ObjectiveTo investigate the influence of empagliflozin combined with donafenib or lenvatinib on the pharmacokinetic parameters of each drug， and to provide a reference for combined medication in clinical practice. MethodsA total of 48 healthy male Sprague-Dawley rats were divided into 8 groups： empagliflozin group 1 and 2， donafenib group， lenvatinib group， donafenib pretreatment+empagliflozin group， lenvatinib pretreatment + empagliflozin group， empagliflozin pretreatment+donafenib group， and empagliflozin pretreatment+lenvatinib group， with 6 rats in each group. The doses of empagliflozin， donafenib， and lenvatinib were 2.5 mg/kg， 40 mg/kg， and 1.2 mg/kg， respectively. The rats in the empagliflozin group， donafenib group， and lenvatinib group were given a blank solvent by gavage for 7 consecutive days， followed by a single dose of empagliflozin， donafenib， or lenvatinib on day 7 after the administration of the blank solvent； the rats in the pretreatment groups were given the pretreatment drug by gavage for 7 consecutive days， followed by a single dose of drug combination on day 7 after administration of the pretreatment drug. Blood samples were collected at different time points， and plasma was separated to measure the concentration of each drug. A validated ultra-performance liquid chromatography-tandem mass spectrometry method was used to measure the plasma concentrations of donafenib， lenvatinib， and empagliflozin， and a non-compartmental model was used to calculate the main pharmacokinetic parameters of each drug （area under the plasma concentration-time curve ［AUC］， time to peak ［T_max］， peak concentration ［C_max］， and half-life time ［t_1/2］）. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. ResultsCompared with the empagliflozin group， the donafenib pretreatment+empagliflozin group had significant increases in the AUC_0-t and AUC_0-∞ of empagliflozin （P=0.011 and 0.008）， while the lenvatinib pretreatment+empagliflozin group had no significant change in the AUC of empagliflozin， with a slightly shorter T_max （P=0.019）. Compared with the donafenib group， the empagliflozin pretreatment+donafenib group had significant increases in the AUC_0-t and AUC_0-∞ of donafenib （P=0.027 and 0.025）， as well as a significant increase in C_max （P=0.015） and significant reductions in CLz/F and Vz/F （P=0.005 and 0.004）； compared with the lenvatinib group， the empagliflozin pretreatment+lenvatinib group had a reduction in the t_1/2 of lenvatinib by approximately 5 hours （P=0.002）， with a trend of reduction in AUC_0-t （P0.05）. ConclusionEmpagliflozin combined with donafenib may alter the pharmacokinetic parameters of both drugs， leading to a significant increase in the exposure levels of both drugs， and efficacy and adverse reactions should be monitored during co-administration. There are no significant changes in the exposure levels of empagliflozin and lenvatinib during co-administration.

Objective To investigate the association between the Chinese visceral adiposity index (CVAI) and diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension among elderly people in Hebei Province. Methods In 2020, a stratified multi-stage random sampling was used to conduct questionnaire survey, physical examination and laboratory detection among permanent residents of 10 monitoring sites in Hebei Province. Logistic regression was used to analyze the association between CVAI and diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension. The area under the ROC curve (AUC) was used to evaluate the predictive value of CVAI for diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension. Results The detection rates of diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension were 19.8%, 74.6%, 78.2%, and 16.2%, respectively. Multivariate logistic regression analysis showed that compared with the lowest quartile of CVAI group Q1, the OR (95% CI) of diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension in the highest quartile Q4 group were 3.55 (2.58~4.89), 2.52 (1.92~3.31), 3.09 (2.31~4.12), and 4.92 (3.40~7.12), respectively. The ROC curve results showed that CVAI had the best predictive value in the diagnosis of diabetes with hypertension, and the optimized critical values in males and females were 128.54 and 141.88, respectively. Conclusion The detection rates of diabetes mellitus and hypertension are high in the elderly population in Hebei Province. CVAI is positively associated with the risk of diabetes mellitus, hypertension, diabetes mellitus or hypertension, and diabetes with hypertension among the elderly in Hebei. CVAI has the strongest prediction ability for diabetes with hypertension.

