Objective:To evaluate the potential causal relationship between tinnitus and the risk of Alzheimer's disease(AD)onset using the two-sample Mendelian randomization(MR)method and to clarify its mechanism of action,so as to provide new ideas for early warning of AD.Methods:Genome-wide association study(GWAS)database was used to search the keywords"tinnitus"and"Alzheimer"to obtain the related datasets of exposure factor tinnitus and outcome AD;the tinnitus datasets included ukb-d-4803_11,ukb-d-4803_12,ukb-d-4803_13,ukb-b-14254 and ukb-a-384;the AD datasets included ieu-b-5067,ieu-b-2,ieu-a-297,ebi-a-GCST90027158 and ebi-a-GCST002245.The single nucleotide polymorphisms(SNPs)closely and independently associated with tinnitus were screened as instrumental variables(IVs),and the SNPs associated with AD were used as outcomes.Inverse variance weighted(IVW)method was used to conduct MR analysis to evaluate its odds ratio(OR)value,95%confidence interval(CI)and P value;P<0.05 indicated significant causal relationship.Sensitivity detection used Cochran's Q test to detect the heterogeneity of IVs to evaluate its Q value,df value and P value;when IVW method P>0.05,it indicated no significant heterogeneity;MR-Egger intercept was used to detect horizontal pleiotropy;when the intercept was 0 or close to 0 and P>0.05,it indicated no significant horizontal pleiotropy;meanwhile,leave-one-out method was used for sensitivity analysis.Finally,visualization results were performed using forest plot,scatter plot,funnel plot and leave-one-out plot.Results:A total of 286 SNPs were screened as IVs.All instrumental variables satisfied F>10,suggesting no weak instrumental variable;after screening by PhenoScanner web tool,all SNPs were unrelated to confounding factors.When the tinnitus and AD datasets were ukb-d-4803 and ebi-a-GCST90027158 respectively,there was a significant positive correlation between tinnitus and the risk of AD onset(IVW:OR=1.842,95%CI:1.065-3.188,P=0.029);Cochran's Q test suggested no significant heterogeneity of IVs(Q=9.788,df=10.000,P=0.459);MR-Egger intercept indicated no horizontal pleiotropy(Egger intercept=-0.006,P=0.147);leave-one-out method showed stable results,and no SNP with significant influence on the results was detected.Conclusion:There is a positive causal relationship between tinnitus and the risk of AD onset.Neuroinflammation accompanied by persistent microglial activation to varying degrees may be the common pathogenesis of tinnitus and AD;in addition,depression may also act as an upstream factor to hyperactivate the hypothalamic-pituitary-adrenal(HPA)axis,leading to the progression of relationship between tinnitus and AD.

Objective To explore the relationship between pathogenic microorganism types,age and season in 2 188 children with respiratory tract infections.Methods A total of 2 188 children with respiratory tract in-fections admitted to the Department of Pediatrics,962 Hospital,Joint Logistic Support Force of PLA from June 2023 to May 2024 were selected as the study subjects.Targeted next generation sequencing(tNGS)tech-nology was used to detect 107 common pathogenic microorganism in children with respiratory tract infections,including Haemophilus influenzae,rhinovirus,Moraxella catarrhalis,Mycoplasma pneumoniae,Staphylococcus aureus,Streptococcus pneumoniae,human parainfluenza virus,human respiratory syncytial virus,etc.The re-spiratory tract infection situation and epidemiological characteristics of children in Harbin were analyzed.Re-sults Among 2 188 pediatric patients,98.5%(2 156/2 188)tested positive for pathogenic microorganism,with Haemophilus influenzae accounting for the highest proportion of 33.5%(732/2 188),followed by rhino-virus of 25.0%(547/2 188)and Moraxella catarrhalis of 24.8%(543/2 188).The positive rates of Hae-mophilus influenzae and human adenovirus in male children were higher than those in female children(P<0.05),while there were no statistically significant differences in the positive positive rates of other pathogenic microorganism between male and female children(P>0.05).Except for human adenovirus and influenza A virus,which showed no statistically significant differences in positive rates among different age groups(P>0.05),there were statistically significant differences in the positive rates of other pathogenic microorganism a-mong different age groups(P<0.05).The positive rates of pathogenic microorganism in preschool children were relatively high.There were no statistically significant differences in the positive rates of Streptococcus and Staphylococcus aureus in different seasons(P>0.05),while there were statistically significant differences in the positive rates of other pathogenic microorganism in different seasons(P<0.05).The positive rates of Haemophilus influenzae,Streptococcus pneumoniae,human metapneumovirus,human parainfluenza virus and SARS-Cov-2 were the highest in summer(P<0.05).Conclusion 2 188 children with respiratory tract infec-tions were mainly caused by pathogenic microorganism such as Haemophilus influenzae,rhinovirus,and Moraxella catarrhalis,etc.Preschool children is a susceptible group,and the prevalence of pathogenic microor-ganism varies seasonally.In clinical practice,relevant prevention and control measures should be developed based on this characteristic to reduce the incidence of diseases.

