A UHPLC-Q-Orbitrap/MS method was developed to identify the related substances in apixaban tablets. Complete separation was accomplished with a Waters Xbridge C18 (250 mm×4.6 mm, 5 μm) column by linear gradient elution using a mobile phase consisting of 30 mmol/L ammonium acetate buffer solution (pH 4.50) and acetonitrile. The related substances were successfully characterized through the accurate mass and elemental composition of the parent ions and their product ions determined by electrospray positive ionization high-resolution Q-Orbitrap/MS methods. Under the established analytical condition, apixaban and its related substances were well separated, and 30 related substances were detected and identified by hyphenated techniques in apixaban tablets and their stressed samples. Among them, 11 were known impurities and the rest 19 were unknown related substances identified for the first time in this study. The results obtained are valuable for apixaban manufacturing process optimization and quality control.

OBJECTIVE To compare the predictive accuracy and clinical applicability of four vancomycin individualized dosing tools （SmartDose， ClinCalc， Gulou， Pharmado） and provide a basis for rational clinical medication use. METHODS A retrospective cohort study was conducted， enrolling 479 adult patients who received vancomycin therapy and underwent steady-state trough concentration monitoring in Zhongshan Hospital， Fudan University （Xiamen Branch） from January 1， 2022， to June 30， 2024. The predictive accuracy of each tool was evaluated using indicators， such as mean error （ME）, mean absolute error （MAE）， mean percentage error （MPE）， mean absolute percentage error （MAPE）， the proportion of patients with an absolute percentage error （APE） of less than 30%， the 95% limits of agreement， and the overall relative percentage difference between predicted and measured values. Using indicators such as accessibility， patient management， and recommendation of multiple treatment options， the clinical panxso@163.com applicability of the tools for all patients was evaluated； using the discrepancy in accuracy between the predicted and actual measured blood drug concentrations as an indicator， the clinical applicability was assessed for patients in different renal function subgroups （hyperfunction， normal， mild impairment， moderate impairment， and severe impairment）. RESULTS In terms of accuracy， SmartDose demonstrated the best overall performance with an MAPE of 46.40% and a proportion of APE ＜30% （46.56%）. Bland-Altman analysis indicated that SmartDose had the smallest overall relative percentage difference （－7.25%）， although the 95% limits of agreement were broad for all tools， with differences between the upper and lower limits exceeding 200%. In terms of applicability， all four dosing tools were freely accessible and demonstrated good availability； SmartDose and Pharmado provided the most comprehensive solutions， offering features such as patient management， multiple regimen recommendations， and drug concentration-time curve plotting. Stratified analysis based on renal function revealed that Pharmado showed optimal prediction for hyperfiltration patients （mean difference： 0.11 mg/L）. SmartDose and ClinCalc showed relatively better performance in normal and mild renal impaiment （mean difference： 0.37， 0.51 mg/L and －1.13， －1.33 mg/L，respectively）. SmartDose performed best in moderate renal impairment （mean difference： －2.60 mg/L）. Pharmado and Gulou had smaller prediction biases in severe renal impairment （mean differences： 1.52 mg/L and －0.23 mg/L， respectively）. CONCLUSIONS The four individualized dosing tools demonstrated limited accuracy in the initial prediction of vancomycin concentrations. Among them， SmartDose demonstrates the highest overall prediction accuracy and possesses comprehensive clinical management features. It is recommended that Pharmado be preferred for patients with renal hyperfiltration； SmartDose or ClinCalc can be used for patients with normal or mildly impaired renal function； SmartDose is recommended for patients with moderately impaired renal function； Pharmado or Gulou may be considered for patients with severely impaired renal function.

