OBJECTIVE To evaluate the therapeutic efficacy of 5 regimens of colistin sulfate for common Gram-negative bacilli infection based on pharmacokinetics （PK）/pharmacodynamics （PD） theory and Monte Carlo simulation. METHODS Minimal inhibitory concentration （MIC） data of colistin sulfate against Acinetobacter baumannii， Pseudomonas aeruginosa， Klebsiella pneumoniae， Escherichia coli and Enterobacter cloacae in 2023 were collected from the China Antimicrobial Resistance Surveillance System. Monte Carlo simulation was conducted with the ratio of the area under the concentration-time curve from 0 to 24 hours in the unbound state to the MIC （fAUC0－24 h/MIC） ≥15 as the target value， the probabilities of target attainment （PTA） of 5 regimens of colistin sulfate to achieve the target ratio were obtained at different MIC； and the expected population PTA， specifically the cumulative fraction of response （CFR）， for each regimen within a specific bacterial population was further calculated， to evaluate the therapeutic efficacy of the five colistin sulfate regimens. RESULTS When bacterial MIC≤0.5 µg/mL， PTA of all colistin sulfate regimens （500 000 IU， q12 h； 500 000 IU， q8 h； 750 000 IU， q12 h； 750 000 IU， q8 h； 1 000 000 IU， q12 h） were all more than 90%. When bacterial MIC＝1 µg/mL， PTA for regimen （750 000 IU， q8 h） against A. baumannii， K. pneumoniae， P. aeruginosa， E. coli and E. cloacae， and for regimen （1 000 000 IU， q12 h） against the other four bacterial species （excluding P. aeruginosa） remained above 90%. When bacterial MIC≥2 µg/mL， PTA of 5 colistin sulfate regimens were all lower than 90%. For E. coli， the CFR of only colistin sulfate regimen （500 000 IU， q12 h） was less than 90%； for K. pneumoniae， the CFR of only colistin sulfate regimen （750 000 IU， q8 h and 1 000 000 IU， q12 h） was greater than 90%； for the other three bacteria， CFR of 5 regimens were all less than 90%. CONCLUSIONS When the MIC of Gram-negative bacteria is less than 0.5 µg/mL， colistin sulfate regimen with a routine dose can be selected for treatment. When MIC was 1 µg/mL， an increase in the dosing amount or frequency is required. The empirical treatment of the other four bacterial infections excluding E. coli requires the use of off-label doses.

Digital biopsy for liver diseases is characterized by the deep integration of artificial intelligence （AI） technologies and large-scale liver disease data， through which intelligent analytics are applied to support clinical decision-making and full-cycle management. This article reviews the AI technical framework based on standardized data governance and centered on multimodal large medical models， covering the application of natural language processing， knowledge map， generative AI， and large language models in the establishment of databases for specialty diseases， diagnosis， prognosis prediction， treatment， and automated medical documentation. This article also discusses the application prospects of this framework in medical education， scientific research， and healthcare management. Although this technique shows broad application potential， it still faces challenges in areas such as multi-center data integration， model interpretability， ethics， and data security. In the future， a smart ecosystem with closed-loop optimization and human-AI collaboration should be established to promote the comprehensive implementation of digital biopsy in the whole process of medicine， education， research， and management， thereby providing help for the precise prevention and control and holistic health management of liver diseases.

Objective:To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma.Methods:A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel′s Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups.Results:(1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P>0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups ( Z=-7.82, P<0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P<0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P>0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P<0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P<0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P<0.05). Conclusions:Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

