OBJECTIVE To investigate the mechanism of Xihuang pill （XHP） against diffuse large B-cell lymphoma （DLBCL）. METHODS The active ingredients of XHP and potential therapeutic targets for DLBCL were identified using TCMSP， GeneCards and DisGeNET databases. Protein-protein interaction networks were constructed using the String database and Cytoscape software to screen core components and core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were then performed. The clinical relevance of core targets was analyzed using the GEPIA and PanCanSurvPlot databases. Molecular docking and molecular dynamics （MD） simulation were conducted to verify the interactions between core components and core targets， and the binding free energy was calculated using the molecular mechanics Poisson-Boltzmann surface area （MM-PBSA） method. The effects of XHP on DLBCL and the related molecular mechanisms were validated using CCK-8 assay， flow cytometry and Western blot. RESULTS Network pharmacology analysis identified 108 active ingredients of XHP and 410 potential therapeutic targets for DLBCL. Six core components （e.g.， 17 beta-estradiol， quercetin） and ten core targets [e.g.， tumor protein 53 （TP53）， proto-oncogene tyrosine-protein kinase Src （SRC）] were obtained. Enrichment analysis indicated that the anti-DLBCL effects of XHP were primarily associated with the apoptotic signaling pathway， the phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway and so on. Clinical correlation analysis revealed that TP53 and SRC expression were significantly up-regulated in DLBCL tissues and associated with poor patient prognosis （P＜0.05）. Molecular docking， MD simulations and MM-PBSA calculations confirmed that the SRC-quercetin complex had a mail：stronger and more stable binding affinity. In vitro experiments demonstrated that XHP concentration-dependently inhibited the proliferation of DLBCL cells； compared with control group， XHP medium- and high-dose groups could significantly induce the apoptosis of SU-DHL2 and SU-DHL4 cells， and significantly down- regulated the expressions of SRC protein， phosphorylated （p）-PI3K/PI3K and p-Akt/Akt in SU-DHL4 cells （P＜0.05）. CONCLUSIONS XHP may inhibit the proliferation and induce the apoptosis of DLBCL cells by regulating the SRC/PI3K/Akt signaling pathway.

The precision dosing of antimicrobial agents serves as a key strategy to improve effectiveness while minimizing adverse drug effects, thereby enhancing therapeutic outcomes. It also aims to reduce the risk of antimicrobial resistance and optimize the utilization of healthcare resource. This article reviews the key technical elements of antimicrobial precision dosing, including novel therapeutic drug monitoring (TDM) methods, the concepts, modelling and stimulation approaches, and model evaluation of model-informed precision dosing (MIPD), and the implementation of MIPD with clinical decision support system (CDSS). Meanwhile, applications on how artificial intelligence (AI) techniques facilitate MIPD are discussed. We hope that the advances discussed and perspectives presented in this article will provide insights into the precision dosing and individualized therapy of antimicrobials in clinical practice.

