OBJECTIVE To evaluate the cost-effectiveness of cefiderocol versus best available therapy （BAT） or standard-of- care （SOC） for the treatment of confirmed or suspected carbapenem-resistant Gram-negative bacterial （CRGNB） serious infections from the perspective of the Chinese healthcare system， and to explore its reasonable pricing. METHODS A decision tree model was constructed based on data from two phase Ⅲ clinical trials （CREDIBLE-CR and GAME CHANGER） to simulate the cost- effectiveness of cefiderocol in two scenarios： salvage therapy for confirmed CRGNB infection （scenario 1） and empirical therapy for suspected CRGNB infection （scenario 2）. The primary outcome measure was the incremental cost-effectiveness ratio （ICER）. The willingness-to-pay （WTP） was set at 1 to 3 times China’s per capita GDP in 2024. To verify the robustness of the results， one- way and probabilistic sensitivity analyses were conducted， and based on these， a reasonable price range for cefiderocol in the Chinese market was explored. RESULTS The results for scenario 1 showed that the clinical cure rate in the cefiderocol group was higher than that in the BAT group （47.50% vs. 34.21%）， but its ICER was 415 065.03 yuan per cured case， exceeding three times China’s GDP per capita. Scenario 2 revealed that the ICER for cefiderocol relative to SOC was as high as 1 362 446.16 yuan per cured case， far exceeding the WTP. Sensitivity analysis indicated that the treatment duration and price of cefiderocol were key factors affecting its cost-effectiveness. In the two scenarios described above， the unit price of cefiderocol must fall below 683.47 and 242.00 yuan/g， respectively， to be considered cost-effective. CONCLUSIONS Based on the current market price， cefiderocol lacks sufficient cost-effectiveness for treating confirmed or suspected CRGNB serious infections within China’s healthcare system. To improve its accessibility， price negotiations or a tiered medical insurance payment strategy are required.

Improving the nitrogen use efficiency (NUE) of Brassica napus is of significant importance for achieving the national goal of zero growth in chemical fertilizer application and ensuring the green development of the rapeseed industry. This study aims to explore the effects of the nitrate transporter gene BnaNRT1.5s on the nitrogen transport and NUE of B. napus, providing excellent genetic resources for the development of nitrogen-efficient B. napus varieties. The spatiotemporal expression of BnaA05.NRT1.5 as a key nitrogen responsive gene was profiled by qRT-PCR at different growth stages and for different tissue samples of B. napus 'Westar'. Subcellular localization was employed to examine its expression pattern in the cells. Additionally, CRISPR/Cas9 was used to create BnaNRT1.5s knockout lines, which were subjected to hydroponic experiments under high nitrogen (12.0 mmol/L) and low nitrogen (0.3 mmol/L) conditions. After the seedlings were cultivated for 21 days, root and shoot samples were collected for weighing, nitrogen content determination, xylem sap nitrate content assessment, and calculation of total nitrogen and NUE. The B. napus nitrate transporter BnaA05.NRT1.5 was localized to the cell membrane. During the seedling and early bolting stages, BnaA05.NRT1.5 was predominantly expressed in roots, while it was highly expressed in old leaves and mature silique skin during the reproductive stage. Compared with the wild type, the mutant BnaNRT1.5s showed significant increases in the dry weight and total nitrogen of seedlings under both high and low nitrogen conditions. Under low nitrogen conditions, NUE in the roots of BnaNRT1.5s significantly improved. Notably, under both high and low nitrogen conditions, the nitrate content in the shoots of BnaNRT1.5s decreased significantly, while that in the roots increased significantly, resulting in a significantly decreased shoot-to-root nitrate content ratio. BnaNRT1.5s is involved in regulating the transport of nitrate from the roots to the shoots, and its mutation enhances nitrogen absorption and utilization in B. napus seedlings, promoting seedling growth. This study not only provides references for understanding the physiological and molecular mechanisms by which BnaNRT1.5s regulates NUE but also offers valuable genetic resources for improving NUE in B. napus.
Brassica napus/genetics* ; Anion Transport Proteins/metabolism* ; Nitrogen/metabolism* ; Nitrate Transporters ; Plant Proteins/metabolism* ; Nitrates/metabolism* ; Gene Expression Regulation, Plant ; Biological Transport