Objective:To establish a paired organoid culture system for primary pancreatic cancer lesions and liver metastatic lesions in mice, and to investigate their morphological and biological behaviors.Methods:C57BL/6 mice aged 6 to 8 weeks were selected. Pancreatic cancer PANC02 cells carrying luciferase were injected into the pancreatic tail. After monitoring the formation of liver metastases using an in vivo imaging system, mice were sacrificed, and paired primary pancreatic cancer lesions and liver metastatic lesions were extracted and cultured in an in vitro organoid culture system. The formation process of organoids was observed under an inverted phase-contrast microscope. Hematoxylin and eosin staining was used to examine the morphological structure of the organoids. The expression of epithelial cell marker CK19 and proliferation marker Ki67 in the organoids was detected by immunohistochemistry and immunofluorescence staining. The expression of invasion markers N-cadherin, E-cadherin, vimentin, snail, and MMP9 was assessed by Western blotting and immunohistochemistry. The drug sensitivity of organoids to gemcitabine was evaluated using the CellTiter-Glo ? 3D Cell Viability Assay, and the half-maximal inhibitory concentration (IC 50) of the organoids was calculated. Results:A spontaneous liver metastasis model of pancreatic cancer in mice was successfully established, along with a paired organoid culture system for primary pancreatic cancer lesions and liver metastatic lesions. The organoids grew in a spherical shape and could be passaged up to 10 generations in vitro. Both liver metastatic lesion organoids and primary pancreatic cancer lesion organoids exhibited lumen-like structures, expressed the epithelial cell marker CK19, and the proliferation marker Ki67, with a significantly higher positive ratio of Ki67 in the liver metastatic lesions compared to the primary pancreatic cancer lesions. The expression levels of invasion markers N-cadherin, vimentin, snail, and MMP9 were significantly higher in liver metastatic organoids than in primary pancreatic cancer organoids, whereas the expression level of E-cadherin was significantly lower in liver metastatic organoids. The IC 50 value of gemcitabine for liver metastatic organoids was 165.0 nM, higher than the 108.5 nM for primary pancreatic cancer organoids. Conclusions:A stable, passagable organoids of primary pancreatic cancer lesions and liver metastatic lesions in mice were successfully established.

Background::China is one of the countries with the largest burden of gastrointestinal and liver diseases (GILD) in the world. The GILD constitutes various causes of mortality and disability. The study aimed to investigate the trend of GILD in China using the Global Burden of Diseases Study 2019 (GBD 2019) data resources from 1990 to 2019.Methods::The data on the age-standardized mortality rates (ASMR) and disability-adjusted life years (DALYs) for GILD in China from 1990 to 2019 were collected from the GBD 2019 data resources. Furthermore, the ranking of the main causes of deaths and DALYs, as well as the trends of ASMR, DALYs, years of life lost (YLLs), and years of life lost due to disability (YLDs) per 1,000,000 in GILD were reported.Results::The ASMR and DALYs for stomach cancer, liver cancer, and esophageal cancer, which ranked top three among the GILDs from 1990 to 2019, were gradually decreasing. Significant decreases in the ASMR and DALYs were found in diarrheal diseases and acute hepatitis (A, E, and C). However, noteworthy increases were found in those of colon and rectum cancer (CRC) and pancreatic cancer. Trend of DALYs, mortality, and YLLs rates for most of GILD were decreasing from 1990 to 2019, except the burden of CRC and pancreatic cancer with an increasing trend. The DALYs, mortality and YLLs of most GILD diseases showed decreasing trends from 1990 to 2019, except the burden of CRC and pancreatic cancer with an increasing trends.Conclusions::The result of the GBD 2019 showed that the rates of most GILDs decreased in China; however, gastrointestinal and liver cancer, such as stomach cancer still held the top ranking. Furthermore, the shift from infectious diseases to non-communicable causes among GILD burden is occurring.

Objective:To investigate the correlation between blood lipid variability and recurrence of cerebrovascular events in patients with ischemic stroke.Methods:Patients with ischemic stroke admitted to Qingdao Municipal Hospital from June 1, 2020 to December 31, 2022 were prospectively enrolled and followed up for 30 months. The standard deviation (SD) and coefficient of variation (CV) of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were calculated during follow-up, and the attainment rate of blood lipid before and after follow-up were compared. The recurrence of cerebrovascular events was monitored, including ischemic stroke, cerebral hemorrhage, and transient ischemic attack. Cox proportional hazards regression model was used to analyze the correlation between the variability of TC, LDL-C, HDL-C, and TG and the recurrence of cerebrovascular events.Results:A total of 142 patients with ischemic stroke were enrolled, including 81 males (57.0%), aged 63.4±5.8 years. During follow-up, 34 patients (23.9%) experienced recurrent cerebrovascular events. At the end of the follow-up, TC, TG, and LDL-C levels decreased significantly compared to before the follow-up (all P<0.05), and the attainment rate of blood lipid increased significantly compared to before the follow-up (51.4% vs. 12.7%; P=0.001). CV of LDL-C in the recurrent group was significantly higher than that in the non-recurrent group ( P=0.005). Cox proportional hazards regression analysis showed that after adjusting for age, gender, body mass index, baseline blood lipids, and baseline blood pressure, LDL-C variability (SD: hazard risk [ HR] 4.051, 95% confidence interval [ CI] 2.671-5.687, P=0.034; CV: HR 3.785, 95% CI 2.356-5.013, P=0.041) and TC variability (SD: HR 3.821, 95% CI 2.450-5.224, P=0.039; CV: HR 3.715, 95% CI 2.401-5.036, P=0.042) during follow-up were independently associated with the recurrence of cerebral vascular events. Conclusions:LDL-C and TC variability are the independent influencing factors for the recurrence of cerebrovascular events in patients with ischemic stroke. Monitoring the variability of LDL-C and TC in patients with ischemic stroke and intervening in a timely manner may reduce the risk of recurrence of cerebrovascular events.