Objective:To explore the clinical characteristics and prognosis of pediatric acute lymphoblastic leukemia with hyperleukocytosis (HL-ALL).Methods:A retrospective case series study was conducted. Clinical data of 153 children with initial diagnosis of HL-ALL from January 2016 to April 2023 in Children's Hospital of Soochow University were retrospectively analyzed. The clinical characteristics, cytogenetic and molecular biological features, immunophenotyping, treatment response and prognosis of the children were recorded. The children were divided into B-lineage and T-lineage groups according to immunophenotyping; the clinical characteristics of the two groups were compared; the overall survival (OS) of children in the two groups was analyzed by the Kaplan-Meier method, and the log-rank test was performed; the factors affecting OS were analyzed by using the Cox proportional hazards model.Results:Among the 153 children, 105 cases were detected with disease-related fusion genes, including 31 cases of Philadelphia chromosome-positive (Ph +)/Philadelphia chromosome-like (Ph-like). Tumor lysis syndrome (TLS) was present during induction therapy in 28 cases, pulmonary infection in 53 cases, intracranial hemorrhage in 6 cases, and sepsis in 12 cases. Immunophenotyping showed 86 cases were lineage B and 67 cases were lineage T. There were statistically significant differences in gender and age of the children between the B-lineage and T-lineage groups (both P < 0.05); the incidence of coagulation abnormalities and the levels of hemoglobin, lactate dehydrogenase and uric acid in the B-lineage group were lower than those in the T-lineage group (all P < 0.001). The positive rates of Ph +/Ph-like, MLL rearrangement, E2A-PBX1 and TEL-AML in the B-lineage group were higher than those in the T-lineage group (all P < 0.05), while the positive rates of SIL-TAL was lower than that in the T-lineage group ( P < 0.05). In terms of early complications, the incidence of TLS in the B-lineage group was lower than that in the T-lineage group ( P < 0.05). The median follow-up time [ M ( Q1, Q3)] was 1 150 (460-2 000) d until 30 April 2024, and the 3-year OS rates of children in the B-lineage and T-lineage groups were 80.6% and 67.1%, respectively; the difference in OS of children between the two groups was not statistically significant ( P = 0.168). The results of univariate Cox analysis showed that white blood cell count, Ph +/Ph-like positivity, occurrence of TLS, pulmonary infection, and intracranial hemorrhage were the influencing factors of OS in B-lineage HL-ALL children (all P < 0.05); white blood cell count and coagulation abnormalities were the influencing factors of OS in T-lineage HL-ALL children (both P < 0.05). Conclusions:There are differences in children's gender, age, laboratory parameters and genetics between the B-lineage and T-lineage groups in HL-ALL. White blood cell count, Ph +/Ph-like positivity, occurrence of TLS, pulmonary infection, and intracranial hemorrhage are the factors affecting OS of B-lineage HL-ALL children; white blood cell count and coagulation abnormalities are the factors affecting OS of T-lineage HL-ALL children.

Objective:To analyze the transition patterns of anal sex and unprotected anal intercourse (UAI), estimate the transition intensity and probability, and identify factors influencing the transition patterns in men who have sex with men (MSM) in Shandong Province.Methods:In August 2019, MSM aged ≥18 years old were recruited as subjects from 11 cities in Shandong Province. The baseline survey were completed in December 2019, and followup surveys were conducted once every 3 mouths from June 2020 to March 2021. Time-continuous, state-discrete multi-state reversible Markov model was constructed based on the status of MSM's sexual behaviors with different types of sexual partners [anal sex occurred or not (S1=No, S2=Yes) and UAI occurred or not (S1=No,S2=Yes)] to analyze the transition patterns and the influencing factors.Results:A total of 735 MSM were included. The transition intensity of starting anal sex with stable and casual partners was 1.935 times and 0.595 times higher than that of discontinuing this behavior, respectively. While the transition intensity to start UAI with stable and casual partners was 0.430 times and 0.169 times higher than that of discontinuing it, respectively. During the follow-up, the transition probabilities of anal sex and UAI with both stable and casual partners increased first and then stabilized. For stable partners, the transition probability of starting anal sex was higher than that of discontinuing it at the same period, for casual partners, it was just the reverse. For both stable and casual partners, the transition probabilities of discontinuing UAI were higher than starting it at the same time. The results of multivariate analysis showed that participants who received intervention materials ( HR=1.47), had an associate degree ( HR=1.77) or a bachelor's degree and above ( HR=1.47) were at higher risk of starting anal sex with stable partners. Those who received intervention materials ( HR=1.39) were at higher risk of discontinuing anal sex with stable partners, while participants identified themselves as non-male gender ( HR=0.49) were at lower risk of discontinuing anal sex with stable partners. Participants received intervention materials ( HR=1.75) were at higher risk of starting UAI with stable partners. Those who lived apart, divorced, or widowed ( HR=3.22) were at higher risk of starting UAI with casual partners, whereas had a bachelor's degree and above ( HR=0.58) were at lower risk of starting UAI with casual partners. Participants identified themselves as non-male gender ( HR=0.45) at lower risk of discounting UAI with casual partners. Conclusions:The transition patterns of homosexual behavior in MSM are different. Marital status, gender identity, educational level and other factors are the influencing factors of sexual behavior status transitions. Future researches should develop targeted interventions for different types of sexual partners and characteristics of MSM.

