The study aimed to establish a population pharmacokinetic/pharmacodynamic (PPK/PD) model of warfarin. PCR-RFLP technique was used to genotype the CYP2C9 and VKORC1 polymorphisms of 73 patients. RP-HPLC-UV method was used to determine the 190 plasma concentrations of warfarin. Application of NONMEM, the clinical information and 263 international normalized ratio (INR) monitoring data were used to investigate the effect of genetic, physiological, pathological factors, other medication on clearance and anticoagulant response. The final model of warfarin PPK/PD was described as follows: CL = θCL · (WT/60)θWT · θCYP · eηCL (if CYP2C9*1/*1, θCYP = 1; if *1/*3, θCYP = 0.708); EC50 = θEC50 · θVKOR · eηEC50 (if VKORC1- 1639AA, θVKOR = 1; if GA, θVKOR = 2.01; V = θV; K(E0) = θK(E0); Emax = θEmax; E0 = θE0 · eηE0. Among them, the body weight (WT), CYP2C9 and VKORC1 genotype had conspicuous effect on warfarin PK/PD parameters. The goodness diagnosis, Bootstrap, NPDE verification showed that the final model was stable, effective and predictable. It may provide a reference for opitimizing the dose regimen of warfarin.

AIM: To investigate the correlations of genetic polymorphisms, infliximab(IFX) serum trough concentration, immunogenicity and clinical outcome in patients with Crohn's disease(CD) to provide reference for optimizing IFX treatment in CD patients. METHODS: The clinical data of CD patients treated with IFX in our hospital from September 2017 to September 2019 were prospectively collected. The genotypes TNF-α-308, TNF-α-238, TNF-α-857, TNFRSF1B, ABCB1, FCGR3A were detected by targeted sequencing using multiple PCR combined with high throughput sequencing before administration. The IFX steady-state concentration was determined by ELISA. SPSS 20.0 software was used for statistical analysis and ROC curve was drawn for clinical efficacy and antibody threshold. RESULTS: A total of 111 patients were included in the study, the IFX trough concentration of patients with TNF-α-238GA was significantly lower than that of GG (0.55±0.52) vs. (1.75±1.46) μg/mL (P=0.003), while there was no significant difference in IFX trough concentration among TNF-α-308, TNF-α-857, TNFRSF1B, ABCB1, FCGR3 Agenotypes. Clinical response rate of TNFRSF1B (TG+GG) was significantly higher than that of the wild type (TT) (75.0% vs. 42.3%) (P=0.001), and there was no statistically significant difference in clinical efficacy among patients with different genotypes of other genes (P>0.05). The efficacy of IFX in the treatment of CD and the production of antibody to IFX were significantly correlated with maintenance trough concentration (P<0.01). The optimal IFX trough concentration thresholds for predicting CPR≤5 mg/L and clinical response after treatment were 1.33, 0.85 μg/mL, respectively. Trough concentration ≤0.51 μg/mL was used as an indicator to predict the generation of antibody. CONCLUSION: Polymorphisms of TNF-α-238 and TNFRSF1B can affect the maintenance trough concentration and clinical response of IFX in CD patients, respectively. The trough concentration at IFX maintenance stage >1.33 μg/mL had certain predictive significance for biological response, while ≤0.51 μg/mL can be used as a predictor of antibody production.

