OBJECTIVE To establish a method for simultaneous determination of ceftazidime， avibactam and aztreonam concentrations in human plasma.METHODS Stable-isotope-labeled compounds ceftazidime-D 5 ， avibactam- 13 C 5 and aztreonam- 2 H 6 were used as internal standards. Plasma samples were pretreated by protein precipitation with methanol， followed by nitrogen blowing. A ultra-performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS） technique was applied to develop a quantitative analytical method for simultaneous measurement of ceftazidime， avibactam and aztreonam in human plasma. An ACQUITY UPLC BEH C 18 column was used as the chromatographic column. Gradient elution was performed with 0.01% formic acid-acetonitrile solution as the mobile phase at a flow rate of 0.3 mL/min. The column temperature was set at 40 ℃， and the injection volume was 5 μL. An electrospray ionization source was operated in both positive and negative ion modes for multiple reaction monitoring. Method validation was carried out according to the Guidelines for Bioanalytical Method Validation contained in volume Ⅳ of the 2020 edition of Chinese Pharmacopoeia .RESULTS The linear ranges of ceftazidime， avibactam and aztreonam were 0.04-200， 0.05-50，0.01-50 μg/mL， respectively， with all correlation coefficients no less than 0.996. The relative error （RE） for accuracy was no more than 12.25% （ n ＝5）， and the RSD for precision was no more than 13.49% （ n ＝5）. The RSD of internal-standard-normalized matrix factors was less than 15.00% （ n ＝6）. The RE in stability tests was lower than 15.00% （ n ＝3）.CONCLUSIONS This study successfully established an UPLC-MS/MS method for simultaneous determination of ceftazidime， avibactam and aztreonam concentrations in human plasma. The method possesses favorable accuracy， precision and stability， and can provide methodological support for therapeutic drug monitoring and individualized medication in patients treated with these three combined drugs.

Breviscapine （Bre）， the effective flavonoid fraction extracted from Erigeron breviscapus ， contains more than 90% scutellarin. It exerts pharmacological effects including cardiovascular protection， neuroprotection， anti-tumor activity and immunomodulation. Nevertheless， Bre has several drawbacks such as low solubility， low permeability， poor stability and short half-life， which greatly restrict its clinical application. Novel drug delivery systems （NDDS） are carriers that integrate multi-dimensional technologies including solubilization， penetration enhancement， sustained/controlled release and targeted delivery to achieve efficient drug delivery. This paper systematically summarizes the research progress of Bre-NDDS， which mainly covers oral preparations （sustained/controlled-release drug delivery systems， immediate-release drug delivery systems）， injectable preparations （liposomes， solid lipid nanoparticles， lipid emulsions， polymeric nanoparticles， polymeric micelles）， mucosal delivery systems （nasal mucosal drug delivery systems， buccal mucosal drug delivery systems， pulmonary mucosal drug delivery systems） and transdermal delivery systems. The preparation routes as well as in vitro and in vivo performances of various Bre-NDDS are analyzed. The design principles for NDDS based on pharmacokinetics/pharmacodynamics are put forward， which can provide scientific evidence for the research， development and industrialization of high-efficiency and safe new Bre preparations.