AIM: To investigate the correlation of serum C-reactive protein(CRP)-to-albumin(ALB)ratio(CAR)and neutrophil-to-lymphocyte count ratio(NLR)with pathological staging and prognosis of retinopathy of prematurity(ROP), and the predictive value of its combined testing for the prognosis of infants.METHODS:Prospective study. A total of 147 children with ROP who were born in our hospital from March 2022 to September 2024 were served as the ROP group, and 100 premature infants without ROP were served as the control group in the same period. Fully automatic biochemical analyzer was used to detect serum CRP and ALB; the flow cytometry nucleic acid fluorescence staining was used to count neutrophils and lymphocytes, and the CAR and NLR were calculated. Spearman correlation was used to analyze the relationship of serum CAR and NLR with ROP staging. Logistic regression was used to analyze the factors affecting the prognosis of children with ROP. ROC curve was drew to analyze the predictive value of serum CAR and NLR for the prognosis of ROP.RESULTS: There was comparability between the ROP group and the control group. The ROP group had significantly higher serum CRP, CAR, neutrophil count, and NLR than the control group, and clearly lower ALB and lymphocyte count than the control group(all P<0.05). Children with stage IV ROP had clearly higher serum CAR and NLR than stages I, II, and III, and the differences among stages I, II, and III were significant(all P<0.05). Serum CAR and NLR were positively correlated with ROP staging(r=0.529, 0.587, all P<0.05), and there was a positive correlation between serum CAR and NLR(r=0.546, P<0.05). The poor prognosis group had clearly higher serum CAR and NLR than good prognosis group(all P<0.001). Elevated serum CAR and NLR were risk factors affecting the prognosis of children with ROP(all P<0.05). The AUC of serum CAR, NLR, and joint detection in predicting the prognosis of ROP children was 0.803, 0.825, and 0.938, respectively. The joint detection showed better predictive performance(Zcombinatoion-CAR=2.637, Zcombinatoion-NLR=2.528, all P<0.05).CONCLUSION:Serum CAR and NLR are elevated in children with ROP, and they are closely related to pathological staging and prognosis. The joint detection has a higher predictive value in evaluating the prognosis of ROP.

Objective:To investigate the application and teaching effect of a new residency training model for emergency medicine in the context of sub-specialty zoning.Methods:A total of 30 emergency medicine residents were randomly divided into experimental group and control group, with 15 residents in each group. The residents in the experimental group received teaching based on the sub-specialty zoning model, while those in the control group received traditional teaching. SPSS 26.0 software was used for the t-test and the chi-square test, and the two groups were compared in terms of demographic variables, training assessment scores, and teaching feedback. Results:There were no significant differences between the two groups in the demographic variables such as age, sex, education background, and years of clinical work, and there was also no significant difference between the two groups in the final assessment score of Chongqing ( P>0.05), but there was a significant difference between the two groups in the score of intra-department theoretical examination before the final assessment [(81.20±2.83) vs. (89.73±3.01), P<0.001]. The survey of teaching feedback showed that both groups had high confidence in independent duty and a high degree of satisfaction with teaching, with no significant differences between the two groups ( P>0.05); however, compared with the control group, the experimental group had a significantly higher recognition of the development of emergency sub-specialties and significantly better orientations of scientific research and self-development. Conclusions:The new residency training model for emergency medicine in the context of sub-specialty zoning may help with the long-term development of emergency medicine and should be further promoted and validated in emergency medicine residency training.

A case of paraneoplastic cerebellar ataxia syndrome caused by immune checkpoint inhibitors(ICI)was treated with ofatumumab(OFA).The patient is a 57-year-old male.He used"Camrelizumab"immunotherapy for his previous history of small cell lung cancer.The main reason was"walking unsteadily for more than one year and shaking his head involuntarily for more than one month".After admission,the head MRI,chest CT,electroencephalogram,lumbar puncture and other related examinations were improved.The antibody spectrum of paraneoplastic neurological syndrome was anti-GAD65 antibody IgG(+),and the case was then diagnosed as the immune checkpoint inhibitor-related paraneoplastic neurological syndromes(PNS)of nervous system.After OFA treatment(20 mg/time),the symptoms were obviously improved.This paper analyzes the clinical features and diagnosis and treatment approaches of this case,in order to improve clinicians'understanding of the disease and provide reference for clinical diagnosis and treatment of similar cases.