Objective? ?To?analyze?the?risk?factors?of?delirium?in?patients?in?cardiac?surgery?intensive?care?unit?(CSICU).? Methods? A?prospective?observational?study?was?performed.?Patients?admitted?to?CSICU?of?Fujian?Medical?University?Union?Hospital?from?March?to?August?in?2017?were?enrolled.?The?combination?of?the?Richmond?agitation?sedation?scale?(RASS)?and?the?ICU-confusion?assessment?method?(CAM-ICU)?were?used?to?evaluate?delirium.?The?patient?was?assessed?on?the?second?day?after?CSICU?admission,?twice?a?day,?the?evaluation?was?stopped,?and?the?follow-up??observation?was?terminated?after?the?patient?was?discharged?from?CSICU.?The?patients?were?divided?into?two?groups?according?to?whether?delirium?occurred?in?CSICU.?The?general?and?clinical?treatment?data?(including?condition,?operation,?anesthesia?and?CSICU?treatment)?of?the?two?groups?were?compared.?The?related?factors?of?delirium?were?identified?by?univariate?analysis?and?multifactor?Logistic?regression?analysis.? Results? A?total?of?318?cases?were?included?in?this?study.?Among?them,?93?cases?had?delirium?and?the?incidence?of?delirium?was?29.2%.?It?was?shown?by?univariate?analysis?that?age,?history?of?hypertension,?type?of?surgery,?surgical?procedure,?American?Society?of?Anesthesiologists?(ASA)?anesthesia?classification,?usage?of?propofol,?plasma?transfusion,?red?blood?cells,?platelet?transfusion,?blood?loss,?operative?time,?cardiopulmonary?bypass?(CPB)?time,?myocardial?block?time,?acute?physiology?and?chronic?health?evaluation?Ⅱ?(APACHEⅡ),?duration?of?mechanical?ventilation,?the?length?of?intensive?care?unit?(ICU)?stay,?postoperative?usage?of?diazepam,?midazolam,?fentanyl,?morphine,?chlorpromazine,?etc.?which?were?related?to?delirium,?and?occupation?? (on-the-job?or?self-employed),?medical?insurance?(city?or?provincial?medical?insurance),?education?(primary?to?junior?high?school,?high?school?or?above)?could?reduce?the?risk?of?delirium.?Colinearity?diagnosis?was?performed?on?variables?with?statistically?significant?differences,?and?variables?with?variance?expansion?factor?(VIF)?

Objective: To explore the effect of early pulmonary rehabilitation on stroke associated pneumonia by the ICU specialist nurses. Methods: Totally 40 cases of stroke patients from January 2017 to June 2017 were selected into the control group, and 44 cases of stroke patients from July 2017 to December 2017 were set as the intervention group. The patients in the control group were given routine care, and those in the experimental group were given early pulmonary rehabilitation in addition to routine care by ICU specialist nurses. The clinical outcome such as the occurrence of SAP, the length of intensive care units (ICU) stay and the duration of mechanical ventilation were compared. Results: The incidence of SAP in the intervention group was 13.64%(6/44), significantly lower than that 32.50(13/40) in the control group (χ²=4.26, P<0. 05), and the length of ICU stay the duration of mechanical ventilation were (5.59±3.93), (3.2±0.84)days, which were lower than (8.50±7.89), ((13.13±9.58)days in the control group (t=2.106,2.678, P<0.05) , the prealbumin levels was (219.43±59.71) mg/L,higher than (192.20±54.85) mg/L in the control group (t=-2.170, P<0.05) , the difference was statistically significant. Conclusion Early pulmonary rehabilitation can effectively reduce the incidence of SAP and better clinical outcome. And we also should improve the SAP risk assessment and the management of swallowing and nutrition.

AIM: To develop software for individualizing dosage regimens of vancomycin (VCM) according to the established population pharmacokinetics (PPK) models. METHODS: VCM dosing software was developed using MyEclipse, SQL Server, and JRE. The software developing schemes included requirement analysis, general design, detailed design, software coding, software test, software maintenance and software redevelopment. RESULTS: The developed software achieved the functions such as input and management of patient information, prediction of trough concentrations under various dosing regimens which could help initial dosage design, and prediction of trough concentrations more accurately based on therapeutic drug monitoring results and Bayesian method which could help dosage adjustment. The software was utilized in the interpretation of VCM serum concentration, pharmacists proposed the suggestions for adjusting dosage regimens. The rechecked serum concentrations all reached the expected target blood concentration range in the group of adopting advice. CONCLUSION: The new developed software based on our established PPK models can provide a useful tool in the clinical setting to facilitate the individualized therapy for the adult and elderly infected patients.

AIM: To provide reference for clinical application of warfarin PPK/PD model, the prediction accuracy of warfarin PPK/PD model and 6 dose models established by multiple linear regression were compared. METHODS: Clinical data of inpatients who took warfarin tablets for oral anticoagulant therapy in our hospital were collected, and the predictive values were simulated by PPK/PD model and other 6 models, respectively. SPSS 23.0 software was used for paired t-test of measured value and predicted value. MAE and percentage of prediction deviation were used to evaluate the results, and the prediction deviation box-plot was drawn to compare the total data, different dose groups and different genotypes. RESULTS: A total of 50 patients were included in the study. Among 7 models, only PPK/PD model, Wen et al., and Du Liping et al.'s model had no statistical difference in predicted values and measured values (P>0.05). The prediction accuracy of PPK/PD model was higher among the total data, low and medium doses, and patients with different genotypes.The prediction accuracy of Wen et al. 's model and Li Chuanbao et al.'s model was higher in the high-dose group. CONCLUSION: The PPK/PD model of warfarin has good clinical prediction performance, which is expected to provide reference for accurate administration of warfarin.