Objective To assess the alterations of negative functional connectivity(FC),its relationship with clinical symptoms,and its potential value in schizophrenia(SZ).Methods Resting-state functional magnetic resonance imaging(rs-fMRI)data were acquired from patients with SZ and healthy controls(HC).For each participant,the whole brain image was first divided into 272 regions and then the FC between each pair of these regions was calculated using Pearson's correlation coefficient.Group-level negative FCs were identified using permutation test for each group.Each of the identified negative FCs was then compared between patients and controls to identify the altered negative FCs.Then,Spearman rank correlation was adopted to examine the relationship between the altered negative FCs and clinical variables.Finally,to evaluate the diagnostic value of negative FC in SZ,a multivariate pattern analysis(MVPA)was performed to distinguish between SZ and HC based on negative FCs.Results Ninety-one patients with SZ and 91 HC were included in this study,and 207 negative FCs in total were identified.Among the identified 207 negative FCs,12(constituting 5.80％of the total 207 negative FCs)were significantly altered in SZ compared with HC(Bonferroni correction,P<0.05),of which 11 were significantly decreased(i.e.,closer to 0)in SZ.The correlation analyses identified 2 significant associations-one was between a negative FC and the total score of the psychotic symptoms rating scales-auditory hallucinations(r=-0.24,P=0.02)and the other was between a negative FC and the weighted total score of the scale for the assessment of thought,language,and communication(r=0.26,P=0.01).Furthermore,the model for distinguishing between SZ and HC based on negative FCs achieved a classification accuracy of 72.6％that was significantly higher than chance-level accuracy(permutation test,P<0.001).Conclusion Negative FCs are altered in patients with SZ.Given that negative FCs are associated with clinical symptoms,thus they may serve as an imaging biomarker for assisting the diagnosis of SZ.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Animals ; Rabbits ; Atrial Fibrillation/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Signal Transduction ; NF-E2-Related Factor 2/pharmacology* ; Molecular Docking Simulation ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism* ; Inflammation/metabolism* ; Heme Oxygenase-1

Objective:To evaluate the relationship between the Panton-Valentine leukocidin (pvl) strain and clinical characteristics, and to describe the molecular biological characteristics of invasive Staphylococcus aureus ( S. aureus) infected clinical isolates. Methods:The isolates of S. aureus caused by invasive infection were collected in Beijing Children's Hospital Affiliated to Capital Medical University from January 2016 to December 2019, and the clinical data of the corresponding children were collected retrospectively using electronic medical records. Multilocus sequence typing, spa typing and pvl gene were analyzed using the PCR. In addition, the minimum inhibitory concentrations (MIC) of antibiotics of all isolates were detected by the micro-broth dilution method, and the isolates were divided into the pvl+ and pvl- groups according to whether or not the S. aureus isolates carried pvl. The t test and the Mann-Whitney U test were used to compare the clinical symptoms between the pvl+ and pvl- groups. Chi-square test was used to compare the drug susceptibility between the two isolates. Results:A total of 127 cases of invasive S. aureus infection were collected during the study period. The white blood cell count, neutrophil count, and C-reaction protein level in the pvl+ group were significantly higher than those in the pvl- group ( P=0.001, P=0.001, P=0.005). The rate of pvl carrier was 44.9%. Among 57 pvl+ pathogenic strains, 64.9% (37/57) were MRSA. The multidrug resistance rate of pvl- isolates was higher than that of pvl+ isolates (70% vs. 49.12%, P=0.02). Conclusions:In invasive S. aureus infection, pvl+ strain is associated with elevated inflammatory markers in children. the positive rate of pvl is higher in clinical isolates, and the multidrug resistance rate of pvl- S. aureus is higher.

