According to the requirements of the regulatory authorities, degree of modification (DP) should be included in the characterisation of the PEGylated protein drug substance, and is one of the critical quality attributes for quality control. In this study, based on the fundamental assumption that the refractive index (RI) signal and the ultraviolet (UV) signal of PEGylated protein are equal to the sum of the corresponding signal produced by the polyethylene glycol (PEG) and protein parts of the conjugates in their uncoupled state, we developed a method to determine the DP of PEGylated recombinant human growth hormone (inpegsomatropin). In this method, 20 μL of 1 mg·mL^-1 human growth hormone (hGH) standard, 2 mg·mL^-1 PEG reference substance and 1 mg·mL^-1 drug substance solution were each injected to size exclusion chromatographic (SEC) column for separation, detected with ultraviolet and refractive index (UV-RI) detectors in series. Finally, the DP was calculated as the formula derived from the fundamental assumption. The developed SEC-UV-RI method showed good specificity, repeatability (RSD = 0.63%, n = 9) and accuracy, with a recovery of 100.0%, compared with the result obtained from the simultaneously established classical acid hydrolysis method, demonstrating pretty handleability and accessibility, and is appropriate for quality control test of DP for this drug substance.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Objective: To analyze the clinical epidemiological characteristics including composition of pathogens , clinical characteristics, and disease prognosis acute bacterial meningitis (ABM) in Chinese children. Methods: A retrospective analysis was performed on the clinical and laboratory data of 1 610 children <15 years of age with ABM in 33 tertiary hospitals in China from January 2019 to December 2020. Patients were divided into different groups according to age,<28 days group, 28 days to <3 months group, 3 months to <1 year group, 1-<5 years of age group, 5-<15 years of age group; etiology confirmed group and clinically diagnosed group according to etiology diagnosis. Non-numeric variables were analyzed with the Chi-square test or Fisher's exact test, while non-normal distrituction numeric variables were compared with nonparametric test. Results: Among 1 610 children with ABM, 955 were male and 650 were female (5 cases were not provided with gender information), and the age of onset was 1.5 (0.5, 5.5) months. There were 588 cases age from <28 days, 462 cases age from 28 days to <3 months, 302 cases age from 3 months to <1 year of age group, 156 cases in the 1-<5 years of age and 101 cases in the 5-<15 years of age. The detection rates were 38.8% (95/245) and 31.5% (70/222) of Escherichia coli and 27.8% (68/245) and 35.1% (78/222) of Streptococcus agalactiae in infants younger than 28 days of age and 28 days to 3 months of age; the detection rates of Streptococcus pneumonia, Escherichia coli, and Streptococcus agalactiae were 34.3% (61/178), 14.0% (25/178) and 13.5% (24/178) in the 3 months of age to <1 year of age group; the dominant pathogens were Streptococcus pneumoniae and the detection rate were 67.9% (74/109) and 44.4% (16/36) in the 1-<5 years of age and 5-<15 years of age . There were 9.7% (19/195) strains of Escherichia coli producing ultra-broad-spectrum β-lactamases. The positive rates of cerebrospinal fluid (CSF) culture and blood culture were 32.2% (515/1 598) and 25.0% (400/1 598), while 38.2% (126/330)and 25.3% (21/83) in CSF metagenomics next generation sequencing and Streptococcus pneumoniae antigen detection. There were 4.3% (32/790) cases of which CSF white blood cell counts were normal in etiology confirmed group. Among 1 610 children with ABM, main intracranial imaging complications were subdural effusion and (or) empyema in 349 cases (21.7%), hydrocephalus in 233 cases (14.5%), brain abscess in 178 cases (11.1%), and other cerebrovascular diseases, including encephalomalacia, cerebral infarction, and encephalatrophy, in 174 cases (10.8%). Among the 166 cases (10.3%) with unfavorable outcome, 32 cases (2.0%) died among whom 24 cases died before 1 year of age, and 37 cases (2.3%) had recurrence among whom 25 cases had recurrence within 3 weeks. The incidences of subdural effusion and (or) empyema, brain abscess and ependymitis in the etiology confirmed group were significantly higher than those in the clinically diagnosed group (26.2% (207/790) vs. 17.3% (142/820), 13.0% (103/790) vs. 9.1% (75/820), 4.6% (36/790) vs. 2.7% (22/820), χ²=18.71, 6.20, 4.07, all P<0.05), but there was no significant difference in the unfavorable outcomes, mortility, and recurrence between these 2 groups (all P>0.05). Conclusions: The onset age of ABM in children is usually within 1 year of age, especially <3 months. The common pathogens in infants <3 months of age are Escherichia coli and Streptococcus agalactiae, and the dominant pathogen in infant ≥3 months is Streptococcus pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. ABM should not be excluded even if CSF white blood cell counts is within normal range. Standardized bacteriological examination should be paid more attention to increase the pathogenic detection rate. Non-culture CSF detection methods may facilitate the pathogenic diagnosis.
Adolescent ; Brain Abscess ; Child ; Child, Preschool ; Escherichia coli ; Female ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Male ; Meningitis, Bacterial/epidemiology* ; Retrospective Studies ; Streptococcus agalactiae ; Streptococcus pneumoniae ; Subdural Effusion ; beta-Lactamases

