OBJECTIVE To prepare reactive oxygen species （ROS）-responsive methotrexate （MTX）-modified paclitaxel （PTX）/icariin （ICA） micelles （MTX-oxi-Ms@PTX/ICA）， and perform technology optimization and in vitro anti-tumor effect evaluation. METHODS Synergistic toxicity concentration range of PTX and ICA was screened by synergistic toxicity test. The micelles were prepared by thin film hydration method， and their technology was optimized by response surface methodology. The fundamental characteristics of the micelles prepared by the optimal technology were evaluated. The micelles’ cytotoxicity， targeting ability to renal carcinoma RENCA cells of mice， and their inhibitory effects on invasion and migration were assessed. RESULTS Results of synergistic toxicity experiments demonstrated that the strongest synergistic effect occurred when PTX concentrations ranged from 2.5 to 10 μmol/L and ICA concentrations ranged from 5 to 15 μmol/L. The optimal technology of MTX-oxi-Ms@PTX/ ICA was determined to include 80 mg Soluplus®， Soluplus® and TPGS1000 mass ratio of 4∶1 （mg/mg）， 2 mg DSPE-PEG2000-TK- PEG5000， 2 mg DSPE-PEG2000-MTX， 1 mg PTX， and 1.5 mg ICA， with a hydration temperature of 35 ℃ and a formulation volume of 5 mL. Under the optimal conditions， average encapsulation efficiency of PTX and ICA in 3 batches of MTX-oxi- Ms@PTX/ICA reached 92.75%， the critical micelle concentration （CMC） was 0.007 9 mg/mL， the particle size was （62.09±1.68） nm， the polydispersity index （PDI） was 0.046±0.032， and the Zeta potential was （－2.47±0.15） mV. Within 30 days of placement， there was no significant change E-mail：yingqiang_1126@163.com in particle size and polydispersity index of micelle. In vitro release experiments showed that MTX-oxi-Ms@PTX/ICA released drugs more rapidly in oxidative environments. The half maximal inhibitory concentration of MTX-oxi-Ms@PTX/ICA against RENCA cells was （5.170±0.036） μmol/L. In vitro cellular uptake experiments indicated that compared with unmodified micelles， MTX modified micelles had stronger targeting effects on cancer cells， and also significantly enhanced the inhibitory ability of invasion and migration of RENCA cells （P＜0.05）. CONCLUSIONS MTX-oxi-Ms@PTX/ICA micelles are successfully prepared， which exhibit high encapsulation efficiency， low critical micelle concentration， and good stability. These micelles demonstrate significant cytotoxicity against RENCA cells and effectively inhibit cancer cell invasion and migration.

Objective: To investigate the mechanism by which serum amyloid P component (SAP) alleviates periodontitis in mice, providing an experimental basis to establish SAP as a novel therapeutic agent for periodontitis. Methods: Ethical approval was obtained from the Institutional Animal Ethics Committee. Periodontitis models were established in wild-type (WT) mice and SAP-transgenic (SAP-Tg) mice, divided into four groups: WT control (WT group), WT periodontitis (WT+P group), SAP-Tg control (Tg group), and SAP-Tg periodontitis (Tg+P group). On day 7, the mice were euthanized, and periodontal tissues, teeth, and alveolar bone were collected. SAP protein expression was detected by enzyme-linked immunosorbent assay (ELISA). Micro-CT and HE staining were used to measure alveolar bone resorption (distance from the cementoenamel junction to the alveolar bone crest). Tartrate-resistant acid phosphatase (TRAP) staining was performed to assess osteoclast number, and immunohistochemistry (IHC) was employed to evaluate macrophage infiltration. The expression levels of inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by qRT-PCR. Oral microorganism composition was analyzed using 16S ribosomal RNA (16S rRNA) gene sequencing. Additionally, macrophages from WT and SAP-Tg mice were isolated to establish an in vitro inflammation model, divided into WT+LPS and Tg+LPS groups. The expression of macrophage polarization-related genes including inducible nitric oxide synthase (iNOS), CD86, CD163, and CD206) were assessed by qRT-PCR. After the induction of osteoclast differentiation, TRAP staining was performed. Results: ELISA results demonstrated that periodontal tissues from Tg+P group mice exhibited higher levels of SAP expression compared to the WT+P group. Micro-CT and HE staining analyses revealed that the Tg+P group showed reduced alveolar bone resorption, indicated by a shorter distance between the cementoenamel junction and alveolar bone crest, compared to the WT+P group. Furthermore, TRAP staining results indicated a decrease in osteoclast numbers in the Tg+P group compared to the WT+P group. IHC and qRT-PCR results indicated reduced macrophage infiltration and decreased expression of IL-1β, IL-6, and TNF-α in the Tg+P group. Oral microorganism sequencing showed no significant difference in periodontitis-associated pathogenic bacteria between WT+P and Tg+P groups. In vitro experiments demonstrated that compared to the WT+LPS group, the Tg+LPS group exhibited downregulated M1 macrophage markers (iNOS and CD86) and upregulated M2 macrophage markers (CD163 and CD206). TRAP staining confirmed fewer osteoclasts in the Tg+LPS group. Conclusion SAP overexpression effectively alleviates periodontitis severity in mice by inhibiting M1 macrophage polarization, reducing pro-inflammatory cytokine expression, and suppressing osteoclast differentiation, thereby attenuating alveolar bone resorption.

