OBJECTIVE To analyze the influencing factors for achieving target plasma drug concentration （trough） （abbreviated as “PDC”） of vancomycin in patients from high-altitude regions and establish a predictive model for PDC using single- center data， providing references for rational clinical drug use. METHODS Inpatients with vancomycin （1 g， q12 h） administered intravenously in our hospital from January 2021 to June 2024 were retrospectively included. Demographic data， liver and kidney function and hematological indexes were collected. Spearman correlation analysis was used to evaluate the correlation between vancomycin PDC and each detection index. Univariate analysis was used to evaluate the differences of each index in patients with different PDC， and the effects of different gender， body mass index， age and underlying diseases （hypertension/diabetes） on vancomycin PDC. Based on the results of correlation analysis and univariate analysis， multiple linear stepwise regression analysis was used to obtain the independent predictors of vancomycin PDC and construct the prediction model. RESULTS A total of 141 patients were included， with an overall attainment rate of 46.81% for the target PDC of vancomycin. Correlation analysis showed that the vancomycin PDC was positively correlated with age， blood urea nitrogen， uric acid （UA）， serum creatinine （CRE） and β2- microglobulin （β2-MG）， and negatively correlated with height， weight， creatinine clearance rate （CCR）， glomerular filtration rate （GFR）， alanine transaminase （ALT）， hemoglobin （HGB）， white blood cell count and neutrophils （P＜0.05）. There were significant differences in age， CRE and other 14 indexes among different PDC groups （P＜0.05 or P＜0.01）. Age and underlying diseases had significant effects on vancomycin PDC （P＜0.05 or P＜0.01）. CCR， direct bilirubin （DBil）， β2-MG， UA， HGB and height （standardized coefficients were －0.371， 0.367， 0.169， 0.232， －0.140， －0.132； P＜0.05） were independent predictors of vancomycin PDC. The F value of the regression equation was 34.858 （P＜0.05）， the R2 was 0.610， and the adjusted R2 was 0.592. CONCLUSIONS The vancomycin PDC of patients in high-altitude regions is affected by multiple factors such as renal function， liver function and hematological indexes. CCR， HGB and height could be used to predict vancomycin PDC negatively， while DBil， β2-MG and UA could be used to predict vancomycin PDC positively. The variables of the established prediction model could explain 59.2% of the variation of vancomycin PDC.

Objective To understand the epidemiological characteristics and risk factors of hospital-acquired pneumonia in elderly diabetic patients. Methods Elderly patients with diabetes mellitus who were hospitalized in the hospital were selected from October 2020 to October 2023 as the research subjects. The epidemiological characteristics of hospital-acquired pneumonia were analyzed, and the risk factors affecting hospital-acquired pneumonia in elderly patients with diabetes mellitus were analyzed . Results There were 65 cases of hospital-acquired pneumonia in 388 elderly patients with diabetes mellitus, with an incidence of 16.75%, of which 56.92% were males and 43.08% were females. The proportion of patients aged≥80 years was higher than that of patients aged<80 years. There were no significant differences in gender, body mass index, education level, course of diabetes mellitus, smoking history, drinking history, hypertension, coronary heart disease and anemia between groups (P>0.05), but significant differences were shown in age, hospitalization time, tracheal invasive operation, types of antibacterial drug use and dysphagia between both groups (P<0.05). Logistic multivariate analysis showed that age≥80 years old, hospitalization time≥30 d, tracheal invasive operation, use of antibacterial drugs≥ 2 types, and dysphagia were independent risk factors for hospital-acquired pneumonia in elderly diabetic patients (P<0.05). Conclusion The risk of hospital-acquired pneumonia is high in elderly patients with diabetes mellitus. Patients with age≥80 years old, hospitalization time≥30 days, tracheal invasive operation, abuse of antibacterial drugs and dysphagia are high-risk population. It is necessary to take active intervention measures for such patients.