Bariatric and metabolic surgery is an effective treatment for obesity and its associated diseases. Gastric bypass has been the gold standard surgery, but now sleeve gastrectomy has become the most commonly used procedure, both procedures have certain disadvantages. In recent years, on the basis of sleeve gastrectomy, a variety of derivative procedures have been developed to improve the efficacy of sleeve gastrectomy. They mainly include sleeve gastrectomy with gastric banding, sleeve gastrectomy with jejunal bypass, sleeve gastrectomy with duodenal-jejunal bypass, single-anastomosis duodeno-ileal bypass with sleeve gastrectomy, stomach intestinal pylorus sparing and single-anastomosis duodenal-jejunal bypass with sleeve gastrectomy. The authors summarize the efficacy and safely of these new operations from sleeve gastrectomy and gastric bypass in order to provide certain references for clinical practice.

Objective To study the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) tail vein transplantation on depressive behavior in chronic unpredictable mild stress (CUMS) model mice. Methods The third generation hUCMSCs were abtained; Sixty C57BL/6 male mice were randomly divided into the normal model group (+ normal saline), the cell group (+hUCMSCs) and the fluoxetine(flu) group (+flu), with 15 mice in each group. The depression model of CUMS mice with a 6 week duration was constructed; From the third week, hUCMSCs and normal saline were transplanted into the mice by tail vein injection, and the mice were gavaged with flu daily from the fifth week; Weight changes in each group were recorded weekly; The depression model and therapeutic effect of mice were evaluated by sucrose preference test, tail suspension test, forced swimming test and open field test; The cell changes of CAI and CA3 region in hippocampus were observed by HE staining; Transmission electron microscopy was used to detect the changes of synapses in CA3 region of hippocampus; Real-time PCR was used to detect mRNA expressions of synaphysin (SYP) and postsynaptic density protein 95 (PSD-95), which are key proteins of synaptic plasticity. Results hUCMSCs improved weight decrease in depressed mice; behavioral experiments observed that the model group mice showed depressive behavior, while the cell group and the drug group mice depression were improved; HE staining showed that, compared with the model group, cells in CA 1 and CA3 regions of the hippocampus of mice in the cell group and the group were arranged orderly and the number of cells increased; Transmission electron microscopy showed that compared with the model group, the number of synapses in the CA3 region of the hippocampus was more, the synaptic gap was narrower, and the density of synaptic spines was higher in the cell group and the drug group; More mRNA expressions of SYP and PSD-95 were detected by Real-time PCR in the cell group and the drug group than in the model group. Conclusion hUCMSCs transplatation showes antidepressant effects, which are associated with improved synaptic plasticity in the hippocampus.