Objective:To investigate the drug resistance of newly diagnosed HIV-1 infected patients in Shanghai and to provide reference value for clinical antiretroviral therapy (ART).Methods:The peripheral venous blood plasma of 196 newly diagnosed HIV-1 infected patients screened according to the inclusion and exclusion criteria at the Shanghai Public Health Clinical Center from April to June 2023 was collected, HIV-1 RNA was extracted, the pol region was amplified by reverse transcription-polymerase chain reaction (RT-PCR) for sequencing, the mutation sites and ART drug resistance were analyzed.Results:The plasma of 196 newly diagnosed HIV-1 infected patients was amplified successfully in 162 cases (amplification success rate was 82.65%). The subtypes consisted of CRF07_BC(51.23%), CRF01_AE (27.78%), and others (6.79%), CRF55_01B (5.56%), B (3.70%), CRF01_AE/B (3.70%) and CRF08_BC (1.23%). The overall transmitted drug resistance rate was 7.41%, the protease inhibitors (PIs), non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), integrase inhibitors (INSTIs) resistance rates were 3.09%, 3.70%, 0.00% and 0.62%, respectively. The proportion of NNRTIs-related mutation sites in B (66.67%) and CRF55_01B (88.89%) was higher than that in CRF07_BC (13.25%); the proportion of NNRTIs-related mutation sites in CRF55_01B (88.89%) was higher than that in CRF01_AE (22.22%) and other subtypes (18.18%), the difference was statistically significant (all P<0.05). Multivariate logistic regression analysis showed that the probability of PIs-related mutation sites in CRF01_AE/B was 21.71 times that of CRF07_BC[odds ratio ( OR)=21.71, 95% confidence interval ( CI): 3.36-140.27, P=0.001]. Conclusions:The transmitted drug resistance among newly diagnosed HIV-1 infected patients in Shanghai is at the moderate epidemic level, mainly NNRTIs and PIs-related drug resistance, and the INSTIs resistance rate is low, the use of INSTIs in ART regimens should be considered.

Objective To investigate the distribution and antimicrobial resistance profiles of clinically isolated Haemophilus influenzae and Moraxella catarrhalis in hospitals across China from 2015 to 2021,and provide evidence for rational use of antimicrobial agents.Methods Data of H.influenzae and M.catarrhalis strains isolated from 2015 to 2021 in CHINET program were collected for analysis,and antimicrobial susceptibility testing was performed by disc diffusion method or automated systems according to the uniform protocol of CHINET.The results were interpreted according to the CLSI breakpoints in 2022.Beta-lactamases was detected by using nitrocefin disk.Results From 2015 to 2021,a total of 43 642 strains of Haemophilus species were isolated,accounting for 2.91％of the total clinical isolates and 4.07％of Gram-negative bacteria in CHINET program.Among the 40 437 strains of H.influenzae,66.89％were isolated from children and 33.11％were isolated from adults.More than 90％of the H.influenzae strains were isolated from respiratory tract specimens.The prevalence of β-lactamase was 53.79％in H.influenzae strains.The H.influenzae strains isolated from children showed higher resistance rate than the strains isolated from adults.Overall,779 strains of H.influenzae did not produce β-lactamase but were resistant to ampicillin(BLNAR).Beta-lactamase-producing strains showed significantly higher resistance rates to these antimicrobial agents than the β-lactamase-nonproducing strains.Of the 16 191 M.catarrhalis strains,80.06％were isolated from children and 19.94％isolated from adults.M.catarrhalis strains were mostly susceptible to both amoxicillin-clavulanic acid and cefuroxime,evidenced by resistance rate lower than 2.0％.Conclusions The emergence of antibiotic-resistant H.influenzae due to β-lactamase production poses a challenge for clinical anti-infective treatment.Therefore,it is very important to implement antibiotic resistance surveillance for H.influenzae and guide rational antibiotic use.All local clinical microbiology laboratories should actively improve antibiotic susceptibility testing and strengthen antibiotic resistance surveillance for H.influenzae.