ObjectiveTo investigate the clinical features and outcomes of recompensation in patients with autoimmune hepatitis （AIH）-related decompensated cirrhosis， to identify independent predictive factors， and to construct a nomogram prediction model for the probability of recompensation. MethodsA retrospective cohort study was conducted among the adult patients with AIH-related decompensated cirrhosis who were admitted to The Fifth Medical Center of PLA General Hospital from January 2015 to August 2023 （n=211）. The primary endpoint was achievement of recompensation， and the secondary endpoint was liver-related death or liver transplantation. According to the outcome of the patients at the end of the follow-up， the patients were divided into the recompensation group （n=16） and the persistent decompensation group（n=150）.The independent-samples t test was used for comparison of normally distributed continuous data with homogeneity of variance， and the Mann-Whitney U rank sum test was used for comparison of non-normally distributed continuous data with heterogeneity of variance； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups； the Kaplan-Meier method was used for survival analysis； the Cox proportional-hazards regression model was used to identify independent predictive factors， and a nomogram model was constructed and validated. ResultsA total of 211 patients were enrolled， with a median age of 55.0 years and a median follow-up time of 44.0 months， and female patients accounted for 87.2%. Among the 211 patients， 61 （with a cumulative proportion of 35.5%） achieved recompensation. Compared with the persistent decompensation group， the recompensation group had significantly higher white blood cell count， platelet count （PLT）， total bilirubin （TBil）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， total bile acid， prothrombin time， international normalized ratio （INR）， SMA positive rate， Model for End-Stage Liver Disease （MELD） score， Child-Pugh score， and rate of use of glucocorticoids （all P0.05）， as well as significantly lower age at baseline， number of complications， and death/liver transplantation rate （all P0.05）. At 3 and 12 months after treatment， the recompensation group had continuous improvements in AST， TBil， INR， IgG， MELD score， and Child-Pugh score， which were significantly lower than the values in the persistent decompensation group （all P0.05）， alongside with continuous increases in PLT and albumin， which were significantly higher than the values in the persistent decompensation group （P0.05）. The multivariate Cox regression analysis showed that baseline ALT （hazard ratio ［HR］=1.067， 95% confidence interval ［CI］： 1.010 — 1.127， P=0.021）， IgG （HR=0.463，95%CI：0.258 — 0.833， P=0.010）， SMA positivity （HR=3.122，95%CI：1.768 — 5.515， P0.001）， and glucocorticoid therapy （HR=20.651，95%CI：8.744 — 48.770， P0.001） were independent predictive factors for recompensation， and the nomogram model based on these predictive factors showed excellent predictive performance （C-index=0.87，95%CI：0.84 — 0.90）. ConclusionAchieving recompensation significantly improves clinical outcomes in patients with AIH-related decompensated cirrhosis. Baseline SMA positivity， a high level of ALT， a low level of IgG， and corticosteroid therapy are independent predictive factors for recompensation. The predictive model constructed based on these factors can provide a basis for decision-making in individualized clinical management.

Objective: The American Heart Association released the Life s Essential 8 (LE 8) for the overall evaluation of cardiovascular health (CVH) on individual level. The present study aimed to describe the overall CVH in Chinese school aged children using LE 8 metrics. Methods: Data of the present analysis came from a national representative multicentered cross sectional study conducted in 7 provinces of China in 2013. The original study used a multistage cluster sampling method. A total of 10 326 children aged 5 to 19 years with complete data of health behaviors and health outcomes were included in the study. Children s health behavior indicators included diet, physical activity, nicotine exposure and sleep health. Health outcome factors included body mass index, fast blood glucose, lipid profile and blood pressure. Results: The median CVH score was 73.3 ( IQR =14.4) in boys and 73.4 ( IQR = 13.5) in girls. Compared to children aged ≤9 years, the health behavior scores were lowest in the 13-15 age group, with boys scoring 7.73 lower (95% CI =-8.35--7.12, P <0.01) and girls scoring 9.15 (95% CI =-9.83--8.48, P <0.01) lower. The ≥16 age group had the lowest health outcome scores, with boys scoring 7.85 (95% CI =-9.07--6.63, P <0.01) lower and girls scoring 6.11 (95% CI =-7.12--5.09, P <0.01) lower. Conclusions Chinese school aged children are generally at a moderate level of cardiovascular health. Specific LE 8 components vary substantially between groups and therefore require targeted intervention strategies.