Objective To explore the effect of LIMK1 on the progression of cervical cancer(CC).Methods HeLa and C-33A human cervical cancer cells overexpressing LIMK1 were established and injected subcutaneously into nude mice.The tumor volume was measured and expression of NOX2,NOX4,p-Src,p-RUNX3,RUNX3,and MMP-9 proteins in tumor cells was detected by Western blot assays.LIMK1-overexpressing HeLa and C-33A cells were cultured in 5％O2 with antioxidants.The protein expression of LIMK1,NOX4,p-Src,p-RUNX3,RUNX3 and MMP-9 in the cells was detected by Western blot assays.Cell migration was assessed by a scratch assay.Transwell assays were used to assess cell migration and invasion.A monoclonal proliferation assay was used to assess cell proliferation.Results The tumor volume in nude mice injected with LIMK1-overexpressing HeLa cells was increased significantly,and NOX2,NOX4,p-Src,p-RUNX3 and MMP-9 protein levels were increased,while RUNX3 protein expression was decreased.In LIMK1-overexpressing HeLa and C-33A cells,the protein expression of LIMK1,NOX4,p-Src,p-RUNX3,and MMP-9 was increased,RUNX3 protein expression was decreased,and cell migration,invasion,and proliferation were increased.However,after adding antioxidants,the expression levels of NOX4,p-Src,p-RUNX3,RUNX3 and MMP-9 proteins,and cell migration,invasion,and proliferation were not different from those of control cells.Conclusions LIMK1 promotes the progression of cervical cancer by enhancing the ROS/Src pathway,thereby promoting the migration,invasion,and proliferation of cervical cancer cells.

The pathogens were isolated and purified from the stomach,jejunum and rectum tissues of a Yunnan snub-nosed monkey who died of vomiting,oral and nasal chyme,and abdominal dis-tension,and the species and biological characteristics of the pathogens were studied by biochemical identification,PCR identification,drug susceptibility test,pathogenicity test,serotype identifica-tion,and drug resistance gene and virulence gene analysis.The results showed that the pathogens i-solated from stomach,jejunum and rectum were Escherichia coli(E.coli)serotype O127,belong-ing to enteropathogenic E.coli.They were resistant to cefoxitin and sensitive to gentamicin,gati-floxacin and ciprofloxacin.All the three strains carried drug resistance genes blaTEM and blaCTX-M and virulence genes opmA and opmC.This study provides reference and data support for the prevention and control of enteritis caused by E.coli in Yunnan snub-nosed monkey.