Objective:To investigate the clinical efficacy, safety and compliance of Voriconazole suspension formula on the prevention and treatment of invasive fungal infection (IFI) in children with allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Clinical data of 25 children treated Voriconazole suspension formula for the prevention and treatment of IFI during the period of allo-HSCT in the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University from August 1, 2020 to April 30, 2021 were retrospectively analyzed.The plasma trough concentration of Voriconazole was detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and the genotype of CYP2C19 was detected by polymerase chain reaction-restriction fragment length polymorphism (RFLP). The effect of CYP2C19 genotype on Voriconazole trough concentration was analyzed by rank-sum test, and Fisher′ s accurate test was used to analyze the influence of severity of gastrointestinal mucositis on serum trough concentration of Voriconazole in children with allo-HSCT. Results:A total of 25 children, including 18 males and 7 females were recruited.The median age at allo-HSCT was 6 (2-13) years.After initial administration of conventional dose of Voriconazole suspension formula during transplantation, plasma trough concentration of Voriconazole was intermittently monitored.Only 13 cases (52.0%) reached the target plasma trough concentration, 11 cases(44.0%) reached the target plasma trough concentration after adjusting the dose according to the plasma concentration, and 1 cases(4.0%) failed to reach it after increasing the dose twice.Genotype detection of CYP2C19 was performed in 20 children, involving 4 cases of poor metabolizers (PM), 9 cases of intermediate metabolizers (IM), 6 cases of extensive metabolizers (EM), and 1 case of ultra extensive metabolizer (UEM). A significant difference in plasma trough concentration was detected among all groups ( F=24.012, P<0.01). During the transplantation, 12 cases developed mild to moderate gastrointestinal mucositis, and 7 cases had severe gastrointestinal mucositis.The stan-dard rate of plasma trough concentration in children with severe gastrointestinal mucositis (1/7 cases, 14.3%)was significantly lower than those with mild to moderate gastrointestinal mucositis (9/12 cases, 75.0%) ( P=0.02). Five children (71.4%) with severe gastrointestinal mucositis could reach the target trough concentration after increasing the drug dose, suggesting that severe gastrointestinal mucositis had a great influence on the plasma concentration of Vorico-nazole suspension.The incidence of IFI in 25 children with allo-HSCT was 0, and the compliance of children taking Voriconazole dry suspension was 100.0%.The incidence of adverse reactions was 24.0% and all adverse reactions were relieved after symptomatic treatment. Conclusions:The plasma concentration of Voriconazole varies greatly among children and in different states of the same patient.Therefore, it is necessary to monitor the trough concentration of the drug and adjust the drug dose.The use of Voriconazole suspension formula for the prevention and treatment of fungal infection during allo-HSCT in children is clinically safe and effective, with a good compliance in children.

The policy implementation model of G. C. Edwards was used to analyze the public policy health impact assessment in Zhejiang province, and summarize its practice and existing problems in four aspects of policy implementation standards, policy resources, policy executors′ intention and management organization structure, so as to provide reference for promoting the national health impact assessment pilot work. The analysis results showed that Zhejiang province has initially established the public policy health impact assessment mechanism and achieved phased results, but there were still some problems, including the imperfection of policy content and implementation strategy, the inadequacy of leadership decision-making and top-level design, the difference in attitude, understanding and implementation preference of policy implementation subjects, and the ambiguity of the authority and responsibility system of each department in cooperation. In order to further promote the smooth development of public policy health impact assessment, Zhejiang province should actively promote the top-level design to strengthen policy support, integrate and optimize policy resources, gradually establish and improve the health governance mechanism of multiple and overall coordination, and promote the high-quality development of public policy health impact assessment by taking cross departmental cooperation as the path of health co-construction.

Extracorporeal membrane oxygenation (ECMO), a kind of life support technology that can replace lung and heart function, is widely used in critical respiratory and circulatory exhaustion. Because of the serious diseases and the use of interventional catheters, patients receiving ECMO life support are often administrated with broad-spectrum antimicrobial agents, which increase the risk of fungal infection. Fungal infection during ECMO can increase mortality. How to effectively control fungal infection is a thorny problem faced by clinicians. During the treatment of ECMO, the patient's physiological status, ECMO oxygenation membrane, circulation pipeline and other factors may change the pharmacokinetic profiles of antifungal drugs, thereby affect the clinical efficacy of drugs. This artical reviews the pharmacokinetic characteristics of antifungal drugs during ECMO support, in order to provide references for clinical antifungal treatment.

Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The