Objective To establish a 13C isotope-labeled hyperinsulinemic-euglycemic clamp model for the assessment of insulin sensitivity in mice.Methods The mouse model of insulin resistance was established by high-fat diet feeding.The phosphorylation level of downstream insulin signaling protein,Protein Kinase,also known as Akt was assessed.Glucose metabolism was evaluated using glucose tolerance test,insulin tolerance test,and pyruvate tol-erance tests and the area under the curve of the respective testes over 2 hours was calculated to quantify overall blood glucose level.Mice underwent jugular vein catheterization surgery,and a 13C isotope-labeled hyperinsulinemic-eugly-cemic clamp experiment was conducted to monitor blood glucose levels and to calculate the glucose infusion rate(GIR).Tail vein serum was collected for liquid chromatography-tandem mass spectrometry(LC-MS/MS)analysis to determine glucose disposal rate(GDR)and hepatic gluconeogenesis rate(HGP).Following the inhibition of glycog-enolysis in mice,Akt phosphorylation level was measured to evaluate insulin signaling.The clamp test was repeated to calculate GIR,and tail vein blood serum was analyzed by LC-MS/MS to determine GDR and HGP.Results After one week of high-fat diet feeding,mice exhibited significantly elevated blood glucose level(P＜0.001)accompanied by reduced p-Akt level in liver and muscle.Glucose tolerance tests,insulin tolerance tests and pyruvate tolerance test demonstrated a significant increase in blood glucose level(P＜0.05)and a higher area under curves(AUC)(P＜0.001)in high-fat-fed mice.During the 13C-labeled hyperinsulinemic-euglycemic clamp experiment,after the blood glucose levels were stable,the GIR of high-fat-fed mice was significantly reduced(P＜0.001),GDR was de-creased(P＜0.0001)and hepatic gluconeogenesis rate was increased(P＜0.01).After pharmacological inhibition of glycogenolysis,mice showed elevated blood glucose level(P＜0.001)and further reductions in p-Akt level in liver and muscle.The 13C-labeled clamp experiment revealed that in the treated group,the GIR decreased(P＜0.01)while GDR was reduced(P＜0.000 1)and HGP increased(P＜0.01).Conclusions An improved hyperinsulinemic-eugly-cemic clamp model was developed to assess insulin sensitivity in mice.