ObjectiveTo observe the effect of Yulin Hukun decoction on autophagy mediated by phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR） signaling pathway in the mouse model of cyclophosphamide-induced diminished ovarian reserve and explore the follicular development-improving mechanism of this decoction. MethodsSixty female ICR mice with normal estrous cycle were assigned into a blank group （n=10） and a modeling group （n=50）. The model was established by intraperitoneal injection of cyclophosphamide （60 mg·kg^-1） for 5 days. The successfully modeled mice were randomly grouped as follows： model， estradiol （0.26 mg·kg^-1）， and high-， medium-， and low-dose （56.42， 28.21， 14.105 g·kg^-1， respectively） Yulin Hukun decoction， with 10 mice in each group. The blank group and the model group received normal saline （10 mL·kg^-1）. The intervention was performed once a day for 21 days. The general conditions， estrous cycle， body weight， and ovary index were observed and recorded for each group. Serum levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， estradiol （E₂）， and anti-Müllerian hormone （AMH） were measured by enzyme-linked immunosorbent assay. Histopathological changes in the ovarian tissue were observed by hematoxylin-eosin staining. Western blot was employed to determine the protein levels of PI3K， Akt， mTOR， autophagy-related protein 7 （Atg7）， beclin1， microtubule-associated protein 1 light chain 3Ⅱ （LC3Ⅱ）， ubiquitin-binding adaptor protein （p62）， forkhead box protein O1 （FoxO1）， and acetylated forkhead box protein O1 （Ac-FoxO1） in mouse ovaries. Real-time PCR was adopted to determine the mRNA levels of PI3K， Akt， mTOR， Atg7， beclin1， and LC3Ⅱ in the mouse ovarian tissue. ResultsCompared with the blank group， the model group had disturbed estrous cycle， decreased body weight （P<0.05）， loose ovarian structure with increased atretic follicles， increased serum FSH level （P<0.05）， and decreased AMH and estradiol levels （P<0.05）. Compared with the model group， the treatment groups showed recovered estrous cycles and body weight. The estradiol group and high- and medium-dose Yulin Hukun decoction groups showed declined FSH level （P<0.05） and elevated AMH levels （P<0.05）. In addition， the treatment groups showed downregulated protein levels of Atg7， LC3Ⅱ， beclin1， FoxO1， and Ac-FoxO1 （P<0.01）， upregulated protein levels of PI3K， Akt， mTOR， and p62 （P<0.01） in the ovarian tissue， gradual repair of the ovarian structure， with more intact and numerous follicles of various stages. ConclusionYulin Hukun decoction can inhibit autophagy in ovarian granulosa cells by activating the PI3K/Akt/mTOR signaling pathway and inhibiting the expression of autophagy-related proteins and transcription factors， thereby improving follicular development and ovarian reserve.

Objective:To investigate the improvement in nutritional indicators, clinical complications, and respiratory infections among children with cerebral palsy (CP) and malnutrition who meet the indications for tube feeding under oral feeding and tube feeding interventions.Methods:In this retrospective cohort study, 82 children with CP and malnutrition that met the indications for tube feeding from the Children′s Rehabilitation Hospital of the Third Affiliated Hospital of Zhengzhou University from January 2022 to April 2024 were included.These patients were divided into an oral feeding group and a tube feeding group.The t-test, Mann-Whitney U test, or Kruskal-Wallis test was used to analyze nutritional indices such as weight-for-age Z-score (WAZ), height/length-for-age Z-score (HAZ), and weight-for-height/length Z-score (WHZ) before and after intervention in both groups.The improvement in clinical complications and respiratory infections was also analyzed. Results:After 3-month nutritional intervention, there were 60 cases in the oral feeding group and 22 cases in the tube feeding group.The tube feeding group showed better improvement in WHZ [-0.23(-1.79, 0.88) vs.-1.62(-2.02, -0.91) ] than the oral feeding group ( P<0.05).After 6-month nutritional intervention, there were 50 cases in the oral feeding group and 16 cases in the tube feeding group.The tube feeding group showed better improvement in WAZ [-0.80(-1.92, -0.42) vs. -2.26(-2.88, -1.84)], HAZ (-1.31±1.23 vs. -2.32±1.19), and WHZ (-0.74±1.39 vs. -1.58±1.03) than the oral feeding group (all P<0.05).After 12-month nutritional intervention, there were 30 cases in the oral feeding group and 10 cases in the tube feeding group.The tube feeding group showed better improvement in WAZ [-1.06(-1.77, -0.88) vs.-2.25(-3.06, -1.47) ] and HAZ (-1.22±1.63 vs. -2.54±1.50) than the oral feeding group (all P<0.05).Clinical complications improved better in the tube feeding group than those in the oral feeding group.In the tube feeding group, significant differences in choking ( χ2=16.29, P=0.001) and vomiting ( χ2=6.81, P=0.013) were observed before and after nutritional intervention.There was a statistically significant difference in frequency of lower respiratory infections 3 and 6 months after nutritional intervention between the 2 groups (all P<0.05). Conclusions:Compared with oral feeding, tube feeding can effectively improve the clinical nutritional indicators and reduce the clinical complications and the risk of respiratory infections in CP children that meet the indications for tube feeding.

This article reports a case of extensive ocular inflammation following zoledronic acid infusion for the treatment of osteoporosis. The patient developed pain, eyelid edema, conjunctival congestion, and decreased vision in the right eye one day after receiving intravenous zoledronic acid, and was diagnosed with uveitis, scleritis, and periorbital soft tissue inflammation. The patient′s symptoms were evaluated using the clinical activity score(CAS). After high-dose corticosteroid pulse therapy combined with other comprehensive treatments, the symptoms improved markedly. This article reviews the incidence, clinical features, potential mechanisms, management, and prognosis of ocular adverse reactions induced by zoledronic acid, and highlights the importance of early recognition and timely treatment of ocular inflammation after zoledronic acid therapy.