With the deepening of modern drug research,traditional computer simulation can not meet the needs of future drug design experiments.As a classic technology of standard computer simulation,molecular simulation can construct and analyze complex molecular models to study the dynamic processes of molecular motion.However,the simulation results are easy to be affected by human factors.In recent years,the integration of artificial intelligence and molecular simulation has become a new method of drug design research.Artificial intelligence technology uses big data to screen out the corresponding compounds for molecular simulation and feedback on the simulation results to the artificial intelligence system to optimize the artificial neural network.The combination of artificial intelligence and molecular simulation technology improves the efficiency of drug design research,reduces the influence of human factors on simulation results,and increases the credibility of simulation results.In this review,we summarized the progress of artificial intelligence and molecular simulation technology in drug design to provide a reference for the change from computer assisted drug design(CADD)to artificial intelligence-aided drug design(AIDD)in future pharmaceutical development.

Objective:To investigate the conversion of stromal vascular fraction (SVF) in the microenvironment of radiation-induced skin injuries to provide guidance for clinical applications.Methods:Based on a random number table, C57BL/6N mice were categorized into four groups: the blank control, negative control, acute injury, and chronic injury groups, with each group containing 25 mice. The backs of mice in the blank control, acute injury, and chronic injury groups were exposed to 15 Gy X-ray irradiation. Then, the mice in the negative control, acute injury, and chronic injury groups were injected subcutaneously with the SVF derived from B6/G-R mice. The survival of these mice was observed 1, 3, 7, 14, and 21 d after the injection through fluorescence tracing and in vivo imaging. Accordingly, the clinical SVF injection regimens were optimized based on the experimental result of mice. Finally, local SVF injection was performed on different frequencies for patients in different wound conditions, with the efficacy being observed. Results:The fluorescence of SVF was observed from the tissue slices of the acute injury, chronic injury, and negative control groups 14 d post-injection. The result showed that the fluorescence intensity of SVF 1, 3, and 7 d post-injection was in the order of the negative control group > the acute injury group > the chronic injury group. The acute injury group ranked at the top and the chronic injury group remained at the bottom 14 d after the injection. The fluorescence of SVF in each group was barely detected 21 d after the injection. Compared to the negative control group, the acute injury group exhibited statistical differences only 14 d post-injection ( t = 4.11, P < 0.05), while the chronic injury group displayed statistical differences 1, 3, 7, and 14 d after the injection ( t = 3.88-5.74, P < 0.05). Furthermore, the acute injury group exhibited significantly higher fluorescence intensity of SVF than the chronic injury group ( t = 4.73-8.38, P < 0.05). The half-life of SVF for the negative control, acute injury, and chronic injury groups was 6.336, 6.014, and 2.163 d, respectively. As indicated by the application of SVF transplantation based on traditional surgical protocols in the clinical trial, SVF can significantly promote wound repair, with earlier SVF transplantation being more beneficial for wound healing. Conclusions:The conversion of SVF differs in the microenvironments of acute and chronic radiation-induced skin injuries. This can serve as an essential guide for the administration timing and injection frequency of SVF in clinical applications.

Objective To investigate the efficacy and complications of one-step and two-step ultrasound-guided percutaneous transhepatic hepatic duct drainage(PTHD)in the treatment of advanced low-level biliary obstruction.Methods A total of 112 patients with advanced low-level biliary obstruction who underwent palliative surgery for reducing jaundice in the hospital from January 2019 to July 2023 were selected,and divided into the one-step group and the two-step group according to the principle of complete randomization(grouped by random number table method).The one-step group(n=56)underwent one-step PTHD,while the two-step group(n=56)underwent two-step PTHD.Surgery related indicators,serum total bilirubin(TBIL),alkaline phosphatase(ALP),alanine transaminase(ALT),the incidence of postoperative complications,and satisfaction were compared between the two groups.Results There was no difference in intraoperative blood loss[(2.96±0.50)ml vs.(3.02±0.53)ml],drainage volume in 48 hours after surgery[(555.84±90.51)ml vs.(560.52±104.23)ml]between the two groups(P＞0.05).Operation time and postoperative VAS score of the one-step group were significantly shorter/lower than those of the two-step group[(32.50±4.26)min vs.(36.43±3.58)min,(3.72±1.57)points vs.(4.53±1.34)points],and the success rate of puncture was significantly higher than that in the two-step group(96.43％vs.76.69％),with statistically significant differences(P＜0.05).After treatment,the levels of TBIL,ALP and ALT in the two groups were significantly reduced(P＜0.05),but there was no statistically significant difference between the groups(P＞0.05).There was no statistically significant difference in the incidence of complications between the two groups(3.57％vs.7.14％,Fisher's exact probability=0.679).The satisfaction rate in the one-step group was significantly higher than that in the two-step group(94.64％vs.75.00％),with a statistically significant difference(P＜0.05).ConclusionThe operation time of one-step PTHD is shorter and the success rate of puncture is higher.In addition,patients undergoing one-step PTHD have milder pain,and are more satisfied.

Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

As one of the traditional computer simulation techniques, molecular simulation can intuitively display and quantify molecular structure and explain experimental phenomena from the microscopic molecular level. When the simulation system increases, the amount of calculation will also increase, which will cause a great burden on the simulation system. Coarse-grained molecular dynamics is a method of mesoscopic molecular simulation, which can simplify the molecular structure and improve computational efficiency, as a result, coarse-grained molecular dynamics is often used when simulating macromolecular systems such as drug carrier materials. In this article, we reviewed the recent research results of using coarse-grained molecular dynamics to simulate drug carriers, in order to provide a reference for future pharmaceutical preparation research and accelerate the entry of drug research into the era of precision drug design.
Molecular Dynamics Simulation ; Drug Carriers

OBJECTIVE: To explore the clinical characteristics and outcomes of adult critically ill patients with COVID-19 and identify the risk factors correlated with in-hospital deaths. METHODS: This study was conducted among 20 confirmed adult cases of COVID-19 in the Intensive Care Unit (ICU) of Honghu People's Hospital in Jingzhou City, Hubei Province. According to the final outcome, the patients were divided into survivor group and death group with 10 patients each. The demographic data, clinical manifestations and signs, laboratory findings, treatment measures and clinical outcomes were obtained from electronic medical records to compare the clinical characteristics and outcomes between the two groups. Univariate logistic analysis was used to analyze the risk factors associated with in-hospital death. RESULTS: The mean age of patients with confirmed COVID-19 was 70 ± 12 years, and 40% of them were male. The patients were admitted to ICU 11 ± 9 days after symptom onset. The most common symptoms on admission were cough (19 cases), fatigue or myalgia (18 cases), fever (17 cases) and dyspnea (16 cases). Eleven (55%) of the patients had underlying diseases, among which hypertension was the most common (11 cases), followed by cardiovascular disease (4 cases) and diabetes (3 cases). Six (30%) of the patients received invasive mechanical ventilation and continued renal replacement therapy but eventually died. Acute cardiac injury was the most common complication (19 cases). Half of the patients died between the 2nd and 19th day after ICU admission. Compared with dead patients, the surviving patients had a lower average body weight (61.70±2.36 68.60±7.15 kg, =0.01) and a higher Glasgow Coma Index (14.69 ± 0.70 12.70 ± 2.45, =0.03), and were less likely to develop shock (2 10, =0.001) or acute respiratory distress syndrome (2 10, =0.001). CONCLUSIONS Critically ill patients with COVID-19 are generally older. A higher body weight and a lower lymphocyte count are potentially associated with a greater likeliness of fatality in ICU patients with COVID-19.
Aged ; Aged, 80 and over ; Betacoronavirus ; Coronavirus Infections ; Critical Illness ; Female ; Humans ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; Retrospective Studies