Objective To analyze the effects of deep learning image reconstruction(DLIR)and adaptive statistical iterative recon-struction V(ASIR-V)on the imaging quality of chest CT in patient with pulmonary nodules,and to evaluate the differences based on different image reconstruction techniques in the detection of efficiency of computer-aided diagnosis(CAD)for pulmonary nodules.Methods The image data of pulmonary nodules of eighty patients with chest CT screening were reconstructed with ASIR-V 80％,DLIR-low(DLIR-L),DLIR-medium(DLIR-M)and DLIR-high(DLIR-H)images,respectively.The objective image quality and sub-jective image quality of the four groups were compared and analyzed.Objective image quality includes CT value of region of interest(ROI),noise,signal-to-noise ratio(SNR),contrast-to-noise ratio(CNR)and image average gradient.The diagnostic efficacy of CAD in detecting pulmonary nodules of reconstructed images among four groups were further evaluated.Results There were no signifi-cant difference in CT value of ROI of reconstructed images among the four groups(P＞0.05).The noise,SNR and CNR of DLIR-H images were similar to those of ASIR-V 80％(P＞0.05),but significantly better than those of DLIR-L and DLIR-M(P＜0.05).The average gradient of DLIR-L,DLIR-M and DLIR-H images were significantly higher than those of ASIR-V 80％(P＜0.05).The subjective image quality scores of DLIR-L,DLIR-M and DLIR-H images were significantly higher than those of ASIR-V 80％(P＜0.05),and the subjective image quality score of DLIR-H image was the highest.CAD showed the highest true positive rate in DLIR-H images for detecting pulmonary nodules(P＜0.05),and CAD showed the highest false positives per capita in ASIR-V 80％images for detecting pulmonary nodules(P＜0.05).Conclusion The noise,SNR and CNR of DLIR-H images are similar to those of ASIR-V 80％,with the significantly higher image clarity and subjective image quality scores.DLIR-H has advantages in CAD detection of pulmonary nodules,which is an ideal image reconstruction technology for chest CT pulmonary nodule screening.

Objective To assess the risk factors for carbapenem-resistant Acinetobacter baumannii(CRAB)bloodstream infection(BSI)and 28-day short-term mortality in elderly patients,and provide reference for the pre-vention and treatment of CRAB BSI.Methods Clinical data of patients aged ≥60 years and diagnosed with AB BSI in a hospital in Yulin City from January 2013 to December 2022 were retrospectively analyzed,including demogra-phic and microbiological characteristics,as well as clinical outcomes of the patients.Variables which were significant in univariate analysis were selected for multivariate analysis using binary logistic regression model and Cox propor-tional hazards model.Independent risk factors for infection were further determined,and survival analysis was per-formed using Kaplan-Meier curve.Results A total of 150 patients were included in the study,out of which 16 pa-tients(10.7％)had CRAB BSI and 134 had carbapenem-sensitive AB(CSAB)BSI.The 28-day short-term mortali-ty of AB BSI in elderly patients was 15.3％(23/150,95％CI:9.6％-21.1％),and the short-term mortality of CRAB BSI was higher than that of CSAB([56.3％,9/16]vs[10.4％,14/134]).Deep venous catheterization(OR:15.598,95％CI:1.831-132.910)and combined infections of other sites(OR:15.449,95％CI:1.497-159.489)were related to CRAB BSI in elderly patients.The independent risk factors for 28-day mortality in elderly patients with AB BSI were hemodialysis(OR:11.856,95％CI:2.924-48.076),intensive care unit admission(OR:9.387,95％CI:1.941-45.385),and pulmonary infection being suspected source of bacteremia(OR:7.019,95％CI:1.345-36.635).Conclusion The occurrence of CRAB BSI in elderly patients is related to the combined infection of other sites and deep vein catheterization.Hemodialysis,admission to ICU,and pulmonary infection being suspected source of bacteremia are independent risk factors for the prognosis of AB BSI in elderly patients.