Objective Based on TLR4/NF-κB/MLCK pathway,the therapeutic effect and mechanism of Baihe Dihuang Decoction on insomnia with intestinal flora disturbance in mice induced by p-chlorophenlalanine(PCPA)and multi-factor stimulation were studied.The aim is to provide theoretical basis for clinical use.Methods Eighty-four KM mice were randomly divided into normal group,model group,positive group(Diazepam,1.38 mg·kg-1),Baihe group(2.25 g·kg-1),Dihuang group(2.25 g·kg-1)and Baihe Dihuang Decoction group(4.5 g·kg-1).Insomnia mouse model was established by intraperitoneal injection of PCPA for 2 days combined with 4 weeks of multi-factor stimulation,including stimulating the tail with forceps clip for 2 minutes,reversing day and night for 24 hours,wetting the padding for 24 hours,tilting the cage at 45° for 24 hours,alternating the cages for 24 hours,fasting food for 24 hours,and getting cold bath for 3 minutes,etc.After successfully modeling,corresponding drug treatment was given.The anxiety-like behavior of mice was observed by elevated cross maze system.The latency and duration of sleep were observed by righting reflex experiment.16sRNA sequencing was used to analyze the composition and structure of intestinal flora in mice.The concentration changes of γ-aminobutyric acid(GABA),glutamic acid(Glu),tryptophan(Trp),5-hydroxytryptophan(5-HTP)and 5-hydroxytryptamine(5-HT)in brain and colon were detected by liquid chromatography-mass spectrometry(LC-MS).Immunohistochemical method was used to detect the expressions of zona atresia protein 1(ZO-1)and Occludin in colon.Real-time fluorescence quantitative PCR(qRT-PCR)was used to detect the genes including interleukin-1β(IL-1β),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),ZO-1,Occludin,Toll-like receptor 4(TLR4),nuclear factor κB(NF-κB)and myosin light chain kinase(MLCK)in colonic tissue.Western Blot was used to detect the expressions of TLR4,NF-κB,phosphorylated nuclear factor κB(p-NF-κB),MLCK,myosin light chain(MLC)and phosphorylated myosin light chain(p-MLC)in colonic epithelial tissue.Results Compared with the normal group,the distance of entering the open arm and the duration of stay in the open arm of model group in the elevated cross maze were significantly shortened(P＜0.05).The sleep latency was significantly prolonged,and the sleep duration was significantly shortened(P＜0.05).The richness and uniformity of intestinal flora were decreased(P＜0.05,P＜0.01).The concentration of neurotransmitters GABA,Trp,5-HTP and 5-HT in the brain decreased significantly(P＜0.01),while the concentration of Glu increased significantly(P＜0.01).The concentration of GABA and Glu in colon decreased significantly(P＜0.01),while the concentration of Trp,5-HTP and 5-HT increased significantly(P＜0.01).The expression levels of inflammatory factors IL-1β,IL-6 and TNF-α in colonic tissue were significantly increased(P＜0.01),and the expression levels of ZO-1 and Occludin genes and proteins were significantly decreased(P＜0.01).The gene expression levels of TLR4,NF-κB and MLCK were significantly increased(P＜0.01),and the protein expression levels of TLR4,p-NF-κB,MLCK and p-MLC were significantly increased(P＜0.01).Compared with the model group,Baihe Dihuang Decoction could significantly prolong the distance of entering the open arm and the duration of stay in the open arm of insomnia mice in the elevated cross maze(P＜0.05).The sleep latency was significantly shortened,and the sleep duration was significantly increased(P＜0.05).The richness and uniformity of intestinal flora were increased(P＜0.05,P＜0.01).The concentration of neurotransmitters GABA,Trp,5-HTP and 5-HT in brain was increased(P＜0.05,P＜0.01),and the concentration of Glu was decreased(P＜0.01).The concentration of GABA and Glu in colon was increased(P＜0.01),while the concentration of Trp,5-HTP and 5-HT was decreased(P＜0.05,P＜0.01).The expression levels of IL-1β,IL-6 and TNF-α genes were down-regulated(P＜0.01),the expression levels of ZO-1 and Occludin genes and proteins were up-regulated(P＜0.01),TLR4,NF-κB,MLCK gene expression levels and TLR4,p-NF-κB,MLCK,p-MLC protein expression levels were down-regulated in the pathway(P＜0.01).Conclusion Baihe Dihuang Decoction can effectively treat insomnia with intestinal flora disorders.Its mechanism of action may be related to the regulation of brain and intestinal neurotransmitter disorders,down-regulating TLR4/NF-κB/MLCK signaling pathway,and up-regulating tight junction proteins expression,reducing inflammatory responses,and then repairing the mechanical barrier of intestinal mucosa.