Meropenem （MEM） is one of the important drugs for the treatment of severe infections， but the standard dose is often difficult to achieve an effective therapeutic concentration target. This article reviews the related studies on the population pharmacokinetics of MEM in patients with severe infection. It is found that the apparent volume of distribution （Vd） and clearance rate are the most important factors affecting the dose adjustment， and the factors affecting Vd include serum albumin， age， overall weight， shock status， and chest/abdomen/cerebrospinal fluid drainage. The main factors affecting the clearance rate were renal function， renal replacement therapy treatment mode and combination therapy. For adult patients with severe infections in China， MEM is recommended to be administered in an individualized manner based on glomerular filtration rate， with a dosage range of 500 to 1 500 mg given every 4 to 6 hours， and prolonged infusion is preferred. When the minimum inhibitory concentration （MIC） of the pathogenic bacteria reaches 64 mg/L， therapeutic drug monitoring is required. For therapeutic efficacy， it is essential to ensure that the trough concentration remains above the MIC； to prevent drug resistance， it should be maintained above 4×MIC. Regarding safety， it is recommended that the upper limit of the trough concentration be 32 mg/L， and blood sampling for monitoring can be conducted as early as after 1 to 2 doses of administration.

This study investigates the effect and underlying mechanism of Guizhi Tongluo Tablets(GZTL) in treating atherosclerosis(AS) in a mouse model. Apolipoprotein E-knockout(ApoE~(-/-)) mice were randomly assigned to the following groups: model, high-, medium-, and low-dose GZTL, and atorvastatin(ATV), and age-matched C57BL/6J mice were selected as the control group. ApoE~(-/-) mice in other groups except the control group were fed with a high-fat diet for the modeling of AS and administrated with corresponding drugs via gavage for 8 weeks. General conditions, signs of blood stasis, and body mass of mice were monitored. Aortic plaques and their stability were assessed by hematoxylin-eosin, Masson, and oil red O staining. Serum levels of total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) were measured by biochemical assays, and those of interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) were determined via enzyme-linked immunosorbent assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL). Single-cell RNA sequencing(scRNA-seq) was employed to analyze the differential expression of CD72hi macrophages(CD72hi-Mφ) in the aortas of AS patients and mice. The immunofluorescence assay was employed to visualize CD72hi-Mφ expression in mouse aortic plaques, and real-time fluorescence quantitative PCR was utilized to determine the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. The results demonstrated that compared with the control group, the model group exhibited significant increases in body mass, aortic plaque area proportion, necrotic core area proportion, and lipid deposition, a notable decrease in collagen fiber content, and an increase in apoptosis. Additionally, the model group showcased elevated serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6, alongside marked upregulations in the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. In comparison with the model group, the GZTL groups and the ATV group showed a reduction in body mass, and the medium-and high-dose GZTL groups and the ATV group demonstrated reductions in aortic plaque area proportion, necrotic core area proportion, and lipid deposition, an increase in collagen fiber content, and a decrease in apoptosis. Furthermore, the treatment goups showcased lowered serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6. The data of scRNA-seq revealed significantly elevated CD72hi-Mφ signaling in carotid plaques of AS patients compared with that in the normal arterial tissue. Animal experiments confirmed that CD72hi-Mφ expression, along with several pro-inflammatory cytokines, was significantly upregulated in the aortas of AS mice, which were downregulated by GZTL treatment. In conclusion, GZTL may alleviate AS by inhibiting CD72hi-Mφ activity.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Atherosclerosis/immunology* ; Mice ; Mice, Inbred C57BL ; Macrophages/immunology* ; Male ; Humans ; Apolipoproteins E/genetics* ; Tablets ; Tumor Necrosis Factor-alpha/genetics* ; Apoptosis/drug effects* ; Interleukin-1beta/genetics* ; Interleukin-6/genetics* ; Disease Models, Animal ; Mice, Knockout