Objective To observe the clinical effects and safety of sodium valproate combined with decitabine for treatment of myelodysplastic syndrome (MDS). Methods Forty-two patients with MDS were enrolled in department of hematology in Shanxi Dayi Hospital from February 2012 to February 2017. According to random number table, the patients were divided into the control group (21 cases) and the experimental group (21 cases). The patients in the control group received decitabine at the dose of 20 mg·m-2·d-1, and intravenous infusion was completed in 2 hours, continuous therapy up to 5 days, 4 weeks as a course; the patients in the experimental group received combined medication, orally given sodium valproate 0.2 g once, 3 times per day. One week later, the dosage was added to 0.4 g once, 3 times per day. Both groups received at least 4 courses of treatment. The treatment was stopped when serious adverse reactions or obvious disease progression occurred. The bone marrow smear was rechecked every 4 weeks after treatment to evaluate the efficacy. The expressions of ASXL1, DNMT3A and TET2 in bone marrow cells were detected by fluorescence quantitative PCR before and after treatment. Results The total treatment response rate of the experimental group and the control group were 76.2 % (16/21) and 57.1 % (12/21) respectively, and there was statistically significant difference (P< 0.05); the total remission rate of the two groups was 47.6 % (10/21) and 38.1 %(8/21) respectively, and there was no significant difference (P> 0.05). All patients had slight adverse reactions, and the adverse reaction rate was 42.9 % (9/21) and 38.1 % (8/21), and there was no significant difference (P>0.05). The content of TET2 mRNA and DNMT3A mRNA after treatment in both groups were decreased compared with the expressions before treatment, and there were significant differences (P<0.05). However, there was no significant difference between the two groups after treatment (P> 0.05); the content of ASXL1 mRNA had no obvious change in the control group and a dramatic decrease in the experimental group compared with that before treatment (P<0.05). Conclusion Sodium valproate combined with decitabine has favorable effects and mild adverse reactions for treatment of MDS, besides, it can influence the expressions of TET2, DNMT3A and ASXL1.

Background High myopia is one of the primary factors of visual impairment,and its prevention and management are researching hot topics.Corneal curvature (CC) measures the steepness of the cornea which is an important parameter leading to myopia.Genome-wide association study (GWAS) showed that several genes are associated with CC in Asian populations.However,the association of corneal curvature-related genes with high myopia is unclear up to now.Objective This study was to investigate the association between single nucleotide polymorphism (SNP) in the rs74225573 (mechanistic target of rapamycin [MTOR]),rs60078183 (cytidine/uridine monophosphate kinase 1 [CMPK1]),rs1800813 (platelet derived growth factor receptor alpha [PDGFRA]),rs11204213 (retinol binding protein 3 [RBP3]) and high myopia in Chinese Han population.Methods A prospective cohort study was performed.Four hundreds and eighty-three patients with high myopia were collected in Sichuan Provincial People's Hospital from February 2012 to August 2013,with the diopter (-10.84±4.69)D in the right eyes and (-10.35±4.67)D in the left eyes or ocular axial length of (28.15±2.27)mm in the right eyes and (27.72±2.51)mm in the left eyes.Five hundreds and nineteen normal volunteers matched in age and gender were included in the same period as controls,and all the subjects were Chinese Han people without genetic relationship.The periphery blood of 4 ml was obtained for the DNA extraction from each subject under the written informed consent.The primers of rs74225573,rs60078183,rs1800813 and rs1 1204213 were designed based on the information of NCBI website.The four SNPs were amplified by real-time PCR and genotyped by SNaPshot method.Results All the genotype frequencies of these four SNPs were in Hardy-Weinberg equilibrium (HWE).There are no significant differences in minor allele frequency (MAF) distribution of rs74225573,rs60078183 and rs11204213 between high myopia group and normal control group (rs74225573:Pag-corrected =0.935,OR =0.98;rs60078183:Page-currected =0.782,OR =1.04;rs11204213:Page-currected =0.058,OR =1.66),and the M AF of rs1800813 was significantly higher in the high myopia group than that in the normal control group (Page-currected =0.001,OR =0.64).The genotype frequency of rs74225573,rs60078183 and rs11204213 was not evidently different in additive model 1 (AB vs.BB),additive model 2 (AA vs.BB),dominant model (AA+AB vs.BB) and recessive model (AA vs.AB+BB) (all at P＞0.05),while significant differences were found in genotype frequency of rs1800813 both in additive model 1 and dominant model (additive model 1:P=0.002,OR=0.59;dominant model:P=0.001,OR=0.58).Conclusions The SNP of rs1800813 in the PDGFRA gene is associated with the pathogenesis of high myopia in the Chinese Han population,but the SNPs of rs74225573 (MTOR gene),rs60078183 (CMPK1 gene) and rs11204213 (RBP3 gene) appear to be not associated with high myopia.