Immunotherapy is a new anti-tumor method. The application of immune checkpoint inhibitor greatly improves the survival benefit for patients, but the drug resistance of immunotherapy affects the efficacy. Therefore, it is very important to explore the mechanism of drug resistance and solve the problem of drug resis-tance in tumor immunotherapy. Hypoxia in tumor microenvironment is the key factor of immune drug resistance. Hypoxia can inhibit the immune cells function and lead to immune escape through various mechanisms. It can be the breakthrough for overcoming the immunotherapy drug resistance that blocking pathway of hypoxia to promote immune resistance. By reviewing the mechanism of immunotherapy drug resistance induced by hypoxia, it is helpful to explore the development prospect of hypoxia-inducible factor-1α (HIF-1α) related targeted drugs in clinical application for immunotherapy.

Background Researches showed that elevatory blood glucose level results in long-term damage of cells and tissue,or metabolic memory phenomenon,and manipulation of hyperglycemic memory is a good approach in the prevention of diabetic complications.However,its mechanism is not clear.It is speculated that the pathogenesis of diabetic retinopathy (DR) in diabetic patients may be associated to related mechanisms.Uncoupling proteins (UCPs) can decrease the production of reactive oxygen species (ROS),which may be related to DR.Objective This study was to explore the association between DR and the single nucleotide polymorphisms (SNPs) of UCP genes in Chinese Han population with type 2 diabetes.Methods A cross-sectional study was performed.This study was approved by Ethic Committee of Affiliated First Hospital of Shanghai Jiao Tong University and complied with Declaration of Helsinki,and written informed consent was obtained from each subject prior to any medical examination.One thousand eight hundreds and seventy-five patients with type 2 diabetes mellitus were enrolled in Xinjing district of Shanghai city by cluster sampling from November 2014 to January 2015.The demographic and medical baseline characteristics,ocular examination and laboratory tests were obtained and periphery blood of 2 ml was collected for extraction of DNA.Eight tag SNPs of UCP1,three tag SNPs of UCP2,and seven tag SNPs of UCP3 were selected as marker locus for the detection of genotype by Sequenom Mass ARRAY.Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry platform were used for genotyping.Hardy-Weinberg equilibrium (HWE) analysis,allele and genotype frequencies,haplotype analysis,and association tests for DR and SNPs were performed by SAS and SHEsis software.Results A total of 530 DR patients were checked out from 1 875 subjects with type 2 diabetes mellitus,with the detection rate of 28.27％.rs660339 locn of UCP2 gene and rs1626521,rs668514 locus of UCP3 gene appeared to have low detectable rates,and the secondary allele base frequency of rs632862 in UCP2 gene was ＜0.01 and rs15763 of UCP3 gene was unmatched with HWE,therefore,these locus analysis was not included.In 13 SNPs locus included in the analysis,only 2 SNPs of UCP1 gene were related to DR.Compared with the non-diabetic retinopathy (NDR) patients,the G allele frequency of rs10011540 was increased (P =0.03,OR =1.31,95 ％ confidence interval[CI] =1.03-1.67,and T allele frequency of rs3811787 was decreased (P=0.04,OR=0.86,95％ CI=0.75-0.99) in DR patients.Genotyping detection showed that the C/C and A/A frequencies of rs3811790 in UCP1 gene were significantly more and C/A frequency was less in DR patients than those in NDR patients (all at P＜0.01).The logistic regression analysis indicated an association of SNPs of rs10011540 and rs3811787 with DR independent from glucose and disease duration.Conclusions The SNPs of rs10011540 and rs3811787 locus in UCP1 gene are associated with DR in Chinese type 2 diabetes patients.

