ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones

Objective:The distribution characteristics of intrathecal drugs and the limitation of current catheterization techniques make traditional intrathecal analgesic treatment nearly useless for refractory craniofacial pain,such as trigemina neuralgia.This technical guideline aims to promote the widespread and standardize the application of intra-prepontine cisternal drug delivery via spinal puncture and catheterization. Methods:A modified Delphi approach was used to work for this guideline.On the issues related to the intra-prepontine cisternal targeted drug delivery technique,the working group consulted 10 experts from the field with 3 rounds of email feedback and 3 rounds of conference discussion. Results:For the efficacy and safety of the intra-prepontine cisternal targeted drug delivery technique,a consensus was formed on 7 topics(with an agreement rate of more than 80%),including the principles of the technique,indications and contraindications,patient preparation,surgical specifications for intra-prepontine cisternal catheter placement,analgesic dosage coordination,analgesic management,and prevention and treatment of complications. Conclusion:Utilizing the intra-prepontine cisternal drug infusion system to manage refractory craniofacial pain could provide advantages in terms of minimally invasive,secure,and effective treatment.This application can not only alleviate the suffering of individuals experiencing the prolonged pain but also support the maintenance of quality of life and dignity in their final moments,justifiing its widespread dissemination and standardized adoption in domestic and international professional fields.

BACKGROUND:Interleukin-8 is an important cytokine that has been found to play an important role in bone regeneration through multiple pathways. OBJECTIVE:To comprehensively review the action mechanism of interleukin-8 effects on bone regeneration to provide ideas for the following studies on interleukin-8. METHODS:By searching the China National Knowledge Infrastructure database for articles published from January 1999 to February 2023 and PubMed database for articles published from January 1985 to February 2023 reporting the role of interleukin-8 in bone-associated cells and vascularisation.Chinese and English search terms were"interleukin-8,bone repair,bone metabolism,mesenchymal stem cells,osteoblasts,osteoclasts,vascularization".The initial review yielded 508 articles in English and Chinese,and a total of 51 articles were included for review and analysis according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:According to the existing research,interleukin-8 can promote bone cell regeneration and assist bone healing through multiple pathways,which is mainly divided into three aspects:(1)Promote the proliferation and differentiation of bone cells such as mesenchymal stem cells and osteoblasts,and promote the development of cells in the direction of promoting bone healing;(2)interleukin-8 can promote angiogenesis and provide sufficient nutrition and oxygen for bone tissue,thus further improving the quality and stability of bone healing.(3)The appearance of interleukin-8 facilitates the expression of hypoxia-inducible factor-1α,vascular endothelial growth factor,and matrix metalloproteinase,which can create a microenvironment conducive to bone regeneration,thus promoting the regeneration and repair of bone tissue.In summary,interleukin-8 plays an important role in bone healing by promoting osteoblast proliferation and differentiation,facilitating angiogenesis and improving the mechanical properties of bone regeneration,as well as influencing bone metabolism through osteoclasts,mesenchymal stem cells,and other action sites.

Objective:To measure the magnetic field correction factor of reference ionization chamber in a 1.5 T magnetic field and to explore the response of the ionization chamber among different angles between magnetic field and ionization chamber axis.Methods:A home-made magnetic compatible one-dimensional water tank was used to measure the response of PTW30013 and IBA FC65-G in 7 MV photon beam of Elekta Unity with and without magnetic field. The ionizing current was collected by PTW UNIDOS Tango electrometer. The effective measurement point of ionization chamber was positioned to the isocenter of MR-linac using electronic portal image device. The influence on water absorbed dose of reference point was obtained by Monte Carlo calculations.Results:The response of ionization chambers in strong magnetic field was related to the angle between chamber axis and magnetic field. The response of ionization chamber was significantly affected in perpendicular magnetic field with a deviation up to 4.54% compared to parallel magnetic field. The deviation between the magnetic field correction factors measured for parallel or reverse-parallel was 0.03%-0.24%. The magnetic field correction factors for PTW30013 and FC65-G measured in parallel magnetic field were 0.9934±0.0077 and 0.9990±0.0076, respectively.Conclusions:This study experimentally verifies that positioning the ionization chamber axis parallel to the magnetic field direction in MR-linac reference dosimetry can minimize the magnetic field impact. The determined magnetic field correction factor and uncertainty in 1.5 T magnetic field can provide necessary data for establishing an MR-linac reference dosimetry protocol.

