AIM:To establish a physiological-based pharmacokinetic(PBPK)model of ertapen-em in elderly patients with chronic kidney disease,and to analyze the pharmacokinetic/pharmacody-namic index f％ T＞MIC at different doses.METH-ODS:The physicochemical properties and pharma-cokinetic characteristics of ertapenem were collect-ed by reviewing the literature and databases,and a healthy adult model was established in PKSim? software,and then extrapolated to the PBPK model of the elderly.The clinical pharmacokinetic re-search data were used to optimize and validate the model,and the mean folding error(MFE)was used as the index to evaluate the prediction perfor-mance of the model.The final model was used to simulate the in vivo exposure of elderly patients with chronic kidney disease after administration,and the pharmacokinetic/pharmacodynamic index of commonly used clinical dosing regimens was an-alyzed,and the recommended dosing regimens were given.RESULTS:The MFE of the area under the curve(AUC0-t),peak concentration(Cmax)and peak time(Tmmax)predicted by the established PBPK model of ertapenem in adults were 0.92,0.79 and 1.02,respectively,and the predicted value of the optimized PBPK model of ertapenem in the elderly was also consistent with the observed value of 0.5＜MFE＜2 standards,all of which have good predictive performance.With f％ T＞MIC greater than 40％as the drug efficacy target,the minimum inhibitory concentration(MIC)is 0.5-1 μg/mL for sensitive bacteria,and elderly patients with chronic kidney disease can consider reducing the drug dose as ap-propriate.CONCLUSION:The PBPK model of ertap-enem in elderly patients with renal insufficiency has been successfully established,and the model has good prediction performance and provides a reference for clinical personalized medication in el-derly patients with renal insufficiency.

AIM:To establish a physiological-based pharmacokinetic(PBPK)model of ertapen-em in elderly patients with chronic kidney disease,and to analyze the pharmacokinetic/pharmacody-namic index f％ T＞MIC at different doses.METH-ODS:The physicochemical properties and pharma-cokinetic characteristics of ertapenem were collect-ed by reviewing the literature and databases,and a healthy adult model was established in PKSim? software,and then extrapolated to the PBPK model of the elderly.The clinical pharmacokinetic re-search data were used to optimize and validate the model,and the mean folding error(MFE)was used as the index to evaluate the prediction perfor-mance of the model.The final model was used to simulate the in vivo exposure of elderly patients with chronic kidney disease after administration,and the pharmacokinetic/pharmacodynamic index of commonly used clinical dosing regimens was an-alyzed,and the recommended dosing regimens were given.RESULTS:The MFE of the area under the curve(AUC0-t),peak concentration(Cmax)and peak time(Tmmax)predicted by the established PBPK model of ertapenem in adults were 0.92,0.79 and 1.02,respectively,and the predicted value of the optimized PBPK model of ertapenem in the elderly was also consistent with the observed value of 0.5＜MFE＜2 standards,all of which have good predictive performance.With f％ T＞MIC greater than 40％as the drug efficacy target,the minimum inhibitory concentration(MIC)is 0.5-1 μg/mL for sensitive bacteria,and elderly patients with chronic kidney disease can consider reducing the drug dose as ap-propriate.CONCLUSION:The PBPK model of ertap-enem in elderly patients with renal insufficiency has been successfully established,and the model has good prediction performance and provides a reference for clinical personalized medication in el-derly patients with renal insufficiency.