Objective:To analyze the evolution path and diffusion mechanism of the unified drug management system of countywide medical communities in China, and provide references for the deepening implementation of the system.Methods:The policy documents of the central and provincial governments were retrieved with the keywords of " medical community" " drug management" " county-township-village integration" and " central pharmacy". By means of the policy diffusion theory, the evolution path of the diffusion of the unified drug management system for the countywide medical communities was identified from such dimensions as time, space and hierarchy. On the other hand, the action mechanism of the diffusion of the system was summarized from such aspects as competition, administrative instruction, learning and imitation.Results:A total of 36 effective policy documents were collected. The time diffusion of the drug unified management system of countywide medical communities was characterized by an " S" curve. By the end of 2022, there were 30 provinces implementing the countywide medical community drug unified management system, and the policy diffusion has entered a saturation and stagnation stage; spatial diffusion showed " proximity effect" ; hierarchy diffusion embodied the " leader follower" mode. In the process of policy diffusion, competition mechanism, administrative instruction mechanism, learning mechanism, and imitation mechanism coexisted, but there were difference in the dominant mechanism at different stages of policy diffusion.Conclusions:The unified drug management system of the countywide medical communities has been widely disseminated. It is recommended to promote the introduction of supporting policies, optimize the system evaluation system, and comprehensively use various diffusion mechanisms to promote the optimization of the system, so as to promote the deepening and sustainable operation of the system.

[Objective]To observe and analyze the vitreoretinal interface changes in type 2 diabetic retinopathy(DR)by using ultra-wide field swept-source optical coherence tomography(UWF SS-OCT)/swept-source optical coherence tomography angiography(SS-OCTA).[Methods]This study enrolled 143 patient with diabetic mellitus.We performed SS-OCT on 258 eyes and OCTA on 69 eyes with proliferative diabetic retinopathy(PDR),then analyzed the images to assess the relationship between posterior vitreous detachment(PVD)and DR severity,and to measure the growth of retinal neovascularization in PDR eyes with different stages of PVD.[Results]PVD stage was negatively correlated with DR severity(Gamma=-0.294,P<0.001),that is,the more extensive the vitreoretinal adhesion,the more severe the DR.The negative correlation between PVD stage and DR severity was more evident in patients with diabetes duration more than 10 years(Gamma=-0.620,P<0.001).Retinal neovascularization occurred more commonly in the area of vitreoretinal adhesion.[Conclusions]The degree of vitreoretinal adhesion is closely related to the DR severity.It is very important to use SS-OCT to evaluate the vitreoretinal interface in the management of DR patients.

Objective To investigate the application value of neutrophil count(N),neutrophil percentage(N％),neutrophil to lymphocyte ratio(NLR)and neutrophil to albumin ratio(NAR)in the evaluation of ul-cerative colitis(UC)patients.Methods A total of 87 UC patients admitted to the hospital from May 2022 to July 2023 were collected as the UC group,and 42 healthy people in the same hospital during the same period were selected as the control group.Blood routine and biochemical routine related inflammatory indicators in-cluding lymphocyte count(L),N,lymphocyte percentage(L％),N％,C-reactive protein(CRP),erythrocyte sedimentation rate(ESR),albumin(ALB)were collected,NLR and NAR were calculated.The clinical data of UC patients were collected.According to medical history,modified Mayo scoring system and Montreal classifi-cation criteria,UC patients were divided into clinical types,disease activity and lesion extent.The levels of N,N％,NLR and NAR in the control group and UC group and different subgroups of UC were evaluated.Spearman correlation analysis was used to analyze the correlation between the four indexes and ESR and CRP.The receiver operating characteristic curve was drawn to test the diagnostic efficacy of the four indicators a-lone and in combination in the detection of UC patients,and the best cut-off value,sensitivity and specificity were calculated.Results The levels of N,N％,NLR and NAR in UC group were higher than those in control group,and the differences were statistically significant(P＜0.05).There were significant differences in N,N％,NLR and NAR levels between UC patients with different activity and lesion range(P＜0.05).Spearman correlation analysis showed that CRP level was positively correlated with N,N％,NLR and NAR in UC pa-tients(r=0.392,0.343,0.354,0.503,P＜0.001).ESR level was positively correlated with N,NLR and NAR(r=0.383,0.233,0.475,P＜0.05).The area under the curve of N,N％,NLR and NAR alone and in combi-nation were 0.668,0.702,0.723,0.741 and 0.882,respectively.The sensitivity and specificity of the combina-tion of the four were higher(80.5％and 88.1％,respectively).Conclusion N,N％,NLR and NAR have cer-tain clinical value in the diagnosis,disease activity and lesion extent prediction of UC patients.

