 15 years. Results The detection rates of HPV infection and CIN2+ were 15.7%?22.3% and 1.1%?4.3% for the baseline visit and the other 3 follow?ups, respectively. The cumulative risk of CIN2+ in HR?HPV positive women at baseline was significantly higher than HR?HPV negative women ( P<0.01) during the 15?year follow?up. The risk of CIN2+ in the four?times HPV positive group was 40. 0%, while the group with four?times negative HPV results was 0.6% (Adjusted RR = 55.0, 95% CI: 11.3 to 268.4). Conclusions The prevalence of HR?HPV infection and CIN2+ lesions were high in Xiangyuan county during the 15 years. HR?HPV positivity elevated the risk of CIN2+ compared to women whose HR?HPV test was negative. The risks of CIN2+incidence in 6 years were low among women with negative HR?HPV test. The risk of CIN2+ increased with the numbers of HPV infection events. The screening interval could be extended to 5?6 years.