OBJECTIVE To systematically analyze the population pharmacokinetics （PPK） studies of lacosamide and expound the influential factors of its pharmacokinetics in different populations. METHODS PPK studies of lacosamide were collected by searching the databases， such as Web of Science， PubMed， Embase， Metasearch， CNKI， Wanfang Data and VIP， both in Chinese and English. Relevant data were extracted， and the Prediction Model Risk of Bias Assessment Tool was used to evaluate the quality of the PPK models in the included studies. RESULTS Among 8 studies ultimately included， 6 were retrospective studies and 2 were prospective studies； 5 studies involved pediatric patients. Seven studies adopted a one-compartment model， while 1 study utilized a two-compartment model. Four studies had a model quality rating of grade A， two of grade B and two of grade C， respectively. Body weight， renal function， and hepatic enzyme inducers were significant covariates influencing PPK of lacosamide. CONCLUSIONS The existing PPK studies of lacosamide are predominantly conducted in pediatric populations. Pharmacokinetic variability is mainly influenced by body weight， renal function， and hepatic enzyme inducers. However， most PPK studies have not conducted external validation， and the generalizability of the models remains to be confirmed.

Objective To investigate the feasibility and safety of transradial approach(TRA)for carotid artery stenting(CAS)using single-layer braided carotid stents with a microporous dense mesh design.Methods A retrospective consecutive series of patients with carotid artery stenosis who underwent CAS via TRA using single-layer braided microporous dense mesh stents admitted to the Department of Neurology,Linyi People's Hospital,Shandong Second Medical University were included from December 2022 to April 2023.General and clinical data,lesion characteristics,procedural metrics,periprocedural conditions,and follow-up outcomes were collected from the patients.General and clinical data including sex,age,medical history(hypertension,diabetes,coronary artery disease),and preoperative modified Rankin scale(mRS)score.Lesion characteristics included stenosis location,normal lumen diameters distal and proximal to the stenosis,stenosis rate,lesion length,and aortic arch type.Procedural metrics included successfully guided catheter placement,stent deployment,retrieval of the embolic protection device and residual stenosis rate.Periprocedural conditions included periprocedural complications(within 72 hours included puncture site bleeding,symptomatic radial artery occlusion,new cerebral infarctions on diffusion-weighted imaging,and cardio-cerebrovascular events[angina,acute myocardial infarction,cerebral infarction,cerebral hemorrhage])and length of hospital stay.The mRS scores at 1 and 6 months after surgery were recorded via telephone follow-ups.At 12 months after surgery,outpatient carotid color Doppler ultrasound was performed to evaluate in-stent restenosis.Results(1)Ten patients(9 male,1 female)aged 57-72 years,with a median age of 70(62,71)years were included.Among them,9 had hypertension,2 had diabetes,and 1 had coronary artery disease.Four patients had symptomatic carotid stenosis:2 presented with hemiparesis,1 with mild dysarthria,and 1 with transient ischemic attack.Preoperative mRS scores among symptomatic patients were 0(1 patient),1(2 patients),and 2(1 patient).The remaining 6 patients had asymptomatic stenosis,all with preoperative mRS scores of 0.(2)Two patients had left internal carotid artery(ICA)stenosis,and 8 had right ICA stenosis.The mean stenosis degree was(79.9±7.1)％,and the mean lesion length was(16.8±5.7)mm.The mean normal distal and proximal lumen diameter of the stenosed blood vessel were(5.1±0.5)mm and(8.1±0.8)mm,respectively.One patient had a type Ⅰ aortic arch,8 patients had type Ⅱ,and 1 patient had type Ⅲ.Among the 8 patients with right ICA stenosis,4 underwent direct catheterization of the right common carotid artery using a glidewire,while the other 4 required exchange technique for guide catheter placement.Both left-sided lesions were treated using exchange technique.Guide catheter placement and stent deployment were successful in all cases.No difficulties were encountered in embolic protection device retrieval.The mean residual stenosis rate was(21.6±6.7)％.(3)The mean postoperative hospital stay was(1.8±0.9)days.No puncture site bleeding or symptomatic radial artery occlusion occurred.One patient experienced a cerebrovascular event due to a pontine perforator artery infarction,presenting with diplopia and impaired left eye adduction,likely caused by postoperative hypotension and hypoperfusion.This patient had an immediate postoperative mRS score of 2 at discharge,which improved to 0 at 6 months.The other 9 patients showed no change in mRS scores compared to preoperative assessments,and no new cerebral infarctions were detected within 72 hours after surgery.At 12-month follow-up,carotid color Doppler ultrasound revealed no in-stent restenosis in any patient.Conclusions CAS performed via TRA using single-layer braided microporous dense mesh stents appears to be feasible and safe.However,this study is a single-center,retrospective analysis with a small sample size.Larger prospective randomized controlled trials are needed to validate these findings.