Objective:To compare the antiplatelet effects of vicagrel and clopidogrel in patients with different cytochrome P450 (CYP) 2C19 genotypes.Methods:This is a post-hoc analysis of a phase Ⅱ clinical trial of vicagrel, which included patients with coronary heart disease who underwent percutaneous coronary intervention from August 2018 to June 2019 in 18 centers. Patients were categorized based on the presence of CYP 2C19 *2 or *3 loss-of-function (LOF) alleles into LOF carrier group ( n=111) and non-LOF carrier group ( n=90). Each group included patients received vicagrel 5 mg, 6 mg, 7.5 mg, or clopidogrel 75 mg for 28 days per study protocol. P2Y 12 reaction units (PRU) were measured using VerifyNow at baseline, 6 to 8 hours after loading dose, 7 to 10 days after randomization, and 28 days after randomization and the percentage inhibition of platelet aggregation (%IPA) was calculated. The primary endpoint was %IPA on day 28. Within the patients from the General Hospital of Northern Theater Command, 8 to 12 patients in each study arms were enrolled in a prespecified pharmacokinetic sub-study, measuring the time to reach maximum plasma concentration (T max), peak plasma concentration (C max), and area under the plasma concentration-time curve (AUC). Results:Among 201 patients, the age was (58.8±8.5) years, and 139 (69.2%) were male. In non-LOF carriers, there was no significant differences in PRU values and %IPA between the vicagrel 5 mg, 6 mg, 7 mg, and clopidogrel groups at all time points (all P>0.05). In LOF carriers, %IPA was significantly higher in the vicagrel-treated groups than in the clopidogrel group at 6-8 hours after loading dose (22.9 (14.2, 31.5)% vs. 19.8 (11.0, 28.6)% vs. 29.5 (20.9, 38.0)% vs. 12.9 (3.9, 21.9)%, P=0.038) and 7-10 days after randomization (22.4 (14.2, 30.5)% vs. 34.4 (26.1, 42.6)% vs. 39.8 (31.8, 47.9)% vs. 24.7 (16.3, 33.2)%, P=0.001), with a trend towards higher %IPA in the vicagrel-treated groups at day 28 (30.4 (21.3, 39.6)% vs. 36.5 (27.2, 45.7)% vs. 40.8 (31.8, 49.8)% vs. 30.7(21.2, 40.2)%, P=0.056). Pharmacokinetic results of 35 patients showed that the C max and AUC of the active metabolite M15-2 of vicagrel was similar to that of clopidogrel in non-LOF carriers, but AUC between vicagrel 5 mg, 6 mg, 7 mg and clopidogrel were significantly different in LOF carriers ((5.6±0.6) h·μg -1·L -1 vs. (6.8±2.7) h·μg -1·L -1 vs. (9.2±3.3) h·μg -1·L -1 vs. (4.2±1.9) h·μg -1·ml -1, P=0.020). Conclusion:Vicagrel and clopidogrel have similar antiplatelet effects in non-LOF carriers, but vicagrel exhibits superior antiplatelet effects in LOF carriers.

The aim of this study was to prepare a high drug-carrying capacity micellar drug delivery system(CTD@Sol)of the polymer zebra tetracycline and to preliminarily investigate the feasibility of this drug delivery system for the treatment of breast cancer.Firstly,CTD@Sol was prepared using sol as the carrier material and CTD as the model drug,and its pharmacological properties such as appearance and morphology,particle size,potential and in vitro release were evaluated.The growth inhibitory and apoptotic effects of CTD@Sol on breast cancer(4T1)cells were investigated by MTT assay and Annexin V-FITC/PI double staining assay;the uptake efficiency of 4T1 to this delivery system was investigated by flow cytometry;and the in vivo tissue distribution of the delivery system and the targeting of tumour tissues were investigated by small animal in vivo imaging technique.The results showed that CTD@Sol appeared as a light pale blue creamy white colour,with an average particle size of(159.73±1.96)nm,a PDI of 0.198±0.006,Zeta potential of-(47.60±1.77)mV,an encapsulation rate of(90.29±1.69)%and a drug loading capacity of(45.00±0.84)%;the in vitro release and haemolysis experiments showed that the drug release rate of CTD@Sol in acidic environment(pH 5.5)was significantly faster than that in neutral environment(pH 7.4),suggesting that the system is acid-sensitive and has good biosafety under endocytosed pH conditions.Cellular uptake,cytotoxicity and apoptosis experiments showed that CTD@Sol was more lethal to 4T1 cells,and the sol-gel polymer micelles as a drug delivery vehicle could significantly improve the cellular uptake efficiency of the drug;in vivo experiments showed that the delivery system had a significant targeting effect on tumour tissues.In conclusion,this study has successfully produced a CTD@Sol drug delivery system with high drug loading capacity(>45%),good pharmacological performance,strong targeting and biosafety,which has the potential to be used in the treatment of breast cancer.