This study investigated the primary pathogenesis and syndrome evolution of different heart failure with preserved ejection fraction(HFpEF)stages based on the classical and clinical experience of traditional Chinese medicine(TCM),combined with the clinical characteristics of pre-heart failure,symptomatic heart failure,and advanced heart failure.This study summarizes and refines the three core syndrome factors:water,deficiency and blood stasis.Water-fluid retention was observed throughout these three stages,from the beginning to the end.With the advancement of the disease,the heart yang changes from stagnation to deficiency,water-fluid retention gradually increases,blood stasis becomes increasingly prominent,and the disease location develops dynamically from the upper to the middle and lower jiao.This study proposes three methods of treating HFpEF.The main pathogenesis of pre-heart failure is lung qi dysfunction-induced water retention,which can be treated by dispersing lung qi and transforming water retention using Fuling Xingren Gancao Decoction.The primary pathogenesis of symptomatic heart failure is yang and qi deficiency-induced water retention,which can be treated with tonifying yang,supplementing qi,and transforming water retention using Shengxian Decoction combined with Linggui Zhugan Decoction.The primary pathogenesis of advanced heart failure is yang deficiency with blood stasis and water retention affecting the heart,which can be treated with tonifying yang,circulating blood,and expelling water retention using Zhenwu Tingli Decoction.Chinese medicine can be flexibly added or subtracted according to the patients'concurrent patterns.However,the daily care of patients should be considered.This study explores the staging treatment of HFpEF from water,deficiency and blood stasis to provide a TCM clinical reference for treating HFpEF.

Background::The Global Leadership Initiative on Malnutrition (GLIM) criteria were published to build a global consensus on nutritional diagnosis. Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings. This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition, as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients.Methods::This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1, 2018, and February 28, 2022, at Beijing You-An Hospital, Capital Medical University. Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography (CT) examination during hospitalization were included in the study. These patients were randomly divided into a modeling group (cohort 1, 667 patients) and a validation group (cohort 2, 335 patients). In cohort 1, optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index (L3-SMI) were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups. Next, patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. Additionally, the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1. Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes.Results::The optimal cut-off values of L3-SMI were 39.50 cm 2/m 2 for male patients and 33.06 cm 2/m 2 for female patients. Based on the cut-off values, 31.63% (68/215) of the male patients and 23.3% (28/120) of the female patients had CT-determined sarcopenia in cohort 2. The prevalence of GLIM-defined malnutrition in cirrhotic patients was 34.3% (115/335) and GLIM-defined malnutrition was an independent risk factor for in-hospital mortality in patients with liver cirrhosis ( Wald = 6.347, P = 0.012). Conclusions::This study provided reference values for skeletal muscle mass index and the prevalence of GLIM-defined malnutrition in hospitalized patients with liver cirrhosis. These reference values will contribute to applying the GLIM criteria in cirrhotic patients.

