Lower-cost genotyping technology has promoted the generation of large genetic datasets with the evolving next-generation sequencing technology. The emergence of genome-wide association studies (GWAS) has facilitated researchers’ understanding of common complex diseases. GWAS refers to finding the sequence variations present in the human genome and screening out disease-related single nucleotide polymorphisms (SNPs). These SNPs are considered as the basis for assessing the stability of complex diseases. However, a single variation is not sufficient to assess an individual’s risk of disease. Polygenic risk score (PRS) is an emerging genetic data analysis method for quantitatively estimating an individual’s genetic risk for complex diseases by comprehensively considering multiple genetic variation sites. A single-value estimate of an individual’s genetic risk for a certain phenotype can be calculated as the cumulative impact of multiple genetic variants by building a PRS model. The finally expected risk score is weighted by the strength and direction of association of each SNP with the phenotype based on the number of alleles carried by each SNP. With the continuous development of various PRS calculation methods and the constant accumulation of genomic data, PRS has received widespread attention in the field of genetics. So far, quite a few studies at home and abroad have shown that PRS is valuable in risk prediction of different types of human traits or complex diseases, and its effectiveness has been further verified in clinical applications. At present, many studies have established PRS models based on GWAS summary statistics to quantify the genetic risk of susceptibility loci and clinical characteristics on diseases such as lung cancer, breast cancer, coronary heart disease, diabetes and Alzheimer’s disease. The disease-susceptible populations can be recognized through comparing the relative risk and absolute risk of the disease in different risk groups according to the population risk stratification results. Additionally, individual-level genotype data and omics data can also be used as data sources for PRS analysis research, especially the latter can dynamically reflect the short-term or long-term effects of environmental factors on human gene expression, and has potential application value in building early warning models to assess health risks. Since the calculation of PRS involves a large amount of genomic data analysis, there are big differences in the methods for data selection, model building and validation. Different PRS construction methods and software have different performances in disease risk prediction, and even the performance of same algorithm varies across diseases. It is worth noting that the PRS model often needs to be re-evaluated and verified for different groups of people, because PRS is affected by race and region. This review combines currently published PRS-related research and algorithms to describe the basic principles of PRS, compares their construction and verification methods, and discusses their applications and prospects. As a powerful genetic risk assessment tool, PRS has great potential in analyzing the genetic code of complex diseases and achieving precise diagnosis and personalized treatment.

Objective To evaluate the bioequivalence and safety of ezetimibe tablets in healthy Chinese subjects.Methods The study was designed as a single-center,randomized,open-label,two-period,two-way crossover,single-dose trail.Subjects who met the enrollment criteria were randomized into fasting administration group and postprandial administration group and received a single oral dose of 10 mg of the subject presparation of ezetimibe tablets or the reference presparation per cycle.The blood concentrations of ezetimibe and ezetimibe-glucuronide conjugate were measured by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS),and the bioequivalence of the 2 preparations was evaluated using the WinNonlin 7.0 software.Pharmacokinetic parameters were calculated to evaluate the bioequivalence of the 2 preparations.The occurrence of all adverse events was also recorded to evaluate the safety.Results The main pharmacokinetic parameters of total ezetimibe in the plasma of the test and the reference after a single fasted administration:Cmax were(118.79±35.30)and(180.79±51.78)nmol·mL-1;tmax were 1.40 and 1.04 h;t1/2 were(15.33±5.57)and(17.38±7.24)h;AUC0-t were(1 523.90±371.21)and(1 690.99±553.40)nmol·mL-1·h;AUC0-∞ were(1 608.70±441.28),(1 807.15±630.00)nmol·mL-1·h.The main pharmacokinetic parameters of total ezetimibe in plasma of test and reference after a single meal:Cmax were(269.18±82.94)and(273.93±87.78)nmol·mL-1;Tmax were 1.15 and 1.08 h;t1/2 were(22.53±16.33)and(16.02±5.84)h;AUC0_twere(1 463.37±366.03),(1 263.96±271.01)nmol·mL-1·h;AUC0-∞ were(1 639.01±466.53),(1 349.97±281.39)nmol·mL-1·h.The main pharmacokinetic parameters Cmax,AUC0-tand AUC0-∞ of the two preparations were analyzed by variance analysis after logarithmic transformation.In the fasting administration group,the 90％CI of the log-transformed geometric mean ratios were within the bioequivalent range for the remaining parameters in the fasting dosing group,except for the Cmax of ezetimibe and total ezetimibe,which were below the lower bioequivalent range.The Cmax of ezetimibe,ezetimibe-glucuronide,and total ezetimibe in the postprandial dosing group was within the equivalence range,and the 90％CI of the remaining parameters were not within the equivalence range for bioequivalence.Conclusion This test can not determine whether the test preparation and the reference preparation of ezetimibe tablets have bioequivalence,and further clinical trials are needed to verify it.