Objective:To investigate whether endoplasmic reticulum aminopeptidase 1 ( ERAP1) is a susceptible gene for pre-eclampsia (PE) and the possible mechanism in the pathogenesis. Methods:This retrospective study included 990 PE patients (case group) and 1 240 healthy pregnant women (control group) in six prefecture-level tertiary hospitals in Shandong Province, including the Affiliated Hospital of Qingdao University and Zaozhuang Maternal and Child Health Hospital, from September 2018 to April 2021. Peripheral blood were collected for DNA extraction. Single-nucleotide polymorphisms in the ERAP1 gene (rs30187, rs27044, and rs469783 loci) were analyzed by Taqman probe polymerase chain reaction (PCR). Two missense mutant plasmids, rs30187(c.1583A>G) and rs27044(c.2188C>G), were constructed by point mutation induction based on wild-type plasmids. Six groups (knock-down control, knock-down, over-expression control, over-expression, variant 1 and 2 groups) were set up in this study. After transfecting Htr8 cells with different transfection molecules, the expression of ERAP1 at mRNA and protein levels were detected. Besides, the effects of different transfections on cell function were detected using Transwell migration assay, Transwell invasion assay, cell scratch assay, and CCK-8 assay. Statistical analysis was performed using two independent samples t-test, rank sum test, and Chi-square test. Results:(1) There were significant differences in the genetic distribution of rs30187 (Genotype: χ2=29.25, Allele: χ2=4.68) and rs469783 (Genotype: χ2=7.01, Allele: χ2=6.45) as well as the genotype distribution of rs27044 ( χ2=28.95) between the case group and the control group (all P<0.05). Statistical analysis of the genetic model revealed that rs30187 and rs27044, both recessive models, were statistically different between the two groups with a higher frequency of CC genotypes in the case group ( χ2=20.82 and 19.97, both P<0.05), but a lower frequency in CC dominant gene pattern for rs469783 ( χ2=5.82, P=0.016). (2) Compared with the knock-down control group, the knock-down group showed significantly inhibited expression of ERAP1 (mRNA: 0.5±0.1 vs 1.0±0.0, t=7.49; protein: 0.4±0.1 vs 0.7±0.1, t=2.81; both P<0.05), reduced cell migration rate after 48 h of scratching [(16.5%±1.8%) vs (23.8%±2.4%), t=3.33, P=0.031] and decreased number of cells crossing Transwell chambers after 24 h of culture (423.7±21.3 vs 499.0±24.6, t=3.29, P=0.031). Compared with the over-expression group, variant 1 group and variant 2 group showed significantly inhibited expression of ERAP1 at mRNA (both P<0.001) and protein ( P=0.003 and 0.006) levels after transfection, decreased number of cells crossing Transwell chambers ( P=0.001 and 0.032) and down-regulated cell migration rate after 48 h of scratching [variant 1: P=0.004; variant 2: (21.1±4.6)% vs (28.3±1.1)%, t=2.10, P=0.099]. ERAP1 expression at both mRNA ( P<0.001) and protein ( P=0.008) levels, as well as cell proliferation ( P<0.001) and invasion ability ( P<0.001), were all enhanced in the over-expression group than those in the over-expression control group. Moreover, the migration rate of cells after 48 h of scratching ( P=0.002) and the number of cells crossing Transwell chambers after 24 h of culture ( P=0.001) were also increased. Conclusions:The rs30187, rs27044, and rs46978 on ERAP1 gene were all associated with PE susceptibility, with more carriers of the CC genotype in PE patients at rs30187 and rs27044 loci and more carriers of the CC genotype in healthy gravida at rs469783 locus. ERAP1 may be involved in the pathogenesis of PE by affecting the migratory and invasive ability of trophoblast cells.

Objective:This study aimed to analyze differential metabolites in patients using a dual metabolic platform and to orientate early nutritional intervention in patients with cirrhosis.Methods:The skeletal muscle index (SMI) was calculated based on computed tomography (CT) measurements of skeletal muscle cross-sectional area at the third lumbar vertebra level. Pre-sarcopenia was diagnosed for males with SMI < 46.96 and for females with SMI < 32.46. Fifteen HBV-related liver cirrhosis patients with pre-sarcopenia were included as Group S while fourteen liver cirrhosis without pre-sarcopenia were Group NS. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) analyses were used to detect differential metabolites and disturbed pathways in the two groups.Results:Five pathways and twenty-eight pathways were defined as disturbed pathways in the plasma of liver cirrhosis patients with pre-sarcopenia by LC-MS and GC-MS, respectively. Most of these pathways are related to amino acid metabolism. Forty-two differential metabolites were imported into the disturbed pathways. Moreover, 3-hydroxypropanal, hydrocinnamic acid, betaine aldehyde, phosphohydroxypyruvic acid, (r)-3-hydroxybutyric acid, and creatinine were identified as potential biomarkers for pre-sarcopenia in HBV-related liver cirrhosis.Conclusions:The study identified a total of 33 pathways and related differential metabolites that were disturbed in HBV-related liver cirrhosis with pre-sarcopenia. The amino acid metabolism, urea cycle, and glyoxylate and dicarboxylate metabolism pathways may be associated with pre-sarcopenia in patients with HBV-related liver cirrhosis. These results provide a direction for nutritional supplementation in liver cirrhosis.