Objective:The National Central Cancer Registry estimates the number of new cancer cases and deaths in China in 2022, using incidence and mortality data collected by the National Cancer Center.Methods:According to the data of 700 cancer registries in 2018 and the data of 106 cancer registries from 2010 to 2018, the age-period-cohort model was used to estimate the incidence rate and mortality rate of all cancers and 23 types of cancer in 2022, stratified by gender and urban and rural areas. We estimated the number of new cancer cases and deaths in China in 2022 based on the estimated rate and population data in 2022.Results:The estimated results showed that in 2022, there were approximately 4 824 700 new cancer cases in China (2 533 900 in males and 2 290 800 in females), with an age-standardized incidence rate of Chinese population (ASIR) of 208.58 per 100 000 (212.67 per 100 000 for males and 208.08 per 100 000 for females). Approximately 2 903 900 new cancer cases occurred in urban areas, with an ASIR of 212.95 per 100 000. It was estimated about 1 920 800 new cancer cases in rural areas, and the ASIR was 199.65 per 100 000. The top five cancers (lung cancer 1 060 600, colorectal cancer 517 100, thyroid cancer 466 100, liver cancer 367 700 and female breast cancer 357 200) accounted for 57.4% of all new cases. The estimated number of deaths from cancer in China in 2022 was 2 574 200 (1 629 300 in males and 944 900 in females), with an age-standardized mortality rate of Chinese population (ASMR) of 97.08 per 100 000 (127.70 per 100 000 in males and 68.67 per 100 000 in females). The number of deaths from cancer in urban and rural areas was about 1 400 600 and 1 173 400, with the ASMR of 92.37 and 103.97 per 100 000 in urban and rural areas, respectively. The top five leading cause of cancers death (lung cancer 733 300, liver cancer 316 500, gastric cancer 260 400, colorectal cancer 240 000 and esophageal cancer 187 500) accounted for 67.5% of all cancer deaths. Lung cancer ranked first in the incidence and mortality in men and women. The incidence rate in urban areas was higher than that in rural areas, while the mortality rate was lower than that in rural areas.Conclusions:The burden of cancer in China is still relatively heavy, with significant differences in cancer patterns in gender, urban-rural, and regional. The burden of cancer presents a coexistence of developed and developing countries, and the situation of cancer prevention and control is still serious in China.

Objective To observe the clinical efficacy of Zhuanyaotang Granules for the treatment of degenerative lumbar spinal stenosis(DLSS).Methods Using a randomized double blind controlled design,104 DLSS patients were divided into an experimental group and a control group using a random number table method,with 52 patients in each group.The treatment group took oral Zhuanyaotang Granules,methylcobalamin tablets and celecoxib capsule simulants.The control group used Zhuanyaotang Granules simulants,methylcobalamin tablets and celecoxib capsules.The course of treatment was 3 weeks for both groups.The follow-ups were conducted at 1 month and 3 months after treatment.The intermittent claudication distance,visual analogue scale(VAS)score and JOA efficacy rating criteria for low back pain score were observed in both groups before treatment,1,2,3 weeks of treatment and 1 month after treatment and 3 months after treatment.Adverse reactions during treatment were recorded.Results There were 5 cases of detachment and 2 cases of exclusion in the experimental group,and 5 cases of detachment and 1 case of exclusion in the control group.Compared with before treatment,there were statistically significant differences in intermittent claudication distance,VAS score,and JOA score between the two groups of patients at various time points during treatment and follow-up(P<0.05);there was no statistically significant difference in intermittent claudication distance,VAS score,and JOA score between the experimental group and the control group before treatment and 1 and 2 weeks of treatment(P>0.05);compared with the two groups at 3 weeks of treatment and 1 and 3 months after treatment,the intermittent claudication distance and JOA score in the experimental group were lower than those in the control group(P<0.05);There was no significant difference in VAS score between the two groups and the control group after 3 weeks of treatment(P>0.05).There were 2 adverse reactions(4.4%)in the experimental group and 5 adverse reactions(10.8%)in the control group,without statistical significance(P>0.05).Conclusion Zhuanyaotang Granules can effectively relieve pain and improve lumbar function in patients with DLSS,which is more effective and safer than oral celecoxib capsules and methylcobalamin tablets.