The therapeutic effects of Yueju Pills on depression and cardiovascular diseases have been widely recognized. Previous studies have shown that the drug can significantly improve depressive-like behaviors induced by chronic unpredictable mild stress(CUMS) combined with atherosclerosis(AS). Given the complex pathogenesis of psychocardiac diseases, this study integrated metabolomics and network pharmacology to systematically elucidate the mechanism of Yueju Pills in alleviating depressive symptoms in psychocardiac diseases. The results demonstrate that, after Yueju Pill intervention, the levels of 9 abnormal metabolites in the hippocampus restore to normal ranges, primarily involving key pathways or signaling pathways, including the cyclic adenosine monophosphate(cAMP), mammalian target of rapamycin(mTOR), glycine/serine/threonine metabolism, and aminoacyl-tRNA biosynthesis. In a high-fat diet-induced CUMS ApoE~(-/-) mouse model, Yueju Pills significantly increases adenosine monophosphate(AMP) levels and decreases L-alanine and D-glyceric acid levels in the hippocampus. In conclusion, Yueju Pills exert antidepressant effects by regulating multiple metabolic axes, including glycine/serine/threonine metabolism and the cAMP, mTOR signaling pathways. Network pharmacology predictions reveal that the treatment of CUMS combined with AS by its core active components may be realized through modulating pathways concerning neuroinflammation and synaptic plasticity, including serine/threonine-protein kinase 1(AKT1), mitogen-activated protein kinase 1(MAPK1), and prostaglandin-endoperoxide synthase 2(PTGS2). This study provides a theoretical reference for the clinical application of Yueju Pills in alleviating the depressive symptoms of psychocardiac diseases.
Animals ; Network Pharmacology ; Mice ; Drugs, Chinese Herbal/administration & dosage* ; Metabolomics ; Male ; Depression/genetics* ; Humans ; Hippocampus/drug effects* ; Mice, Inbred C57BL ; Signal Transduction/drug effects*

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective To establish an efficient DNA extraction method for the batch identification of genotypes in model mice.Methods We extracted total DNA from transgenic mouse tails using four methods:alkaline simplified group,alkaline routine group,protease K cleavage group and DNA extraction kit group.The purity and concentration of DNA obtained by the four methods were measured,the effects of gel electrophoresis were evaluated,and the time and experimental costs of the four methods were compared.Results The protease K cleavage method produced the highest concentration of DNA,followed by the simplified alkaline boiling and routine alkaline boiling method.The reagent kit produced the highest DNA purity,followed by the simplified alkaline boiling method.The DNA templates obtained by the four method could be amplified by polymerase chain reaction and gel electrophoresis to obtain clear DNA target bands.In addition,the DNA template extracted by the simplified alkaline boiling method could be used for gene identification after storage at-20℃for 1 month,as well as requiring the least time and lowest costs.Conclusions The simplified alkaline boiling method is currently the simplest,fastest,and most economical DNA template-extraction method for batch identification of genotypes in model mice.

Aim To explore the protective effects and underlying molecular mechanisms of periplogenin(Ppg)in preventing acetaminophen(APAP)-induced drug-induced liver injury(DILI).Methods An APAP-induced liver injury model was established in vi-vo and in vitro.Liver/spleen indices were recorded,and serum aspartate aminotransferase(AST)and ala-nine aminotransferase(ALT)levels were measured.The pathological changes in liver tissue were observed using hematoxylin-eosin(HE)staining.The influence of Ppg on inflammatory cytokines(IL-6,TNF-α,IL-1 β)and key proteins within the associated signaling pathways was examined using enzyme-linked immu-nosorbent assay(ELISA),quantitative polymerase chain reaction(qPCR),and Western blot.Additional-ly,glutathione(GSH),malondialdehyde(MDA),and superoxide dismutase(SOD)activity levels were meas-ured.The expression of markers related to the NF-κB signaling pathway was assessed using qPCR,Western blot,and immunofluorescence.Results In vivo exper-iments showed that Ppg improved the liver and spleen index of mice with drug-induced liver injury,and the levels of AST and ALT in the serum decreased signifi-cantly,reducing the pathological damage of liver tis-sue.In vitro experiments showed that Ppg significantly inhibited the expression of IL-6,TNF-α and IL-1 β,and decreased the levels of GSH and MDA and in-creased SOD activity in AML-12 cells.Additionally,the inhibition of the NF-κB signaling pathway using pyrrolidinedithiocarbamate ammonium(PDTC),an NF-κB signaling pathway inhibitor reduced inflammato-ry cytokine expression and significantly decreased p65 nuclear translocation,showing results comparable to those observed in the high-dose Ppg group.Conclu-sions Ppg alleviates APAP-induced liver injury,po-tentially by inhibiting the NF-κB signaling pathway in hepatocytes,thereby reducing the inflammatory re-sponse and protecting liver from APAP-induced dam-age.