Objective To analyze the stresses in implanted titanium solid and bone trabecular prosthesis hip replacements.Methods A femur model was built inversely based on Mimics software,and optimized using Geomagic software,and then materialized by SolidWorks software.The osteotomized femur was assembled with the metal femoral stem to form a model,and then the model was imported into ABAQUS for finite element calculation.The upper femur was divided into four regions in different states of integration:medial proximal point(small trochanter region),lateral proximal region(large trochanter region),proximal point of the femoral stem(region around the mid-portion of the styloid process)and distal region(around the end of the styloid process and distal portion).Calculations were carried out over the femoral stresses before and after implantation of titanium solid and trabecular prostheses under gait and stair-climbing loads and the interfacial stresses when the region was unintegrated.The type of deformation at the bone interface was analyzed by means of a stress ellipsoid.Results At the small trochanter region,the stress shielding rates of the trabecular prosthesis under gait and stair climbing loads were reduced by 20.5％and 14.7％compared to the titanium solid prosthesis,respectively.In case of different integration states of the titanium solid prosthesis,the interface tensile stresses under the gait and stair climbing loads were up to 10.842 MPa and 12.900 MPa,and the shear stresses reached 7.050 MPa and 6.805 MPa,respectively;in case of different integration states of the trabecular prosthesis,the interface tensile stresses under the gait and stair climbing loads were up to 3.858 MPa and 4.389 MPa,and the shear stresses reached 4.156 MPa and 3.854 MPa,respectively.Under the 2 different loads,the inboard shear stress ellipsoid of the interface opened toward the sides and the bone interface showed tensile deformation;the outboard shear stress ellipsoid of the interface opened up and down and had compressive deformation.Conclusion After total hip arthroplasty,the overall performance of the trabecular prosthesis is better than that of the titanium solid prosthesis.The unintegrated edges of the prosthesis-bone interface are susceptible to stress concentrations and distortion which may result in occurrence of failures.[Chinese Medical Equipment Journal,2024,45(3):29-35]

Objective To investigate the impacts of different levels(1,3 and 5)of iDream reconstruction on CT quantitative analysis of lung function parameters,providing references for quantitative measurement of emphysema indicators by iDream reconstruction technology.Methods A retrospective study was performed for 50 patients who underwent noncontrast chest CT scan in some hospital from December 2021 to January 2022,and the images were reconstructed using four methods:fittered back projection(FBP)and level 1,3 and 5 iDream techniques.For the four groups of images,the main tracheal CT values and standard deviation(SD)values were measured,the signal to noise ratio(SNR)was calculated and the total lung volume(TLV),emphysema volume(EV),emphysema index(EI),15th percentile of lung attenuation(Perc 15)and pulmonary density 15％(PD15％)were detected with quantitative lung function analysis software.Statistical analysis was performed using SPSS 24.0 software.Results The four groups did not have significant differences in the main tracheal CT value and TLV(P＞0.05),while did in SD,SNR,EV,EI,PD15％and Perc 15(P＜0.05).As the reconstruction level of iDream increased,the main tracheal SD value,EV and EI decreased gradually,and level 3 and 5 iDream reconstruction groups had no significant differences in EV and El(P＞0.05);as the reconstruction level of iDream increased,PD15％and Perc 15 rose gradually,and level 3 and 5 iDream reconstruction groups had no significant differences in PD15％and Perc 15(P＞0.05).Conclusion Increase of the level of iDream reconstruction algorithm affects the results of CT quantitative analysis of lung function by reducing image noise.Level 3 and 5 iDream reconstruction ensures the stability of EV,EI,PD15％and Perc 15,which are not influenced by the strength of the iterative reconstruction algorithm.[Chinese Medical Equipment Journal,2024,45(9):57-61]