Objectives:To investigate the impact of the Micra AV leadless pacemaker on cardiac function.Methods:A total of 76 patients who received the implantation of Micra AV leadless pacemaker due to sick sinus syndrome or atrioventricular block at Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from September 2022 to April 2023 were included in this study.Among them,26 patients(34.2%)had sick sinus syndrome,and 50 patients(65.8%)had atrioventricular block.The patients were followed up for 1 year postoperatively.Cardiac function was evaluated by echocardiography,and the parameters of the pacemaker were collected through the outpatient clinic programming system.Results:After a follow-up of 120(87,181)days,compared with the preoperative state,the left ventricular ejection fraction(LVEF)decreased postoperatively([66.6±5.6]%vs.[63.8±5.2]%,P<0.001),and the cardiac output increased[(4.3±1.2)L/min vs.(5.3±1.5)L/min,P<0.001].There were no statistically significant differences in various cardiac function indexes of patients with sick sinus syndrome between the postoperative and preoperative states(all P>0.05).Compared with the preoperative state,in patients with atrioventricular block,the LVEF decreased postoperatively([67.0±5.1]%vs.[63.4±4.4]%,P<0.001),the cardiac output increased([4.2±1.1]L/min vs.[5.2±1.2]L/min,P<0.001),and the left ventricular end-diastolic diameter decreased[(49.9±5.4)mm vs.(48.6±5.0)mm,P=0.044].Firth's logistic regression analysis indicated that the preoperative LVEF(for every 1%increase,OR=1.56,95%CI:1.12-2.17,P=0.001),stroke volume(for every 1 ml increase,OR=1.15,95%CI:1.04-1.28,P=0.001),body mass index(for every 1 kg/m2 increase,OR=1.49,95%CI:1.02-2.17,P=0.020),and hypertension(OR=12.71,95%CI:1.11-145.13,P=0.039)were independent risk factors for the decrease in LVEF after surgery in patients with atrioventricular block.After the implantation of the MciraTM AV leadless pacemaker,the overall atrioventricular synchrony rate was 81.2%(68.8%,89.0%).The atrioventricular synchrony rates of patients with sick sinus syndrome and those with atrioventricular block were 70.6%(59.5%,83.4%)and 82.4%(74.2%,89.3%)respectively(P<0.05).Firth's logistic regression analysis indicated that sick sinus syndrome(OR=0.26,95%CI:0.07-0.89,P=0.029)and preoperative LVEF(for every 1%increase,OR=1.18,95%CI:1.03-1.35,P=0.015)were independent predictive factors for the atrioventricular synchrony rate>80%.Conclusions:There are differences in the impacts of the Micra AV leadless pacemaker on the LVEF and atrioventricular synchrony rate between patients with sick sinus syndrome and those with atrioventricular block.The preoperative LVEF,stroke volume,body mass index,and hypertension have independent predictive effects on the decrease in postoperative LVEF in patients with atrioventricular block.Sick sinus syndrome and preoperative LVEF are independent predictive factors for the atrioventricular synchrony rate>80%after surgery.