Objective:To share related knowledge and experiences with countries along the line, literature regarding current cohort studies was summarized. Distribution, establishment and development of cohort studies among large prospective general population were analyzed in 17 countries of Western Asia and the 16 countries of Central and Eastern Europe.Methods:Literature review was conducted to collect basic information on cohort studies, with descriptive study used to analyze the characteristics of these cohort studies.Results:There were 562 cohort studies with sample size as more than 1 000 stated in Western Asia and Central and Eastern Europe, including 468 (83.27 %) carried out in the nation itself and 94 (16.73 %) with international multicentered collaboration. According to the nature of cohort studies, 347 (61.74 %) were etiologically based. As for the contents involved, 310 (55.16 %) of them targeted on chronic/non-communicable diseases, 125 (22.24 %) concentrated on maternal and child health. Among those on chronic/non-communicable diseases, 51 (16.45 %) were on cancers and 83 (26.77 %) on cardiovascular disease studies. There appeared 10 large prospective cohort studies targeting on general population, mainly ongoing in Iran and European countries, with a duration of 8-29 years, including 4 of them with sample size as more than 50 000. In terms of the contents, epidemiological investigation, physical examination and biological samples collection took the major parts. Few papers were published in 9 out of the 10 cohort studies at the early stage of those projects but the number of papers increased annually and stabilized to certain extent. Conclusions:The regional distribution of cohort studies carried out in countries from the Western Asia and Central and Eastern European areas appeared unbalanced. Contents of these designs would mainly involve etiological studies, with focus on non-communicable diseases as cancer, cardiovascular disease, diabetes, respiratory diseases, mental and psychological diseases, and maternal and infant health etc.. However, only few large prospective cohort studies would base on general population.

Objective:To explore the relationship of body mass index and blood pressure with the incidence of diabetes in Jinchang cohort.Methods:We designed a nested case-control study, a total of 29 572 workers who had no history of diabetes in baseline survey in Jinchang cohort were selected as the study cohort from June 2011 to December 2013. After 2 year follow-up, 1 021 workers with first diagnosed diabetes were selected as the case group, after 1∶1 matching according to the same gender and age ±2 years among those without diabetes, circulatory system, or endocrine system diseases during the same follow-up period, 1 021 controls was selected and 2 042 subjects were finally included. We used multivariate conditional logistic regression model, additive interaction model and multiplicative interaction model to explore the relationship of body mass index and blood pressure with the incidence of diabetes.Results:After adjusting for factors such as occupation, alcohol use, family history of diabetes, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, low-HDL cholesterolemia and high-LDL cholesterolemia, multivariate conditional logistic regression analysis showed that the risk of diabetes increased with body mass index and blood pressure. Hypertension and overweight/obesity had a multiplicative interaction on the incidence of diabetes. The risks of diabetes in men and women with hypertension and overweight/obese were 2.04 times (95% CI: 1.54-2.69) and 3.88 times (95% CI: 2.55-5.91) higher than those in men and women with normal body weight and blood pressure, respectively. In the combination of BMI and blood pressure, obese individuals with SBP≥160 mmHg were 4.57 times (95% CI: 2.50-8.34) more likely to have diabetes than those with normal BMI and SBP, obese individuals with DBP≥90 mmHg were 3.40 times (95% CI: 2.19-5.28) more likely to have diabetes than those with normal BMI and DBP. Conclusions:Overweight/obesity and hypertension can increase the risk of diabetes. Health education about body weight and blood pressure controls should be strengthened to reduce the risk of diabetes.

Objective To explore the effect of exposure to noise of 3.0T magnetic resonance imaging(MRI)on children's cochlear function.Methods We prospectively recruited 72 children who underwent cranial MRI examination at our hospital from May to November 2018;3M earplugs and sponge mats were used for hearing protection during MRI scanning.Noise level(dBA)of each MRI sequence was detected with a nonmagnetic microphone and a sound level meter.Distortion product otoacoustic emissions(DPOAE)test at 2-7 kHz was performed 24 hours before and 30 minutes after the MRI examination.Paired t-test or Wilcoxon signed-rank test was used to analyze differences in DPOAE amplitude before and after the MRI examination.Results The average noise level of MRI measured in the study was(107.7±3.92)dBA.Compared with that before the MRI examination,the DPOAE amplitude(dB)changed little after the MRI examination;the range of amplitude differences in each age group was as follows:left ear(-0.24-1.10)and right ear(-0.24-0.74)in the 0-1 year-old group;left ear(-0.07-0.59)and right ear(-0.57-0.75)in the 2-5 year-old group;left ear(-0.36-0.44)and right ear(-0.30-0.57)in the 6-12 year-old group.No statistically significant difference was found(correction P＞0.05).Conclusion No potential impact of 3.0T MRI noise on children's cochlear function was observed under routine hearing protection.