Pharmaceutical cocrystals is an advanced technology to improve the physicochemical and biological properties of drugs. However, there are few studies on the in vivo metabolism of pharmaceutical cocrystals. In this study, the pharmacokinetics of wogonin cocrystal in normal rats was further studied on the basis of the previous preparation of wogonin-aloperine cocrystal. Firstly, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established for simultaneous determination of wogonin and its metabolite wogonoside in rat plasma, and to investigate the methodology. The method was applied to the pharmacokinetic study of wogonin-aloperine cocrystal (Wog-Alop) in rats. The results showed that wogonin and its metabolite wogonoside had a good linear relationship in the range of 1-800 ng·mL^-1, and the precision, accuracy, matrix effect and stability in this range met the requirements of biological analysis. Compared with direct administration of wogonin, the C_max of wogonin and its metabolite in rats increased to 7.44-fold and 9.15-fold, AUC_0-t increased to 1.67-fold and 3.72-fold, and oral bioavailability of wogonin increased to 187.66% after cocrystal administration. Wog-Alop cocrystal can significantly improve the C_max, AUC, and oral bioavailability of wogonin and its metabolite, which provides a new perspective for the clinical application of wogonin. This study was approved by the Experimental Animal Ethics Review Committee of Beijing University of Chinese Medicine (approval number: BUCM-2023032307-1148).

Objective To explore the correlation between serum lipid levels of total cholesterol(TC)and triglyceride(TG)and the survival prognosis in postoperative patients with early lung cancer,and to observe the effect of Fuzheng Quxie Prescription on serum lipid levels in postoperative patients with early lung cancer,so as to explore the mechanism of Fuzheng Quxie Prescription in improving the survival prognosis of postoperative patients with early lung cancer.Methods The correlation of serum TC and TG levels with survival prognosis of 257 postoperative patients with early lung cancer admitted in Shanghai Municipal Hospital of Traditional Chinese Medicine from July 2010 to December 2015 was retrospectively analyzed.The changes of serum TC and TG levels in postoperative patients with early lung cancer before and after treatment with Fuzheng Quxie Prescription were statistically analyzed.From January 2017 to April 2021,a prospective analysis of the one-year,two-year,three-year and four-year disease-free survival rates and serum TC and TG levels was carried out in 281 postoperative patients with early lung cancer treated with Fuzheng Quxie Prescription orally in Shanghai Municipal Hospital of Traditional Chinese Medicine(treatment group)and in 287 postoperative patients with early lung cancer who were followed up in clinic while had no medciation in Shanghai Pulmonary Hospital(control group).Results(1)The retrospective study showed that pre-treatment TC level was correlated with progression-free survival(PFS)in postoperative patients with early lung cancer,and the patients with high TC level had longer PFS.There was no significant correlation between pre-treatment TG level and PFS in postoperative patients with early lung cancer.The patients with high TG level had higher short-term survival rate while the patients with low TG level had higher long-term survival rate.(2)The prospective study showed that there were nine cases of recurrence in the treatment group and 24 cases of recurrence in the control group till the last follow-up time on April 1,2021.The one-year,two-year,three-year and four-year disease-free survival rates in the treatment group were 99.3％,96.8％,95.7％and 95.7％,respectively,which were superior to 97.6％,92.3％,89.2％and 87.1％in the control group(P＜0.05),indicating that the recurrence and metastasis in the postoperative patients with early lung cancer treated by Fuzheng Quxie Prescription were significantly reduced when compared with the control group,and the disease-free survival rate was significantly improved.After treatment,the serum levels of TC and TG in the treatment group were increased when compared with those before treatment(P＜0.05)while the control group showed no obvious changes(P＞0.05).The intergroup comparison showed that the increase of serum TC and TG levels in the treatment group was superior to that in the control group(P＜0.05),indicating that Fuzheng Quxie Prescription had regulatory effect on the blood lipid level of patients to a certain extent.Conclusion The analysis of the correlation between pre-treatment blood lipids and PFS prognosis in postoperative patients with early lung cancer indicated that lung cancer patients with high TC level had longer PFS;Fuzheng Quxie Prescription can regulate the blood lipid level of postoperative patients with early lung adenocarcinoma.It is speculated that Fuzheng Quxie Prescription may improve the survival prognosis of postoperative patients with early lung cancer probably by regulating the blood lipid level of the patients.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