Objective:To investigate the predictive value of visceral fat area (VFA) on multiple metabolic risk factors in obese patients undergoing bariatric surgery.Methods:The retrospective case-control study was conducted. The clinical data of 146 obese patients undergoing bariatric surgery in the West China Hospital of Sichuan University from June 2015 to May 2020 were collected. There were 57 males and 89 females, aged (33±9)years, with a range from 15 to 65 years. All patients underwent multi-slice spiral computed tomography (CT) examination, and the total fat area (TFA), VFA and subcutaneous fat area (SFA) were measured. Observation indicators: (1) CT findings of abdominal fat area and patients with multiple metabolic risk factors; (2) receiver operator characteristic(ROC) curve of different clinical indicators for predicting multiple metabolic risk factors; (3) relationship between different VFA and clinicopathological features in patients; (4) analysis of factors influencing multiple metabolic risk factors in patients. Measurement data with normal distribution were expressed as Mean± SD, and comparison between groups was analyzed by independent sample t test. Measurement data with skewed distribution were expressed as M (range) and comparison between groups was analyzed by nonparametric rank sum test. Count data were represented as absolute numbers, and comparison between groups was analyzed using the chi-square test. The ROC curve was used to analyze the predictive value of different clinical indicators for multiple metabolic risk factors in patients. Logistic regression analysis was used for univariate and multivariate analysis. Results:(1) CT findings of abdominal fat area and patients with multiple metabolic risk factors. CT findings of 146 patients showed that VFA was (212±122)cm 2, SFA was (419±147)cm 2, visceral-to-subcutaneous fat ratio (VSR) was 0.60±0.54. The levels of systolic blood pressure (SBP), diastolic blood pressure, fasting blood glucose (FBG), triglyceride and highdensity lipoprotein cholesterol (HDL-C) were (131±16)mmHg(1 mmHg=0.133 kPa), (86±12)mmHg, (6.4±2.5)mmol / L, 4.43 mmol /L(range, 1.23-9.99 mmol/L), (1.5±1.3)mmol/L, respectively. Among the 146 patients, 85 had impaired FBG or diabetes, 82 had hypertension, 139 had high triglyceride, 91 had low serum HDL-C; 128 had multiple metabolic risk factors. (2) ROC curve analysis of different clinical indicators for predicting multiple metabolic risk factors: the ROC curve showed that VFA had better ability to predict or diagnose multiple metabolic risk factors in patients ( hazard ratio=0.617, 95% confidence interval as 0.470-0.764, P<0.05). The cutoff value of VFA was 163.52 cm 2 by calculating Yoden index in ROC curve. (3) Relationship between different VFA and clinicopathological features in patients: according to the cutoff value of 163.52 cm 2 in ROC curve, 146 patients were divided into high VFA group (≥163.52 cm 2) and the low VFA group (<163.52 cm 2), with 49 cases and 97 cases respectively. Cases with hypertension, level of SBP, cases with impaired FBG or diabetes, cases with multiple metabolic risk factors were 64, (134±17)mmHg, 63, 90 for the high VFA group, versus 18, (127±13)mmHg, 22, 38 for the low VFA group; there were significant differences in above indicators between the two groups ( χ2=11.309, t=6.916, χ2=5.380, 6.988, P<0.05). (4) Analysis of factors influencing multiple metabolic risk factors in patients: results of univariate analysis showed that VFA was a related factor for multiple metabolic risk factors in patients ( hazard ratio=3.722, 95% confidence interval as 1.341-10.328, P<0.05). Results of multivariate analysis showed that the VFA≥163.52 cm 2 was an independent rsik factcor or multiple metabolic risk factors in patients ( hazard ratio=5.182, 95% confidence interval as 1.441-18.641, P<0.05). Conclusions:VFA is positively correlated with hypertension, systolic blood pressure, impaired FBG and diabetes. VFA≥163.52 cm 2 is an independent predictor for multiple metabolic risk factors in obese patients undergoing bariatric surgery.

To elucidate the absorption and metabolism of alkaloids in Berberis kansuensis in vivo, a high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC-QqQ-MS) method was developed to qualitatively and quantitatively analyze the absorption components in rat serum in multiple-reaction monitoring mode. The mobile phase consisted of 0.1% formic acid and acetonitrile with a gradient elution mode. In addition, to investigate the effects of gut microbiota on five absorbed components of B. kansuensis in rat serum, diabetic rat and pseudo germ-free diabetic rat models were established, and partial least squares discriminant analysis and One-way ANOVA were used to study the content differences of five components among different groups. In this study, a HPLC-QqQ-MS method for quantitative analysis of five components in rat serum after oral administration of B. kansuensis was established for the first time. It was found that there were differences in the five constituents in rat serum between different groups. By comparing the normal group with the diabetic model group, we found that the absorption and metabolism capacities of berberine and magnoflorine were different under the health and pathological conditions. It was also found that the serum levels of berberine, magnoflorine and jatrorrhizine in pseudo germ-free diabetic rats were significantly lower than those in diabetic rats, indicating that gut microbiota plays an important role in the metabolism of alkaloids of B. kansuensis in vivo. These results provide a good reference for clarifying the active ingredients of B. kansuensis in the treatment of diabetes.
Alkaloids/pharmacokinetics* ; Animals ; Berberis/chemistry* ; Chromatography, High Pressure Liquid ; Diabetes Mellitus, Experimental/blood* ; Gastrointestinal Microbiome ; Mass Spectrometry ; Phytochemicals/pharmacokinetics* ; Rats