Objective:To analyze clinical features, short-term efficacy and side effects of salvage re-irradiation therapy for patients with locally recurrent esophageal cancer after definitive chemoradiotherapy, to investigate the prognostic factors of re-irradiation with precise radiotherapy techniques.Methods:A retrospective analysis was performed on patients with locally recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy treated in the Fourth Hospital of Hebei Medical University from January 2008 to December 2016. The patients underwent re-irradiation therapy (re-RT) or re-irradiation therapy concurrent chemotherapy (re-CCRT). The main observation index was after-recurrence survival (ARS), which was calculated by Kaplan-Meier method for survival analysis. Univariate analysis was conducted by log-rank test, and multivariate analysis was performed by Cox regression model.Results:A total of 109 patients were included, with a median age of 66 years (43-89 years), and a median follow-up time of 120.8 months (79.0-176.5 months). The objective response rates (ORR) and dysphagia improvement rates (DIR) in all patients were 64.2% and 63.0%, respectively. The median ARS and 1-, 3-, 5-, 8-year survival rates in all patients were 7.8 months and 32.1%, 9.2%, 7.3% and 2.3%, respectively. The median ARS and 1-, 3-, 5-years survival rates were 10.8 months and 45.9%, 13.5%, 10.8% for patients with time to recurrence (TTR) ≥24 months, significantly longer than those of 5.7 months and 25.0%, 6.9%, 5.6% for patients with TTR<24 months ( χ2=7.99, P=0.005). The median ARS in groups with re-irradiation dose of ≤50 Gy,>50-54 Gy, and>54 Gy groups were 5.7, 10.0 and 8.1 months, respectively ( χ2=6.94, P=0.031). The 1-, 3- and 5-year survival rates were 30.4%, 5.1%, and 3.8% for re-RT versus 36.7%, 20.0%, and 16.7% for re-CCRT ( χ2=2.12, P=0.145). Multivariate analysis showed that TTR ( HR=0.607, 95% CI=0.372-0.991, P=0.046) and lesion length ( HR=0.603, 95% CI=0.371-0.982, P=0.042) were the independent factors for ARS. There was no significant difference in ≥2 grade pneumonitis and 2-3 grade radiation esophagitis between the re-RT and re-CCRT groups ( χ2=0.25, P=0.619; χ2=0.51, P=0.808). The morbidity of ≥2 grade myelosuppression in the re-RT group was significantly lower than that in the re-CCRT group (3.7% vs. 36.7%, χ2=18.15, P<0.001). Conclusions:Precise re-irradiation therapy for patients with locally recurrent esophageal cancer after definitive chemoradiotherapy can alleviate dysphagia, but ARS remains poor. Re-irradiation dose range from>50-54 Gy may be suitable for locally relapse patients as salvage treatment. Patients with TTR≥24 months and lesion length ≤5 cm obtain favorable prognosis.

Background Diurnal temperature range (DTR) is closely associated with cardiovascular health in the elderly, but there is a lack of research on the relationship between DTR and ischemic heart disease (IHD) in the elderly. Objective To investigate the effect of DTR on daily hospital admissions for IHD in people 65 years and older in Wuhan. Methods The study obtained data on elderly inpatients with IHD from all secondary and tertiary hospitals in Wuhan between January 1, 2017 and December 31, 2018, along with synchronous meteorological and air pollution data. Daily DTR was calculated as the difference between the maximum and minimum temperatures in a day. We employed distributed lag nonlinear models based on quasi-Poisson distribution to analyze the association between DTR and hospitalization risk in individuals aged 60 years and above. We assessed the extreme effects of DTR by selected DTR percentiles (the 1st percentile, P₁: 1.8 ℃; the 5th percentile, P₅: 2.9 ℃; the 95th percentile, P₉₅: 14.3 ℃; and the 99th percentile, P₉₉: 16.2 ℃) on hospitalization for IHD in the elderly population. Additionally, we conducted stratified analyses by gender, age (60-74 years and ≥75 years) and different subtypes (acute IHD and chronic IHD) to investigate the effects of DTR on hospitalizations for IHD across different genders, ages, and subtypes. Results This study included a total of 64212 first-time IHD hospitalizations among individuals aged 65 years and above in Wuhan from 2017 to 2018. The results showed a "J"-shaped exposure-response relationship between DTR and the cumulative risk of IHD hospitalization with a lag of 7 d; the optimal DTR was 5.0 ℃, and as DTR increased or the lag time lengthened, the risk of hospitalization for IHD in the elderly population increased. Extremely high DTR (P₉₉: 16.2 ℃) had a significant impact on the day of exposure (lag 0), with a cumulative RR of 1.58 (95%CI: 1.25, 1.99) at a lag of 7 d. The overall effects of DTR on IHD for different genders, ages, and subtypes of IHD exhibited similar patterns to the effects for overall population. High DTR had a significantly higher impact on hospitalization for chronic IHD (RR=1.46, 95%CI: 1.20, 1.79), compared to acute IHD (RR=1.29, 95%CI: 1.04, 1.61). At a cumulative lag of 7 d, elderly individuals aged 60-74 (RR=1.78, 95% CI: 1.30, 2.42) were more affected by high DTR in terms of IHD hospitalizations compared to those aged ≥75 (RR=1.35, 95% CI: 1.08, 1.70). Conclusion High DTR significantly increases the risk of hospitalization for IHD among elderly individuals. The effect of high DTR is particularly pronounced in patients with chronic IHD and elderly individuals aged 60–74 years.