This article reports a case of extensive ocular inflammation following zoledronic acid infusion for the treatment of osteoporosis. The patient developed pain, eyelid edema, conjunctival congestion, and decreased vision in the right eye one day after receiving intravenous zoledronic acid, and was diagnosed with uveitis, scleritis, and periorbital soft tissue inflammation. The patient′s symptoms were evaluated using the clinical activity score(CAS). After high-dose corticosteroid pulse therapy combined with other comprehensive treatments, the symptoms improved markedly. This article reviews the incidence, clinical features, potential mechanisms, management, and prognosis of ocular adverse reactions induced by zoledronic acid, and highlights the importance of early recognition and timely treatment of ocular inflammation after zoledronic acid therapy.

Objective:To investigate the improvement in nutritional indicators, clinical complications, and respiratory infections among children with cerebral palsy (CP) and malnutrition who meet the indications for tube feeding under oral feeding and tube feeding interventions.Methods:In this retrospective cohort study, 82 children with CP and malnutrition that met the indications for tube feeding from the Children′s Rehabilitation Hospital of the Third Affiliated Hospital of Zhengzhou University from January 2022 to April 2024 were included.These patients were divided into an oral feeding group and a tube feeding group.The t-test, Mann-Whitney U test, or Kruskal-Wallis test was used to analyze nutritional indices such as weight-for-age Z-score (WAZ), height/length-for-age Z-score (HAZ), and weight-for-height/length Z-score (WHZ) before and after intervention in both groups.The improvement in clinical complications and respiratory infections was also analyzed. Results:After 3-month nutritional intervention, there were 60 cases in the oral feeding group and 22 cases in the tube feeding group.The tube feeding group showed better improvement in WHZ [-0.23(-1.79, 0.88) vs.-1.62(-2.02, -0.91) ] than the oral feeding group ( P<0.05).After 6-month nutritional intervention, there were 50 cases in the oral feeding group and 16 cases in the tube feeding group.The tube feeding group showed better improvement in WAZ [-0.80(-1.92, -0.42) vs. -2.26(-2.88, -1.84)], HAZ (-1.31±1.23 vs. -2.32±1.19), and WHZ (-0.74±1.39 vs. -1.58±1.03) than the oral feeding group (all P<0.05).After 12-month nutritional intervention, there were 30 cases in the oral feeding group and 10 cases in the tube feeding group.The tube feeding group showed better improvement in WAZ [-1.06(-1.77, -0.88) vs.-2.25(-3.06, -1.47) ] and HAZ (-1.22±1.63 vs. -2.54±1.50) than the oral feeding group (all P<0.05).Clinical complications improved better in the tube feeding group than those in the oral feeding group.In the tube feeding group, significant differences in choking ( χ2=16.29, P=0.001) and vomiting ( χ2=6.81, P=0.013) were observed before and after nutritional intervention.There was a statistically significant difference in frequency of lower respiratory infections 3 and 6 months after nutritional intervention between the 2 groups (all P<0.05). Conclusions:Compared with oral feeding, tube feeding can effectively improve the clinical nutritional indicators and reduce the clinical complications and the risk of respiratory infections in CP children that meet the indications for tube feeding.

Objective:To investigate urinary pH distribution and its influencing factors in gout patients, to provide insights for individualized treatment.Methods:This is a retrospective study. The gout patients in the Gout Outpatient Department of the Affiliated Hospital of Qingdao University from September 2019 to August 2021 were collected. Clinical data were collected and relevant indicators were measured. The patients were divided into different groups according to urinary pH. Clinical characteristics and factors related to urinary pH were compared among the groups. SPSS 23.0 software was used.Results:A total of 2 553 patients were enrolled. There were significant statistical differences in age, body mass index, triglyceride, alanine aminotransferase(ALT), blood urea nitrogen, serum creatinine, estimated glomerular filtration rate(eGFR), blood uric acid, urinary uric acid/creatinine ratio, fraction excretion of uric acid(FEUA) among groups with different urinary pH( F were 5.114, 4.772, 7.170, 4.721, 13.603, 2.812, 3.422, 22.834, 18.230, 26.332, all P<0.05). Urinary uric acid and FEUA in acute group were higher than those in remission group( Z were -2.295, -3.528, both P<0.05). After adjusting for gender, age, eGFR, logistics regression analysis showed that body mass index, triglyceride, total cholesterol, ALT, blood uric acid, and blood urea nitrogen were still risk factors. Multivariate logistic regression analysis showed that triglyceride, blood uric acid, and blood urea nitrogen were independent risk factors associated with acid urine. Linear correlation analysis showed that urinary pH was negatively correlated with body mass index, triglyceride, total cholesterol, blood uric acid, fasting glucose, blood urea nitrogen, ALT( r were -0.079, -0.106, -0.051, -0.186, -0.040, -0.122, -0.051, all P<0.05), but positively correlated with eGFR( r=0.058, P=0.003). Conclusion:The overall urine pH levels in patients with primary gout are below normal reference. Several metabolic components are related to it. Triglyceride, blood uric acid, and blood urea nitrogen are independent risk factors of acidic urine. In clinical practice, attention should be paid to timely alkalization of urine to prevent complications.