Objective:To investigate effects of human umbilical cord mesenchymal stem cell-derived exosomes(hUCMSCs-Exo)on bisphenol AF(BPAF)-induced oxidative damage and inflammatory factor release from endometrial stromal cells(hESCs).Methods:hESCs were divided into Control group,BPAF group(25 μmol/L BPAF treatment),BPAF+Exo group(25 μmol/L BPAF+hUCMSCs-Exo treatment),BPAF+Exo+LY group(25 μmol/L BPAF+hUCMSCs-Exo+10 μmol/L LY294002 treatment).Cell prolifera-tion was detected by MTT assay;apoptosis,intracellular ROS level,and mitochondrial membrane potential level were detected by flow cytometry;protein expressions of Bcl-2,Bax,Cleaved-caspase-3 and PI3K/AKT signaling pathway were detected by Western blot;mRNA expressions of inflammatory factors TNF-α,IL-6 and IL-1β were detected by RT-qPCR.Results:Compared with Control group,hESCs survival rate was gradually decreased(P<0.01),apoptosis rate was gradually increased with the increased concentration of BPAF(≥25 μmol/L).Compared with Control group,BPAF group showed increased ROS level,decreased mitochondrial membrane potential level,increased Bax and Cleaved-caspase-3 protein expressions,and decreased Bcl-2,p-PI3K and p-AKT protein expressions.Compared with BPAF group,cell survival rate of BPAF+Exo group was increased(P<0.01),ROS level decreased,mitochondrial membrane potential level increased,expressions of Bax and Cleaved-caspase-3 proteins decreased,and expressions of Bcl-2,p-PI3K and p-AKT increased.Compared with BPAF+Exo group,expressions of Bax and Cleaved-caspase-3 protein in cells of BPAF+Exo+LY group were increased,while expressions of Bcl-2,p-PI3K and p-AKT protein were decreased.Expressions of inflammatory factors TNF-α,IL-6 and IL-1β mRNA were significantly up-regulated in BPAF group compared with Control group(P<0.01),and expressions of inflammatory factors mRNA were significantly down-regulated in BPAF+Exo group compared with BPAF group(P<0.05).Conclu-sion:BPAF(≥25 μmol/L)inhibits proliferation of hESCs and promoted apoptosis.hUCMSCs-Exo inhibits BPAF-induced oxidative dam-age and inflammatory factors expressions in hESCs through PI3K/AKT signaling pathway.

Phospholipid pharmaceutical excipients are primarily composed of a glycerol backbone,fatty acid chains,and phosphate groups.Due to their amphiphilic structure and unique physicochemical properties,they are commonly used as emulsifiers and carrier materials in pharmaceutical formulations.The pharmacopoeias of various countries have included phospholipid based pharmaceutical excipients and specified the testing methods and limits for their critical quality attributes.This article focuses on the current inclusion status,characteristic indicators,component content determination indicators,and functionality-related indicators determination methods and limits of phospholipid pharmaceutical excipients of various countries,in order to provide references and a basis for the rational applicatione of phospholipid pharmaceutical excipients.

Objective To investigate the application value of spectral CT multi-quantitative parameters combined with clinical characteristics in predicting high-risk gastroesophageal varices(GOV)in patients with liver cirrhosis.Methods The results of upper abdominal spectral CT enhancement and electronic gastroscopy in 112 patients diagnosed with liver cirrhosis were analyzed retrospec-tively,and the clinical data were collected.According to the gastroscopic manifestations,the patients were divided into high-risk GOV group(n=74)and low-risk GOV group(n=38).Univariate analysis was used to compare the spectral CT quantitative parameters and clinical characteristics between the two groups.Multivariate logistic regression analysis was used to screen the independent risk factors for high-risk GOV.R software was used to construct a nomogram model for predicting high-risk GOV,and the differentia-tion,calibration and clinical practicability of the prediction model were evaluated.Results The normalized iodine concentration(NIC)of liver left lobe,prothrombin time(PT),albumin(ALB)and liver function grading were independent risk factors for high-risk GOV(P＜0.05).The area under the curve(AUC)of receiver operating characteristic(ROC)curve of predicting high-risk GOV in nomo-gram model was 0.893.Calibration curve showed that the predicted results were basically consistent with the actual results.Decision curve analysis(DCA)showed that the prediction model had good clinical practicability.Conclusion The nomogram model based on NIC of liver left lobe,PT,ALB and liver function grading is helpful to predict patients with high-risk GOV in liver cirrhosis,and pro-vides a reference for clinical prevention and treatment of esophagogastric variceal bleeding(EVB).