Aim To investigate the enhanced efficacy and reduced toxicity of GanoExtra in combination with cyclophosphamide(CTX)on inhibiting lung metastasis and immune function in mice.Methods The CCK-8 method was used to verify the cytotoxic effects of Gano-Extra on MCF-7 and 4T1 tumor cells.In vivo experi-ment,a mouse model of lung metastasis of breast canc-er was established by injecting 4T1 tumor cells into the tail vein,which was divided into four groups including 4T1 model group,CTX group,GanoExtra group and GanoExtra+CTX group.The control group was set.After 21 days,the mice were euthanized under anes-thesia,and the body weight of the mice was recorded.Average lung index and spleen index were calculated.The mouse spleen lymphocyte transformation experi-ment was used to determine the activity of spleen cells.The NK cell activity assay was used to determine the activity of NK cells.Blood cells were determined in mouse blood samples.Flow cytometry was used to de-termine the levels of CD4+and CD8+T cells in blood samples.ELISA was used to measure the levels of TNF-α and IL-6 in serum.HE staining was used to ob-serve the pathological morphological changes in tumors and various tissues;and CFSE staining was used to de-termine the proliferative effect of GanoExtra on CD8+cells.Results In vitro GanoExtra at 50 mg·L-1 sig-nificantly inhibited the activity of MCF-7 and 4T1 tumor cells.In the breast cancer pulmonary metastasis model,compared with the model group,the spleen in-dex and blood WBCs content were significantly re-duced,while the activity of NK cells,spleen cells,and the proportion of RBCs,CD 3+and CD 8+T cells in the blood were significantly increased.At the end of the treatment,compared with the CTX group,the number of lung metastases and lung index of the Gano-Extra+CTX group were significantly reduced,and the levels of HGB,CD8+cells,IL-6,and TNF-α in the blood of mice were significantly increased.GanoExtra at 10 mg·L-1 significantly promoted the proliferation of CD8+T cells in vitro.Conclusions GanoExtra can enhance the inhibitory effect of CTX on tumor metasta-sis,alleviate adverse reactions such as splenomegaly and pulmonary enlargement caused by CTX,and have a health-promoting function of promoting the prolifera-tion of CD8+T cells to enhance the immune efficacy of the body.

Immunotherapy is an important breakthrough in canc-er treatment.Unfortunately,low drug concentration in tumor sites almost ineffectively initiates immune responses and thereby severely limits immune therapy applications in clinics.Nanoma-terials are well-recognized drug delivery system in cancer thera-py.Nanographene oxide(NGO)have shown immense perti-nence for anti-cancer drug delivery owing to their ultra-high sur-face area,chemical stability,good biocompatibility and excel-lent photosensitivity.In addition,functionalized modifications on the surface of NGO increase tumor targeting and minimize cy-totoxicity.This study focuses on reviewing the literature and up-dates on NGO in drug delivery and discussing the possibilities and challenges of NGO in cancer synergetic therapy.

OBJECTIVE: This study aimed to reveal the insomnia burden and relevant influencing factors among informal caregivers (ICs) of hospitalized patients with lung cancer. METHODS: A cross-sectional study on ICs of hospitalized patients with lung cancer was conducted from December 31, 2020 to December 31, 2021. ICs' burden was assessed using the Caregiver Reaction Assessment (CRA), Hospital Anxiety and Depression Scale (HADS), and Insomnia Severity Index (ISI). Linear and logistic regression models were used to identify the influencing factors. RESULTS: Among 289 ICs of hospitalized patients with lung cancer, 83 (28.72%), 53 (18.34%), and 14 (4.84%) ICs experienced mild, moderate, and severe insomnia, respectively. The scores concerning self-esteem, lack of family support, financial problems, disturbed schedule, and health problems were 4.32 ± 0.53, 2.24 ± 0.79, 2.84 ± 1.14, 3.63 ± 0.77, and 2.44 ± 0.95, respectively. ICs with higher Activities of Daily Living Scale (ADLS) scores were associated with a lower risk of insomnia, with an odd ratio ( OR) and 95% confidence interval ( CI) of 0.940 (0.898-0.983). Among the ICs, female gender ( OR = 2.597), alcohol consumption ( OR = 3.745), underlying medical conditions ( OR = 11.765), long-term caregiving experience ( OR = 37.037), and higher monthly expenses ( OR = 5.714) were associated with a high risk of insomnia. CONCLUSION Of the hospitalized patients with lung cancer, 51.9% experienced insomnia. Patients' ADL, ICs gender, alcohol consumption, underlying medical conditions, caregiving duration, and monthly expenses were influencing factors. Therefore, prompt screening and early intervention for ICs of patients with lung cancer is necessary.
Humans ; Female ; Caregivers ; Activities of Daily Living ; Cross-Sectional Studies ; Sleep Initiation and Maintenance Disorders/epidemiology* ; Lung Neoplasms/epidemiology*