This study aimed to determine the protective effect of Qizhi hypoglycemic tablet (QZHGT) on foot ulcer in diabetic rats and explore its possible mechanism. Diabetes was induced by streptozotocin injection in rats. The rats received QZHGT (780 mg·kg^-1), metformin hydrochloride tablet (Metf, 200 mg·kg^-1) or glibenclamide tablet (Glib, 1.5 mg·kg^-1) alone via intragastric administration once a day for three months. Food ulcer was prepared by foot skin excision after drug therapy lasted for two months, and the dynamic changes in food ulcer healingwere determined. During the experiment, blood glucose, serum levels of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS), factor Ⅲ (FⅢ) and four coagulation parameters [thrombin time (TT), activated partial thromboplatin time (APTT), prothrombin time (PT), fibrinogen (FIB)] were detected. Finally, the protective mechanisms of QZHGT against diabetes and foot ulcer were analyzed by network pharmacology, and immunohistochemistry was used to confirm the expression of transforming growth factor-β (TGF-β) and nuclear factor κB (NF-κB) in pancreatic tissue. All animal procedures were approved by the Animal Experimentation Ethics Committee of Henan University (permission number HUSAM 2016-288). The results showed that the lasting hyperglycemia, polydipsia, polyphagia, polyuria and body weight lost took place in model rats compared to those in normal rats. These model rats also showed an increase in serum VEGF and iNOS, FⅢ, TT, APTT and PT, and a reduction in FIB and wound healing. Metf or Glib significantly improved hyperglycemia, polydipsia, polyphagia, polyuria and emaciation, but failed to ameliorate hypercoagulation and wound healing. QZHGT showed a similar effect on polydipsia, polyphagia, polyuria and emaciation to Metf or Glib, although it was inferior to them in hypoglycemic action. Importantly, QZHGT significantly improved hypercoagulation and wound healing, and attenuated serum VEGF and iNOS. Network pharmacology revealed that QZHGT decreased hyperglycemia through "insulin resistance pathway", improved coagulation status through "HIF-1 signaling pathway", prevented diabetic foot ulcers through "VEGF signaling pathway", "MAPK signaling pathway" and "NF-κB signaling pathway". Immunohistochemistry showed that QZHGT could inhibit the expression of TGF-β and NF-κB in pancreatic tissue to maintain islet function in diabetic rats. In summary, these data suggest that QZHGT can prevent pancreatic injury for adjunctive hypoglycemia and diabetic foot ulcer treatment, and is a better preventive and therapeutic drug for diabetic foot ulcer.

Objective To explore the feasibility of low-concentration contrast agent and low-dose technology for pulmonary angiography by comparing the image quality and radiation doses to the patient by different tube voltages and concentrations of contrast agents.Methods Totally 60 patients suspected with pulmonary embolism were divided into C, L1 and L2 groups, of which,Group C had the scanning parameters of 120 kV and 350 mgI/ml,Group L1 had the parameters as 100 kV and 350 mgI/ml and Group L2 had the parameters of 100 kV and 270 mgI/ml.The three groups had the tube voltage as 500 mA, the contrast agent dose as 25 ml,physiological saline dose as 40 ml and flow rate as 4.5 ml/s.SPSS 19.0 software was used to compare and analyze the CT values of pulmonary artery segment,superior vena cava and ascending aorta,main pulmonary artery noises,the image quality as well as the radiation doses of volume scanning. Results The three groups had the main pulmonary aortas and their branches display clearly to meet clinical requirements.When compared with Group C,Group L1 had higher CT values of the main pulmonary aorta and its branches,higher image noise while lower radiation dose (P<0.01);Group L2 had equivalent CT values of the main pulmonary aorta and its branches (P>0.05),higher image noise while lower radiation dose (P<0.01).When compared with Group L1,Group L2 had lower CT values of the main pulmonary aorta and its branches (P<0.01),and equivalent image noise and radiation dose (P>0.05).Conclusion Low-concentration contrast agent and low-dose technology gains feasibility and advantages when used in 320-slice CT pulmonary angiography.

Objectives: To compare the effect of 2 different occlusion devices for treating cryptogenic stroke (CS) patients combining patent foramen ovale (PFO) and large right-to-left shunt (RLS). Methods: A total of 123 CS patients combining PFO and large RLS treated in our hospital from 2013-05 to 2016-08 were enrolled. All patients received percutaneous PFO interventional closure, based on different occlusion devices, the patients were divided into 2 groups: Cardi-O-fix PFO occluder group, n=80 and Amplatzer PFO occluder group, n=43. CS diagnosis was confirmed by 3 experienced neurologists via medical imaging examination; PFO and large RLS were diagnosed by transthoracic echocardiography and right heart contrast echocardiography. The baseline features, clinical symptoms, operation and follow-up data were reviewed to observe the efficacy of 2 occlusion devices. Results: Each group had 1 patient suffered from paroxysmal atrial fibrillation after the operation; 1 patient in Cardi-O-fix PFO occluder group had inguinal hematoma. No stroke recurrence, no death during follow-up period; the residual shunt was similar between 2 groups. Conclusions: PFO occlusion was beneficial for preventing stroke recurrence in CS patients combining PFO and large RLS. The safety and efficacy were similar in Cardi-O-fix and Amplatzer PFO occlusion devices.