Objective:To explore the relationship between adipocytokine levels in bone marrow and the onset,progression,and prognosis of myelodysplastic syndromes(MDS).Methods:Retrospective analysis of adipocytokine levels in the bone marrow of 72 patients with MDS and 16 patients with MDS-related secondary acute myeloid leukemia(sAML),including adiponectin(ADP),leptin(LEP),visfatin/nicotinamide phosphoribosyltransferase(NAMPT),adipsin/complement factor D(CFD),and C1q/TNF-related protein 1(CTRP1),detected by enzyme-linked immunosorbent assay(ELISA)at The Affiliated Cancer Hospital of Zhengzhou University from February 2020 to February 2022.High-throughput sequencing was used to detect MDS-related genes in 70 patients and the relationship between adipocytokines and the clinical characteristics,disease subtypes,mutant genes,and prognosis of patients were analyzed.Seventy-eight MDS-related genes were identified.Results:Clinical characteristics showed that ADP(P=0.027)and LEP(P=0.019)levels were significantly lower in men than inwomen;ADP(P=0.020),CFD(P<0.001),and NAMPT(P=0.021)levels were significantly lower in patients aged<65 years than in patients aged≥65,where-as LEP levels were significantly higher(P=0.043).Adiponectin levels were significantly higher in patients with BMI<24 than in patients with BMI≥24(P=0.025),whereas LEP levels were significantly lower(P=0.020);NAMPT levels were significantly higher in the group with in-creased blasts than in the group with no blasts(P=0.037).The CTRP1 levels were significantly higher in the MDS group than in the sAML group(P=0.010).Abnormal gene correlation analysis showed that elevated CTRP1 levels were positively correlated with the occurrence of epigenetically related abnormal genes(P=0.001)and were positively correlated with the occurrence of TET2 and U2AF1(P<0.001 and P=0.036,respectively);ADP and CFD levels were positively correlated with the occurrence of NPM1(P=0.048 and P=0.026,respectively).Multifactorial Cox proportional hazards regression model analysis showed that LEP<0.2 ng/mL was an independent risk factor for progres-sion-free survival(PFS)and overall survival in patients with MDS(P=0.002 and P<0.001,respectively),whereas NAMPT<2.1 ng/mL was a protective factor for PFS in patients with MDS(P=0.043).Conclusions:Adipocytokines in the bone marrow microenvironment are closely as-sociated with the clinical characteristics,gene mutations,and prognosis of patients with MDS,with LEP<0.2 ng/mL being an independent prognostic risk factor and NAMPT<2.1 ng/mL being a prognostic protective factor.

Objective:To explore the value of amide proton transfer-weighted (APTw) imaging and intravoxel incoherent motion (IVIM) imaging for diagnosing and evaluating the pathological differentiation of cervix squamous cell carcinoma (CSCC).Methods:This study was a diagnostic trial. Totally 56 patients pathologically diagnosed with CSCC at the First Hospital of Lanzhou University from October 2021 to October 2022 were retrospectively collected, as the CSCC group. And 36 female healthy volunteers who underwent physical examinations at the First Hospital of Lanzhou University from October 2021 to October 2023 were recruited as the control group. CSCC patients were divided into well-moderately differentiated ( n=34) and poorly differentiated groups ( n=22). The region of interest was placed in the lesions of CSCC group and normal cervical stroma of control group, and the quantitative parameters for asymmetric magnetization transfer ratio (MTR asym) of APTw imaging and pure diffusion coefficient (D), false diffusion coefficient (D *) and perfusion fraction (f) for IVIM were obtained. The independent sample t test was used to compare the differences in quantitative parameters between the two groups, the logistic regression model was used to establish combined parameters for the quantitative parameters with statistical significance between the two groups. The receiver operator characteristic curve was used to evaluate the diagnostic efficacy of single quantitative parameters and combined parameters to distinguish the CSCC group from the control group, and the well-moderately differentiated group from the poorly differentiated group in CSCC patients. The area under the curve (AUC) was compared using the DeLong test. Results:There were significant differences in MTR asym, D and f between CSCC group and control group ( t=-9.79, 10.09, 11.35, P<0.001). Also, significant differences were found for MTR asym and D between the well-moderately differentiated and poorly differentiated group ( t=4.11, -3.76, P<0.001). There was no significant difference in other quantitative parameters ( P>0.05). When comparing the CSCC group and control group, the AUC (95% CI) of MTR asym, D, f and combined parameter (MTR asym+D+f) were 0.887 (0.804-0.944), 0.940 (0.871-0.979), 0.968 (0.909-0.993), 0.995 (0.950-1.000). The AUC of the combined parameter was higher than those of MTR asym and D, with statistical significance ( Z=3.07, 2.06, P=0.002, 0.040). When comparing the well-moderately differentiated and poorly differentiated group, the AUC (95% CI) of MTR asym, D, and combined parameter (MTR asym+D) were 0.789 (0.660-0.887), 0.775 (0.644-0.876), 0.852 (0.731-0.932). There was no significant difference between each two AUCs ( P>0.05). Conclusion:The quantitative parameters of APTw and IVIM imaging can be used to diagnose and preliminarily evaluate the pathological differentiation of CSCC. Joint parameters can improve the diagnostic efficiency of CSCC.