OBJECTIVE To systema tically evaluate the efficacy and safety of blinatumomab for acute lymphoblastic leukemia （ALL）in order to provide evidence-based reference for clinical use. METHODS Retrieved from PubMed ，Embase，Web of Science，the Cochrane Library ，CNKI，Wanfang database and CBM during the inception to February 3，2022，randomized controlled trials （RCTs）and cohort studies of blinatumomab （experimental group ） versus conventional chemotherapy （control group ）in the treatment of ALL were collected. After literature screening and data extraction ，the quality of RCTs was evaluated by the risk bias evaluation tool recommended by Cochrane handbook 5.1.0，and the quality of cohort studies was evaluated by the Newcastle-Ottawa scale （NOS）. Meta-analysis was performed by RevMan 5.4 software. GRADE grading system was used to evaluate the evidence quality of outcomes. The publication bias was analyzed by inverted funnel plot. RESULTS A total of 8 studies were included ，involving 3 RCTs and 5 cohort studies ，with a total of 2 841 patients. Results of Meta-analysis showed that the overall survival rate more than one year [RR ＝1.30，95％CI（1.14，1.48），P＜0.000 1]，relapse-free survival rate [RR ＝1.78，95％CI（1.50，2.12），P＜0.000 01]，complete remission rate [RR ＝1.42，95％CI（1.11，1.82），P＝0.006]，the incidence of tremor [RR ＝16.98，95％CI（2.17，133.12），P＝0.007]，and the incidence of cytokine release syndrome [RR ＝14.11， 95％CI（3.43，58.01），P＝0.000 2] in trial group were all significantly higher than control group ，but there was no statistical significance in the incidence of headache between two groups [RR ＝1.31，95％CI（0.66，2.59），P＝0.44]. The incidence of adverse events with grade more than or equal to 3，infection，stomatitis，thrombocytopenia，febrile neutropenia ，anorexia， constipation，diarrhea，abdominal pain ，hypokalemia in trial group were significantly lower than control group （P＜0.05）. The incidence of cough ，rash and hypogamma globulinemia and fever in the trial group were significantly higher than control group （P＜0.05）. There was no statistical significance in the total incidence of adverse events ，sepsis，anemia，leucopenia，neutropenia， lymphopenia，nausea，vomiting，hyperglycemia，hypotension，hypertension，elevated transaminase or epistaxis between two groups（P＞0.05）. Results of subgroup analysis by study type showed that the overall survival rate ，relapse-free survival rate and complete response rate （except for cohort studies ）of patients in trial group were significantly higher than control group in both RCTs and cohort studies （P＜0.05）. The results of GRADE evaluation showed that the overall quality of index evidence included in this study was low. There was little possibility of publication bias in this study based on the publication bias analysis. CONCLUSIONS Blinatumomab is effective in the treatment of ALL ，with low incidence of infection and adverse events of digestive system ，but high incidence of tremor ，cough，rash，fever，hypoproglobulinemia and cytokine release syndrome. The evidence quality of the indicators included in this study is generally low .

Objective To analyze the clinical characteristics and treatment strategy of phosphaturic mesenchymal tumors in hips.Methods From May 2017 to November 2017,five patients with phosphaturic mesenchymal tumors in hips,who treated in our hospital were retrospectively reviewed.The clinical manifestations,laboratory inspection,radiological examination,pathological examination and treatment were analyzed.Results Two male cases (40％) and 3 female (60％) were included.The overall age was 49～63 years old (average 54.40±5.37 years old).The course was 19～101 months (average 51.20±32.41months).Four cases of tumor were located in femoral head and 1 case was in femur intertrochanteric region.The maximum tumor diameter was 0.76～1.83 cm (average 1.28±0.39 cm).The early clinical manifestations of the patients were mainly non-specific bone pain or fatigue.The symptoms of the hip were not obvious.All patients had been misdiagnosed.After pathological frac-ture of the hip,the patient suffered from hip pain,thigh pain,fatigue,etc.,or limited hip function.The severe patients had a systemic multiple pathologic fractures.The serum phosphorus was lower than normal in preoperative period and recovered to normal level in 3-8 days after surgery.The postoperative ALP decreased significantly than preoperative in 4 patients and 1 case was slightly higher than preoperative.Preoperative 1,25-(OH)2-D3 and PTH were in normal range.99Tcm-octreotide (OCT) scan or 68Ga DOTA-TATE PET/CT can detect the disease.X-ray,CT and MRI can identify the lesions.The lesions of femoral head were basically under the joint surface,with a nodular change.Part of the tumor was infiltrating and close to the cortex.The pathology was mainly manifested as a large number of thin-walled vessels in the bone trabeculae.There were dense spindle cells or astrocytes between the blood vessels and the atypia is not obvious.Three patients were treated with total hip arthroplasty and two with segmental resection and bone graft.After surgical removal of the tumor,the patient's systemic pain or anemic symptoms were gradually relieved and the joint function was restored.Meanwhile,the bone density was increased.Conclusion The clinical features of the phosphaturic mesenchymal tumors in hips were not obvious.Comprehensive diagnosis should be carried out in combination with the clinical manifestations,laboratory examination,radiological examination and pathological examination.Total hip arthroplasty or segmental resection with bone graft can effectively remove the tumor and achieve good prognosis.

Objective To investigate the current situation and existing problem of development and management of intravenous therapy in Ningxia region. Methods A total of 42 hospitals from Ningxia region were admitted to questionnaire survey. Results Venous vascular access tools usage:42 hospitals used scalp needle for infusion, 73. 80% of the hospitals used intravenous indwelling needle, 14. 28% of the hospitals carried out the PICC tube, only 1 hospital had umbilical vein for newborns, med-long catheter and implantable infusion port were not carried out in all hospitals; intravenous therapy equipment: 3 hospitals had vein of the configuration center, 39 hospitals 3 hospitals with a vein of the configuration center, 39 hospitals in the therapeutic room of the hospital to complete the work in the to complete the anti tumor drug allocation of only 3 hospitals completed the work in the therapeutic room, only 3 hospitals completed the anti tumor drug distribution in the biological cabinet; management of intravenous therapy: 3 hospitals established venous treatment team to carry out consultation work, 23 hospitals had the relevant procedures for venous treatment, 2 hospitals carried out the special quality control work. Conclusions Intravenous therapy in Ningxia hospital is lagging behind, and there are security risks in occupational protection of vein disposition, so development of venous management, training, scientific research and other aspects should be systematic, professional and standardized.