Objective : To investigate the effects and mechanism of small ubiquitin-like modifier ( SUMO) specific proteinase-1 (SENP-1) on chronic intermittent hypoxia ( CIH) induced myocardial injury in rats． Methods : 32 male SD rats were randomly divided into : control group，CIH group，negative control adeno-associated virus interven- tion group (AAV-shNC) and SENP-1 shRNA adeno-associated virus intervention group (AAV-shSENP-1) ，with 8 rats in each group．After 6 weeks of CIH induction，echocardiography was performed．The levels of cardiac troponin I (cTNI) ，creatine kinase MB isoenzyme ( CKMB) ，myoglobin (Mb) ，lactate dehydrogenase (LDH) in serum and malondialdehyde (MDA) ，uperoxide dismutases ( SOD) ，glutathione ( GSH) ，interleukin( IL) -1 β , IL-6 and tumor necrosis factor-α(TNF-α) in myocardial tissue were detected by ELISA．The pathological changes of myocardial tis- sue was observed by HE staining．The reactive oxygen species ( ROS) level in myocardial tissue was detected by DCFH-DA fluorescence probe labeling．The small ubiquitin-like modifier (SUMO) level of hypoxia inducible factor- 1 α (HIF-1 α) protein in myocardial tissue was detected by kit．The mRNA and protein levels of SENP-1 and HIF- 1 α in myocardial tissue were detected by qRT-PCR and Western blot. Results : Compared with the control group， the pathological damage of myocardial tissue in CIH group was serious，the levels of left ventricular end diastolic diameter (LVEDD) ，left ventricular end systolic dimension (LVESD) and serum cTNI，CKMB，Mb and LDH signif- icantly increased (P＜0. 05) ，and the levels of ROS，MDA，IL-1 β , IL-6，TNF-α and the mRNA and protein levels of SENP-1 and HIF-1α in myocardial tissue also significantly increased (P ＜0. 05 ) ，while the levels of LVEF， LVFS，serum GSH and SOD significantly decreased (P ＜0. 05) ，and the SUMOylates level of HIF-1α protein in myocardial tissue also significantly decreased (P ＜0. 05 ) ．Compared with CIH group，AAV-shSENP-1 group had less myocardial pathological damage，the levels of LVEDD，LVESD and serum cTNI，CKMB，Mb and LDH signifi- cantly decreased (P＜0. 05) ，and the levels of ROS，MDA，IL-1 β, IL-6，TNF-α and the mRNA and protein levels of SENP-1 and HIF-1α in myocardial tissue also significantly decreased (P＜0. 05) ，the levels of LVEF，LVFS，serum GSH and SOD significantly increased (P＜0. 05) ，and the SUMOylates level of HIF-1α protein in myocardial tissue also significantly decreased (P＜0. 05) ． Conclusion Inhibition of SENP-1 expression can alleviate CIH induced myocarditis and oxidative stress in rats，improve myocardial injury and cardiac dysfunction，and its mechanism may be related to the improvement of HIF-1α SUMOylates level，thus inhibiting HIF-1α expression.