Objective:To explore the influencing factors of clinical pregnancy outcomes in patients with hydrosalpinx undergoing in vitro fertilization-embryo transfer(IVF-ET) after interventional embolization and whether residual hydrops has an adverse impact on pregnancy outcomes.Methods:Clinical data from 65 patients who underwent interventional embolization and IVF-ET for hydrosalpinx at the Third Affiliated Hospital of Zhengzhou University from March 2021 to October 2022 were collected retrospectively. The hydrops index was quantified by the ratio of the widest diameter to the pelvic transverse diameter of the intraoperative hydrops, and the patient′s age, body mass index(BMI), follicle-stimulating hormone(FSH), lutenizing hormine(LH), estradiol(E2), automated matetials hangling(AMH), endometrial thickness at the time of transplantation, the number of transplanted embryos, embryo type, and location of the hydrosalpinx were recorded. In addition, the clinical pregnancy outcomes of the first transplantation after embolization were followed. Two independent samples t-test, rank sum test and chi-square test were used to analyze the difference of the above indexes among different clinical pregnancy outcomes by SPSS 25.0. The receiver operating characteristic (ROC) curves and Youden index were used to calculate the cut-off value of the water accumulation index. Results:Among 65 patients, the clinical pregnancy rate was 63.1%(41/65), among the 45 patients who underwent embryo transfer before embolization without success, the clinical pregnancy rate after embolization was 62.2%(28/45). Based on data analysis, it showed that IVF-ET clinical pregnancy outcomes were not associated with age, BMI, FSH, LH, E2, AMH, endometrial thickness at the time of transplantation, the number of transplanted embryos, embryo type, as well as location of hydrosalpinx( P>0.05), but associated with hydrosalpinx index( P<0.001). ROC curve analysis showed that the hydrops index could be used as a predictor of pregnancy outcome, and the area under the curve was 0.825, and the optimal cut-off value of the hydrops index was 12.925% based on the Youden index analysis result. Conclusions:Interventional embolization of hydrosalpinx may improve clinical pregnancy rates. When the hydrosalpinx is large enough, it could adversely affected IVF-ET clinical pregnancy, and further aspiration of hydrosalpinx should be performed prior to transplantation.

Objective To explore the relationship between C1q tumor necrosis factor related protein 13(CTRP13)and gestational diabetes mellitus(GDM),and the predictive value of CTRP13 for adverse pregnancy outcomes in GDM patients.Methods A total of 163 pregnant women who underwent prenatal examination in the Second Affiliated Hospital of Zhengzhou University from January to May 2023 were enrolled in GDM group(n=83)and normal glucose tolerance(NGT)group(n=80)according to the results of oral glucose tolerance test at 24-28 weeks of gestation.Collect general information,biochemical data,and adverse pregnancy outcomes from two groups of subjects.Analyze the correlation between serum CTRP13 and glucose and lipid metabolism indicators in GDM pregnant women.The receiver operating characteristic(ROC)curve was drawn to analyze the predictive value of CTRP13 for adverse pregnancy outcomes in GDM pregnant women.Results The pre pregnancy body mass index,prenatal body mass index,triglycerides,total cholesterol,low density lipoprotein,fasting blood glucose,2-hours plasma glucose,glycosylated hemoglobin,fasting insulin,and homeostasis model assessment of insulin resistanc index in GDM group was significantly higher than those in NGT group,while CTRP13 was significantly lower than that in NGT group(P＜0.05).Serum CTRP13 was negatively correlated with total cholesterol,triglycerides,low density lipoprotein,2-hours plasma glucose,and glycosylated hemoglobin in GDM patients(P＜0.05).The incidence of adverse pregnancy outcomes such as gestational hypertension and premature rupture of membranes in GDM group were significantly higher than those in NGT group(P＜0.05).The area under the curve of serum CTRP13 for predicting adverse pregnancy outcomes in GDM pregnant women was 0.805,with sensitivity and specificity of 75.80％and 76.00％,respectively.Conclusion Serum CTRP13 is associated with glucose and lipid metabolism in GDM pregnant women,and is a potential biomarker for predicting adverse pregnancy outcomes in GDM pregnant women.