OBJECTIVE: To conduct a preliminary study on joint injuries of anterior and calcaneal fibular ligaments of the lateral ankle joint, and to analyze mechanism of action of shaking and poking in treating ankle joint and biomechanical properties of ankle during the recovery of joint injuries. METHODS: CT scan was performed on a male volunteer with right ankle sprain. Mimics 10.0, Solidworks 2016, Hypermesh 12.0 and Abaqus 6.13 software were used to establish 3D nonlinear finite element analysis model of foot and ankle, and the validity of model was verified. Combined with clinical study, the finite element simulation analysis was carried out on the toe flexion, dorsiflexion, varus and valgus of ankle joint under different treatment periods by adjusting elastic modulus of ligament to simulate ligament injury. RESULTS: With the treatment of shake and prick and recovery of ligament injury, the maximum stress and area with large stress on tibial pitch and fibular joint surface gradually increased under the four working conditions, and the stress value of the maximum stress ligament gradually increased, and the stress of the anterior and calcaneal fibular ligament dispersed and transferred, and the axial force gradually decreased. CONCLUSION The finite element method was used to simulate the mechanical condition of the shaking and stamping technique, and the changes of the forces of the ligament and articular surface before and after treatment of anterior and calcaneal ligament combined injury of ankle talus were intuitively observed. The treatment effect was quantified, and could provid objective and scientific basis for clinical promotion and application of this technique.
Male ; Humans ; Ankle Joint ; Finite Element Analysis ; Ligaments, Articular ; Sprains and Strains/therapy* ; Ankle Injuries/therapy*

OBJECTIVE: To investigate the relationship between serum matrix metalloproteinase-1(MMP-1) and matrix metalloproteinase-2(MMP-2) and the formation of deep venous thrombosis(LDVT) in lower extremity patients after surgery for lower extremity fracture, and to analyze the value of MMP-1 and MMP-2 in predicting the occurrence of LDVT after lower extremity fracture. METHODS: From June 2018 to December 2021, 352 patients who planned to receive surgical treatment of lower limb fracture in our hospital were selected as the research objects. Venous blood was collected at 1, 2 and 3 days after surgery, respectively, and serum MMP-1 and MMP-2 levels were detected. The incidence of LDVT during hospitalization was analyzed, and the risk factors of postoperative LDVT in patients with lower limb fracture surgery and the predictive value of MMP-1 and MMP-2 for LDVT were analyzed. RESULTS: LDVT occurred in 40 patients (LDVT group), the incidence of LDVT was 11.36%, and 312 patients did not occurred(no occurred group). The serum levels of MMP-1 and MMP-2 in LDVT group increased gradually after surgery; the serum levels of MMP-1 and MMP-2 in the no occurred group increased slightly after surgery at 2 days and then decreased at 3 days after surgery (P<0.01);the serum levels of MMP-1 and MMP-2 in LDVT group were higher than those in the no occurred group at 2 days and 3 days after surgery (P<0.05). Serum levels of MMP-1 and MMP-2 were positively correlated with serum levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor -α (TNF-α) in LDVT patients at 2 days and 3 days postoperatively (P<0.05). Operative time, MMP-1 and MMP-2 postoperative 3 days were related to the occurrence of LDVT after lower limb fracture (P<0.01). The area under the curve(AUC) predicted by MMP-1 and MMP-2 postoperative 3 days for LDVT after lower limb fracture was 0.738 and 0.744 respectively, and the AUC predicted by combined MMP-1 and MMP-2 was 0.910, which was higher than that predicted by single indicator(Z=2.819 and 2.025, P<0.05). CONCLUSION High levels of MMP-1 and MMP-2 after lower extremity fracture are closely related to the occurrence of LDVT, and 3 d mMP-1 and MMP-2 after surgery maybe used as evaluation indexes for LDVT risk prediction.
Humans ; Lower Extremity/surgery* ; Matrix Metalloproteinase 1/blood* ; Matrix Metalloproteinase 2/blood* ; Risk Factors ; Venous Thrombosis/etiology* ; Fractures, Bone/surgery*