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To observe the efficacy and safety of flumatinib conversion in chronic myelogenous leukemia-chronicphase(CML-CP)patients with suboptimal TKI response or intolerance.Methods Patients who did not have the best response or intolerance to first-line imatinib,dasatinib,and nilotinib and switched to flumatinib(600 mg/d)from February 2020 to August 2022 were collected from 5 hospitals from Chongqing and affiliated hospitals of North Sichuan Medical College.The efficacy and safety of flumatinib were observed.The optimal response rate,major molecular response(MMR),cumulative complete cytogenetic response(CCyR)rate,cumulative MMR rate,cumulative deep molecular response(DMR),progression-free survival(PFS),event-free survival(EFS)and adverse reactions in 3,6 and 12 months after treatment were observed and analyzed.Results A total of 100 patients with CML-CP were enrolled,with a median follow-up of 18(3～36)months.The optimal response rate was 92.6％(88/95),94.4％(85/90)and 92.9％(79/85)respectively,at 3,6 and 12 months after treatment.Till August 20,2023,the cumulative CCyR and MMR rate was 98.0％(98/100)and 81.9％(77/94),respectively,the median time to reach CCyR and MMR was 3 months,and cumulative DMR rate was 51.0％(51/100).PFS rate was 100.0％(100/100)and 1-year EFS rate was 85.6％(75/90).The most common non-hematologic adverse reactions of flumatinib were diarrhea and abdominal pain(7.0％),followed by renal dysfunction(6.0％)and musculoskeletal pain(2.0％).The main hematologic adverse reactions were thrombocytopenia(12.0％),anemia(6.0％)and leukopenia(2.0％).Conclusion Flumatinib has better MMR and DMR and is well tolerated in CML-CP patients with TKI resistance or intolerance.

OBJECTIVE To investigate the protective effect and potential mechanism of cornuside on diabetic nephropathy （DN） model mice. METHODS Male KK-Ay mice were fed with high-fat and high-sugar diet for two weeks to reproduce the DN model. The successfully modeled mice were randomly grouped into model group， aminoguanidine group （positive control，100 mg/kg） and cornuside group （100 mg/kg）， and male C57BL/6J mice were included as normal group， with 6 mice in each group. Administration groups were given relevant medicine intragastrically， and normal group and model group were given a constant volume of normal saline intragastrically， once a day， for 8 consecutive weeks. The levels of fasting blood glucose （FBG）， 24 h urinary protein， serum interleukin-12 （IL-12）， IL-10， blood urea nitrogen （BUN） and serum creatinine （Scr） were detected； the pathological injury， fibrotic change and glomerular microstructure of renal tissue were observed； the expressions of the receptor of advanced glycation end products （RAGE）， collagen type Ⅳ （COL-Ⅳ） and inducible nitric oxide synthase （iNOS） in renal cortex were detected in each group. RESULTS Compared with normal group， the renal cortex of mice in model group showed obvious inflammatory cell infiltration and fibrotic changes； the mesangial hyperplasia of glomerulus was serious and the basement membrane had a large number of irregular dark dense deposits； the levels of FBG and 24 h urinary protein， the serum levels of IL- 12， BUN and Scr， and the expression levels of RAGE， COL-Ⅳ and iNOS in the renal cortex were significantly increased， while the serum level of IL-10 was significantly decreased （P＜0.01）. Compared with the model group， the renal pathological injuries， fibrotic changes and glomerular microstructure of mice in administration groups were improved significantly， and the above quantitative indexes were generally improved （P＜0.05 or P＜0.01）. CONCLUSIONS Cornuside has a certain protective effect on DN model mice. It can inhibit the inflammatory response， reduce urinary protein excretion， and alleviate renal fibrosis， which may be related to the inhibition of the advanced glycation end products/RAGE signaling pathway.