Abstract OBJECTIVE Oxcarbazepine(OXC) is an antiepileptic drug, which is metabolized to the active 10-monohydroxy derivative(MHD) after oral administration. The half-life period of MHD in children is significantly shorter than that in adults, and the clearance is increased by 30% to 160% compared with that in adults, which indicates that the pharmacokinetics(PK) of MHD in children is obviously different from that in adults, while adults and children exhibit different levels of expression of metabolism enzymes and transporter proteins with the same genotype. At present, there is no study describing the influence of genetic polymorphism of PK-related enzymes on MHD plasma concentrations in children with epilepsy. This study investigates whether the polymorphism of metabolic enzymes and transporter genes have significant effects on MHD plasma concentrations in children with epilepsy in China, so as to provide the reference for individualized application of OXC in pediatric patients. METHODS The plasma samples from pediatric patients with epilepsy aged 0-14 years old at the First Affiliated Hospital of Fujian Medical University who received OXC were prospective collected from June 2021 to June 2023. The MHD blood concentrations of the patients were measured using enzyme amplified immunoassay, and the metabolic enzyme genes UGT2B7 802T>C, UGT1A9 I399C>T, as well as the transporter genes ABCB1 3435C>T and ABCB2 1249G>A polymorphism were detected using dideoxy chain-termination method in epilepsy children. According to Hardy Weinberg's law of genetic balance, the theoretical values of genotype frequency of the patients were calculated, and a Chi-Square test method was used to compare whether there was a significant difference between the theoretical value and the measured value, to examine whether the genotype of the patients included in the study is accordance with the law of genetic balance. One-way ANOVA statistical method was used to analyze the correlation of the four single nucleotide polymorphisms, daily maintenance dosage of OXC, and MHD blood concentrations. Subsequently, Fisher's least significant difference(LSD) test was performed. LSD test is a pairwise comparison of the differences between the mean values of each group, calculated based on the standard error and degrees of freedom to obtain the minimum significant difference between each two groups, while P<0.05 indicated that the difference was significant. RESULTS In this study, 161 trough concentrations were collected from children with epilepsy. The genotype of the included population conformed to the genetic balance law, which indicated that the included patients were representative for the population. Unite analysis of variance showed a significant correlation between the transporter gene ABCB1 3435C>T and MHD blood drug concentration(P<0.05). Subsequently, Fisher's minimum significant difference test was conducted, and MHD plasma concentrations of patients carrying the ABCB1 3435C>T mutation allele were significantly higher than that of non-carriers. No significant association was found between the four single nucleotide polymorphisms and the daily maintenance dosage of OXC, and no significant impact of the other metabolic enzyme and transporter genetic polymorphisms on MHD plasma concentrations was found. CONCLUSION The results of research shows that the ABCB1 3435C>T polymorphism significantly affect the MHD blood concentration of pediatric patients with epilepsy, and the effects of UGT2B7 802T>C, UGT1A9 I399C>T and ABCB2 1249G>A genetic polymorphisms on MHD blood concentration and daily maintenance dosage of OXC are not found. The results suggest that MHD blood concentrations are significantly increased by affecting the expression of the encoded MDR1 transporter protein after ABCB1 3435C>T site mutation, which also may increase the risk of adverse reactions of OXC. The genetic polymorphisms of ABCB1 3435C>T can be detected in children with epilepsy when taking OXC, and the dosage can be adjusted appropriately for patients with genetic mutations. The results of this study can provide the reference for the individualized administration of OXC in clinic.

Multiple myeloma (MM) is still an incurable hematologic malignancy, which is eagerly to the discovery of novel therapeutic targets and methods. N-acetyltransferase 10 (NAT10) is the first reported regulator of mRNA acetylation that is activated in many cancers. However, the function of NAT10 in MM remains unclear. We found significant upregulation of NAT10 in MM patients compared to normal plasma cells, which was also highly correlated with MM poor outcome. Further enforced NAT10 expression promoted MM growth in vitro and in vivo, while knockdown of NAT10 reversed those effects. The correlation analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and ribosome profiling sequencing (Ribo-seq) combined with RIP-PCR tests identified centrosomal protein 170 (CEP170) as an important downstream target of NAT10. Interfering CEP170 expression in NAT10-OE cells attenuated the acceleration of cellular growth caused by elevated NAT10. Moreover, CEP170 overexpression promoted cellular proliferation and chromosomal instability (CIN) in MM. Intriguingly, remodelin, a selective NAT10 inhibitor, suppressed MM cellular growth, induced cellular apoptosis in vitro and prolonged the survival of 5TMM3VT mice in vivo. Collectively, our data indicate that NAT10 acetylates CEP1 70 mRNA to enhance CEP170 translation efficiency, which suggests that NAT10 may serve as a promising therapeutic target in MM.

Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.
Biomarkers ; Carrier Proteins ; Child ; Humans ; Immunoglobulin Fc Fragments ; Immunoglobulin G ; Macrolides ; Mycoplasma pneumoniae ; Pneumonia, Mycoplasma/drug therapy* ; Proteomics