Background::Breast cancer is ranked among the most prevalent malignancies in the Chinese female population. However, comprehensive reports detailing the latest epidemiological data and attributable disease burden have not been extensively documented.Methods::In 2018, high-quality cancer surveillance data were recorded in 700 population-based cancer registries in China. We extracted data on female breast cancers (International Classification of Diseases, Tenth Revision [ICD-10]: C50) and estimated the incidence and mortality in 2022 according to the baseline data and corresponding trends from 2010 to 2018. Pathological types were classified according to the ICD for Oncology, 3rd Edition codes. Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost (YLLs) and years lived with disability (YLDs).Results::In 2022, approximately 357,200 new female breast cancer cases and 75,000 deaths occurred in China, accounting for 15.59% and 7.94% of total new cancer cases and deaths, respectively. The age-standardized incidence rate (ASIR) was 33.04 per 100,000. When analyzed by pathological type, the ASIRs for papillary neoplasms, invasive breast carcinoma, rare and salivary gland-type tumors, and other types were 1.13, 29.79, 0.24, and 1.88 per 100,000, respectively. The age-standardized mortality rate (ASMR) was 6.10 per 100,000. A total of 2,628,000 DALYs were found to be attributable to female breast cancer in China, comprising 2,278,300 YLLs and 349,700 YLDs. The ASIR, ASMR, and age-standardized rate (ASR) for DALYs in urban areas were consistently higher than those in rural areas. We observed a four-fold increase in the ASIR and ASR for DALYs and an eight-fold increase in the ASMR among females over 55 years compared with those aged under 55 years.Conclusion::These data provide invaluable insights into the latest epidemiology of female breast cancer in China and highlight the urgency for disease prevention and control strategy formulation.

Objective:The National Central Cancer Registry estimates the number of new cancer cases and deaths in China in 2022, using incidence and mortality data collected by the National Cancer Center.Methods:According to the data of 700 cancer registries in 2018 and the data of 106 cancer registries from 2010 to 2018, the age-period-cohort model was used to estimate the incidence rate and mortality rate of all cancers and 23 types of cancer in 2022, stratified by gender and urban and rural areas. We estimated the number of new cancer cases and deaths in China in 2022 based on the estimated rate and population data in 2022.Results:The estimated results showed that in 2022, there were approximately 4 824 700 new cancer cases in China (2 533 900 in males and 2 290 800 in females), with an age-standardized incidence rate of Chinese population (ASIR) of 208.58 per 100 000 (212.67 per 100 000 for males and 208.08 per 100 000 for females). Approximately 2 903 900 new cancer cases occurred in urban areas, with an ASIR of 212.95 per 100 000. It was estimated about 1 920 800 new cancer cases in rural areas, and the ASIR was 199.65 per 100 000. The top five cancers (lung cancer 1 060 600, colorectal cancer 517 100, thyroid cancer 466 100, liver cancer 367 700 and female breast cancer 357 200) accounted for 57.4% of all new cases. The estimated number of deaths from cancer in China in 2022 was 2 574 200 (1 629 300 in males and 944 900 in females), with an age-standardized mortality rate of Chinese population (ASMR) of 97.08 per 100 000 (127.70 per 100 000 in males and 68.67 per 100 000 in females). The number of deaths from cancer in urban and rural areas was about 1 400 600 and 1 173 400, with the ASMR of 92.37 and 103.97 per 100 000 in urban and rural areas, respectively. The top five leading cause of cancers death (lung cancer 733 300, liver cancer 316 500, gastric cancer 260 400, colorectal cancer 240 000 and esophageal cancer 187 500) accounted for 67.5% of all cancer deaths. Lung cancer ranked first in the incidence and mortality in men and women. The incidence rate in urban areas was higher than that in rural areas, while the mortality rate was lower than that in rural areas.Conclusions:The burden of cancer in China is still relatively heavy, with significant differences in cancer patterns in gender, urban-rural, and regional. The burden of cancer presents a coexistence of developed and developing countries, and the situation of cancer prevention and control is still serious in China.

Cerebral organoids are three-dimensional nerve cultures induced by embryonic stem cells(ESCs)or induced pluripotent stem cells(iPSCs)that mimic the structure and function of human brain.With the continuous optimization of cerebral organoid culture technology and the combination with emerging technologies such as organ transplantation,gene editing and organoids-on-chip,complex brain tissue structures such as functional vascular structures and neural circuits have been produced,which provides new methods and ideas for studying human brain development and diseases.This article reviews the latest advances in brain organoid technology,describes its application in neurological diseases and advances in stroke modeling and transplantation treatment.