OBJECTIVE To provide a reference for the adjustment of antibacterial drug regimens， identification of adverse reactions， and personalized pharmaceutical care for patients with bullous pemphigoid and pulmonary aspergillosis combined with disseminated Nocardia farcinica infection. METHODS Clinical pharmacists participated in the entire treatment process of a patient with bullous pemphigoid and pulmonary aspergillosis combined with disseminated N. farcinica infection. Evidence-based medicine was used to assist in the selection of an initial combined drug regimen against nocardiosis， and timely communication with the microbiology laboratory to provide early antimicrobial susceptibility data. When the patient exhibited epilepsy， the suspected drugs were identified， and it was reminded that imipenem-cilastatin sodium could affect the efficacy of valproic acid. It was suggested to replace valproic acid with levetiracetam for anti-epileptic treatment and to discontinue imipenem-cilastatin sodium. During treatment， it was recommended to monitor the blood concentrations of voriconazole and linezolid， and assist in adjusting the dosage promptly based on the monitoring results. RESULTS The physicians accepted the recommendations of the clinical pharmacists. The patient’s condition improved， and they were discharged with medication. CONCLUSIONS Based on evidence-based medical evidence， antimicrobial susceptibility test results， and blood concentration monitoring data， clinical pharmacists assist clinicians in selecting a sensitive anti-infective regimen for the patient， identifying adverse reactions， adjusting the treatment regimen and providing full-course medication monitoring to ensure the safety and efficacy of clinical drug therapy.

Senile macular degeneration（SMD） is a degenerative disease of the macular region of the eye that causes visual impairment in older people worldwide. It is the focus and difficulty of the treatment of ophthalmic diseases at home and abroad. This paper reviewed traditional Chinese medicine （TCM） active ingredients for the treatment and prevention of SMD， and its new ocular delivery preparations. Studies have shown that many active ingredients of TCM can inhibit the progression of SMD through various ways such as anti-oxidation， solid lipid nanoparticles， microemulsions/nanoemulsions， in-situ gel， etc. However， due to the low solubility， chemical instability and difficulty in overcoming the eye barrier of most TCM active ingredients， their clinical application in the treatment of SMD is seriously hindered. New preparations， such as liposomes， solid lipid nanoparticles， microemulsion/nanoemulsion， in situ gels， have good application prospects in ocular drug delivery.

ObjectiveTo investigate the possible mechanism of Hewei Anshen Formula （和胃安神方） in the treatment of insomnia. MethodsSixty male SD rats were randomly divided into the normal group， the model group， the eszopiclone group and the low-， medium- and high-dose Hewei Anshen Formula groups. The insomnia model was constructed by intraperitoneal injection of p-chlorophenylalanine （PCPA） for 2 days in all groups except the normal group. After successful modelling， the eszopiclone group was given 0.33 mg/（kg·d） eszopiclone aqueous solution by gavage， the low-， medium- and high-dose Hewei Anshen Formula groups were given 10 ml/kg of Hewei Anshen Formula with a concentration of 1， 2 and 4 g/ml， respectively， and the rats in the normal group and the model group were given 10 ml/kg of saline by gavage， once a day for 7 consecutive days. The general condition of the rats was observed during the experiment， and the body mass of the rats was measured every day after medication administration. The following day after the last medication administration， pentobarbital sodium co-test was used to observe the sleep condition， and the sleep latency and sleep duration were recorded； immunohistochemistry and Western blot were used to detect the expression of hypothalamic clock rhythm regulating protein （CLOCK） and brain and muscle aromatic hydrocarbon receptor nuclear transporter-like protein 1 （BMAL1） in the rats. ResultsThe body mass of rats in the model group was lower than that of rats in the normal group at all time points （P＜0.01）； compared with the same time in the eszopiclone group， the body mass of rats in the low-dose Hewei Anshen Formula group was elevated on the 5th， 6th and 7th days of medication administration （P＜0.05）. Compared with the normal group， the sleep duration of rats in the model group was shortened （P＜0.01）； compared with the model group， the sleep duration of rats in each dosage group increased （P＜0.01）， and the difference between the high-dose Hewei Anshen Formula group and the eszopiclone group showed no statistically significant （P＞0.05）， while the sleep duration of the low- and medium-dose Hewei Anshen Formula groups were shorterned than the eszopiclone group （P＜0.01）. The difference in sleep latency showed no statistically significant among each group （P＞0.05）. The results of both immunohistochemistry and Western blotting showed that the expression of CLOCK and BMAL1 in the hypothalamus of rats in the model group was significantly reduced compared with that in the normal group （P＜0.01）； the expression of CLOCK and BMAL1 in the hypothalamus of rats in the low- and high-dose Hewei Anshen Formula groups increased than that in the model group （P＜0.05 or P＜0.01）. ConclusionHewei Anshen Formula can improve insomnia in model rats， and its mechanism of action may be related to the up-regulation of the expression of the hypothalamic biological clock genes CLOCK and BMAL1 protein.

PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.