Objective To develop a novel electric stapler, so as to improve the automation, convenience and precision of minimally invasive surgery. Methods The clamping, firing and turning mechanism of the new electric stapler was innovatively designed to realize the electric drive of minimally invasive surgical anastomosis on the basis of traditional mechanical stapler. The motion process of electric clamping, firing and double-screw turning mechanism was analyzed in detail, and the equations for motion function of three mechanisms were solved, providing a theoretical basis for the intelligent control algorithm of electric stapler. Results The electric clamping and firing process was simulated using ADAMS software to verify the equation of motion. The prototype of the new electric stapler was made, and the anastomosis experiment and blasting pressure experiment of the in vitro small intestine tissues were carried out. The range of anastomotic blasting pressure was between 3.7 kPa and 11.67 kPa, meeting the basic requirements in clinic. Conclusions The structure of the new electric stapler can meet the requirements of electric pressing and firing in minimally invasive surgery, contributing to achieve tissue anastomosis more conveniently, quickly and effectively.

ObjectiveTo investigate the effect of total alkaloids of Corydalis saxicola on a rat model of lipopolysaccharide（LPS）-induced depression， as well as the pharmacokinetic characteristics of 8 of its major components. MethodTwenty-four male SD rats were randomly divided into normal group， model group， fluoxetine group（10 mg·kg^-1） and total alkaloids of C. saxicola group（210 mg·kg^-1）， with 6 rats in each group. In addition to the normal group， the rats were injected intraperitoneally with LPS to establish the inflammation model of depression， and the drug administration was started 1 week after modeling， and the administration groups were gavaged according to the corresponding dose， and the normal and model groups were intragastric administration with equal volume of distilled water， and the administration was performed along with the modeling. After two weeks of continuous administration， the effect of total alkaloids of C. saxicola on the behavior of depressed rats were tested by sucrose preference， forced swimming and open field experiments， the levels of tumor necrosis factor-α（TNF-α）， interleukin（IL）-1β and IL-6 in serum of rats were determined by enzyme-linked immunosorbent assay（ELISA）， the histopathological changes of rat hippocampus were observed by hematoxylin-eosin（HE） staining. After the last administration， blood was collected from orbit according to the set time， and ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry（UPLC-QqQ-MS） was established to simultaneously detect the concentrations of dehydrocavidine， tetrahydropalmatine， coptisine， palmatine， jatrorrhizine， berberine， berberrubine and epiberberine in plasma， and drug-time curves were drawn. The pharmacokinetic parameters were analyzed by DAS 2.0 software. ResultCompared with the normal group， the model group exhibited a decrease in sucrose preference rate， total distance traveled in the open field， as well as an increase in swimming immobility time and serum inflammatory factor expression（P<0.01）. In contrast， compared with the model group， rats in each administration group showed an increase in sucrose preference rate and total distance traveled in the open field， a decrease in swimming immobility time， and a reduction in serum inflammatory factor expression（P<0.05， P<0.01）. Additionally， HE staining results revealed that neurons in the hippocampus of rats from the model group were characterized by loss， disorganization and residual vacuoles， whereas those from the total alkaloids of C.saxicola group displayed an increase in number with orderly arrangement and clear cytoplasm. Pharmacokinetic results showed that the time to peak（t_max） and half-life（t_1/2） of the 8 active ingredients were 0.19-2.06 h and 3.71-8.70 h after continuous administration of total alkaloids of C. saxicola. Among them， the area under the curve（AUC_0-∞） of tetrahydropalmatine was the highest and the t_1/2 was the shortest， and the AUC_0-∞ of coptisine， palmatine， jatrorrhizine， berberine， berberrubine and epiberberine were low. The curves of dehydrocavidine， coptisine， palmatine， berberine and epiberberine showed obvious double peak phenomenon. ConclusionTotal alkaloids of C. saxicola can improve the depression-like behavior of rats， inhibit the expression of inflammatory factors in serum， improve the pathological injury of hippocampus， and has the antidepressant effect. Meanwhile， the effective site is absorbed quickly and eliminated slowly in the depressed model rats， and the efficacy is maintained for a long time.