Aim To evaluate the bioequivalence of two oral preparations of rivaroxaban tablets(test preparation T and refe-rence preparation R)in fasting/postprandibular state in healthy Chinese subjects.Methods A randomized,open,single-dose,four-cycle,completely repeated crossover experiment was used in this study.A total of 70 healthy male and female subjects were enrolled,including 38 subjects in the fasting group and 32 sub-jects in the postprandial group.Rivaroxaban tablets(2.5 mg/tablet)were taken orally once per cycle and their reference preparations were tested.The plasma rivaroxaban concentration was determined by LC-MS/MS method.The pharmacokinetic parameters of rivaroxaban tablets were calculated by WinNonlin software,and the parameters were analyzed and processed.Re-sults The PK parameters of rivaroxaban tablets and reference preparations in fasting group were as follows:Cmax was(72.48±17.08)and(66.36±15.64)μg·L-1,respectively.AUC0-t were(383.49±101.06)and(370.43±102.16)h·ng·mL-1,and AUC0-inr were(389.58±102.28)and(375.84±103.01)h·μg·L-,respectively.Main PK parameters of subjects taking rivaroxaban tablets orally after meals:Cmax were(66.48±15.64 and 60.87±13.44)μg·L-1,AUC0-t were(404.44±72.58)and(381.80±79.93)h·μg·L-1,re-spectively.AUC0_inf was(410.88±73.55)and(393.64±69.71)h·μg·L-1,respectively.Under fasting and postmeal conditions,subjects took rivaroxaban test and reference prepara-tion orally,one tablet(2.5 mg/tablet)each time.The geometric mean of the main pharmacokinetic parameters of rivaroxaban in plasma(Cmax,AUC0-t,AUC0-inf)and their corresponding values had a 90％confidence interval ranging from 80.00％to 125.00％.No serious adverse events or unexpected adverse e-vents occurred in both groups.Conclusion Rivaroxaban tablets are bioequivalent and safe in vivo under fasting and postprandial conditions.

Objective To investigate the mechanism by which blue light irradiation-activated microglia mediate immune cell recruitment and exacerbate retinal damage,and to explore the role of microglial depletion in inhibiting immune infiltration and protecting the retina.Methods SPF-grade C57BL/6J mice were randomly divided into control group,blue light irradiation group,and PLX5622 pretreatment blue light irradiation group.A retinal injury model was established by continuous LED blue light irradiation for 2 days.In the PLX5622 pretreatment group,microglia were specifically depleted before blue light irradiation.After modeling,HE staining and OCT examination were used to examine retinal histomorphological changes;ERG examination was performed to evaluate retinal function;DHE staining and RT-qPCR were used to detect oxidative stress and inflammatory responses,and Iba1,CD68,CD11b immunofluorescence staining and flow cytometry were used to analyze microglial activation status and immune cell infiltration.Results After blue light irradiation,the retinal outer nuclear layer thickness was significantly reduced;ERG a-wave and b-wave amplitudes decreased;expression of oxidative stress-related genes Nrf2,Sod2,and HO-1 was upregulated;expression of inflammatory factors IL-1β,TNF-α,and ICAM-1 increased;the number of Iba1-positive microglia increased and migrated extensively to the outer nuclear layer;the proportion of CD68+cells and CD11b+immune cells was elevated;and activated microglia aggregated around blood vessels to mediate immune cell infiltration.After PLX5622 pretreatment to deplete microglia,immune cell infiltration was significantly reduced;inflammatory responses were alleviated;retinal structural damage was markedly improved,and visual function was protected.Conclusions Blue light irradiation activates microglia and promotes their migration to the injury area.Activated microglia mediate immune cell recruitment and infiltration,exacerbating retinal inflammatory damage.Microglial depletion can effectively inhibit immune infiltration,rescue retinal structure and function,and provide new therapeutic strategies for the prevention and treatment of blue light-related ocular diseases.