Objective:To investigate the clinical characteristics and risk factors of multiple tophi among gout patients.Methods:Gout patients treated at Affiliated Hospital of Qingdao University from September 2017 to September 2021 were included retrospectively. According to the number of tophi, the patients were divided into the multiple tophi group, the single tophi group and the non-tophi group. Clinical data were collected, biochemical indices and urine pH value were determined. One- way ANOVA or Chi-square test was used to compare groups, and multivariate logistic regression was used to analyze the risk factors. Results:The age, disease course, blood pressure, serum uric acid, urea nitrogen, and the rate of family history, smoking, drinking, gout attacks≥2 twice per year, hypertension, cardio-cerebrovascular diseases, kidney stones in the multiple tophi group were significantly higher than those in the single tophi group and the non-tophi group. The glomerular filtration rate, urine pH value and the rate of regular exercise were significantly lower than those of single tophi group and non-tophi group. In the multiple tophi group, 245 cases(44.46%) were involved in the interphalangeal joint or metacarpophalangeal joint, 212 cases(38.47%) were involved in other joints of the upper limb, which was second only to the first metatarsophalangeal joint(349 cases, 63.33%). Logistic regression analysis showed that the course of disease, urea nitrogen, serum uric acid, positive family history, drinking, gout attacks ≥twice per year and hypertension were the risk factors for multiple tophi in gout patients. Conclusion:Patients with a long disease course, elevated uric acid, high urea nitrogen, positive family history, alcohol consumption, frequent gout flare and hypertension are more likely to develop multiple tophi.

Objective:To analyze the clinical characteristics and risk factors of impaired liver and renal function in hospitalized patients with gout.Methods:A total of 494 hospitalized patients with confirmed gout were selected and divided into four groups according to liver and renal function, control(Con), impaired liver function (ILF), impaired renal function (IRF), and both function impaired (ILRF) group. Multivariate logistic regression was used to analyze the risk factors related with impaired liver and renal function.Results:Compared to Con group, ILF group were younger with shorter gout duration, higher body mass index, waist circumference, homeostasis model assessment for insulin resistance (HOMA-IR), serum uric acid, low density lipoprotein-cholesterol (LDL-C), total cholesterol, triglycerides, C reactive protein, higher prevalence of dyslipidemia, obesity, fatty liver, and monosodium urate crystal (MSU) deposition (all P<0.05). IRF group were older and with higher serum uric acid, serum creatinine, C reactive protein, and hypertension, MSU deposition prevalence, with lower prevalence of fatty liver (all P<0.05). Compared to ILF group, IRF group were older, with longer gout duration, lower level of body mass index, waist circumference, HOMA-IR, LDL-C, total cholesterol, triglycerides, lower prevalence of obesity, fatty liver, and higher prevalence of hypertension and type 2 diabetes (all P<0.05). The univariate logistic regression analysis showed that age( OR=0.941, 95% CI 0.906-0.977, P<0.001), serum uric acid ( OR=1.002, 95% CI 1.000-1.005, P=0.043), HOMA-IR ( OR=1.147, 95% CI 1.024-1.285, P=0.018), and MSU deposition ( OR=1.959, 95% CI 1.154-3.326, P=0.013) were the independent risk factors of impaired liver function, while the independent risk factors of impaired renal function were age ( OR=1.104, 95% CI 1.048-1.162, P<0.001), serum uric acid ( OR=1.007, 95% CI 1.004-1.010, P<0.001), and MSU deposition ( OR=2.393, 95% CI 1.191-4.805, P=0.014). Conclusions:Serum uric acid and MSU deposition are the common independent risk factors for impaired liver and renal function in patients with gout. Younger patients with insulin resistance are susceptible to impaired liver function, older patients with hypertension and diabetes are susceptible to impaired renal function.