OBJECTIVE To establish population pharmacokinetic model of levetiracetam （Lev） for Chinese patients with post- stroke epilepsy （PSE）， and provide reference for formulating individualized dosing regimens for Lev therapy in this specific population. METHODS Blood concentration data and clinical diagnosis and treatment information of PSE patients meeting the inclusion criteria were retrospectively collected and divided into model group and validation group at an 8∶2 ratio using a random number method. Based on the model group data， a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Internal evaluation was performed through goodness-of-fit tests and bootstrap analysis， while external validation was conducted using the validation group data. RESULTS A total of 75 blood concentration measurements from 70 PSE patients were collected， with 60 measurements from 55 patients used for model development and 15 measurements from 15 patients reserved for external validation. The final model estimated a population typical value of clearance at 2.98 L/h. Estimated glomerular filtration rate， daily dose， and homocysteine level significantly influenced clearance of Lev （P＜0.01）. The model demonstrated satisfactory predictive performance， as evidenced by goodness-of-fit tests， bootstrap analysis， and external validation results. CONCLUSIONS Daily dose， estimated glomerular filtration rate， and homocysteine level are identified as significant covariates influencing Lev clearance in Chinese PSE patients. When making clinical decisions， comprehensive consideration should be given to the patient’s treatment response， physiological and pathological conditions， and the occurrence of adverse reactions， etc. The dosage of Lev should be adjusted based on the results of population pharmacokinetic model.

Objective To investigate the comparative neuroprotective effects of human umbilical cord mesenchymal stem cells(hUC-MSCs-Exos)administered via different routes on hypoxic ischemic brain damage(HIBD)in neonatal mice.Methods Healthy one-week-old SPF-grade BALB/c mice were randomly divided into 4 groups:sham operation group(n=6),model group(n=6),exosome group 1(n=8),exosome group 2(n=8).HIBD was induced using the Rice-Vannucci method.Exosome group 1 and Exosome group 2 were intraperitoneal injection/intranasal drip of phosphate buffer(PBS)100 μl containing 10 μl exosomes within 24 h after successful modeling,respectively.Sham operation and model groups were intraperitoneal injection of PBS 100 μl.On the 7th day after the intervention,neuromotor function was assessed using the horizontal grid test and pole climbing test.On the 2nd day after the evaluation,all mice were killed and their brains were removed by decapitation.HE staining was used to observe the pathological injury of brain tissue,toluidine blue staining was used to observe the survival of neurons in cerebral cortex,and TUNEL staining was used to observe the apoptosis of cerebral cortex cells.Results Compared with sham operation group,model group,exosome group 1 and exosome group 2 exhibited increased hind limb drops in horizontal grid test and climbing scores(P<0.05).No significant difference was found in model group,exosome group 1 and exosome group 2 in these measures(P<0.05).Significant pathology was observed in model group,exosome group 1 and exosome group 2 compared to sham operation group(P<0.05),with significantly reduced damage in exosome group 1 and exosome group 2 compared to model group(P<0.05).Compared with sham operation group,Nissl body count was lower in model group and exosome group 1 and exosome group 2,with a higher count in exosome group 2 compared to exosome group 1(P<0.05).Compared with sham operation group,apoptotic cells were higher in model group and exosome group 1 and exosome group 2,with a significant reduction in exosome group 1 and exosome group 2 compared to model group,and the lowest in exosome group 2(P<0.05).Conclusions hUC-MSCs-Exos can improve the neuronal motor function,promote neuron repair and inhibit apoptosis in HIBD mice.Intranasal administration of hUC-MSCs-Exos is more effective than intraperitoneal administration for reducing neuronal apoptosis in HIBP neonatal mice,offering a convenient and rapid method suitable for clinical application.

Objective To investigate the feasibility and safety of transradial approach(TRA)for carotid artery stenting(CAS)using single-layer braided carotid stents with a microporous dense mesh design.Methods A retrospective consecutive series of patients with carotid artery stenosis who underwent CAS via TRA using single-layer braided microporous dense mesh stents admitted to the Department of Neurology,Linyi People's Hospital,Shandong Second Medical University were included from December 2022 to April 2023.General and clinical data,lesion characteristics,procedural metrics,periprocedural conditions,and follow-up outcomes were collected from the patients.General and clinical data including sex,age,medical history(hypertension,diabetes,coronary artery disease),and preoperative modified Rankin scale(mRS)score.Lesion characteristics included stenosis location,normal lumen diameters distal and proximal to the stenosis,stenosis rate,lesion length,and aortic arch type.Procedural metrics included successfully guided catheter placement,stent deployment,retrieval of the embolic protection device and residual stenosis rate.Periprocedural conditions included periprocedural complications(within 72 hours included puncture site bleeding,symptomatic radial artery occlusion,new cerebral infarctions on diffusion-weighted imaging,and cardio-cerebrovascular events[angina,acute myocardial infarction,cerebral infarction,cerebral hemorrhage])and length of hospital stay.The mRS scores at 1 and 6 months after surgery were recorded via telephone follow-ups.At 12 months after surgery,outpatient carotid color Doppler ultrasound was performed to evaluate in-stent restenosis.Results(1)Ten patients(9 male,1 female)aged 57-72 years,with a median age of 70(62,71)years were included.Among them,9 had hypertension,2 had diabetes,and 1 had coronary artery disease.Four patients had symptomatic carotid stenosis:2 presented with hemiparesis,1 with mild dysarthria,and 1 with transient ischemic attack.Preoperative mRS scores among symptomatic patients were 0(1 patient),1(2 patients),and 2(1 patient).The remaining 6 patients had asymptomatic stenosis,all with preoperative mRS scores of 0.(2)Two patients had left internal carotid artery(ICA)stenosis,and 8 had right ICA stenosis.The mean stenosis degree was(79.9±7.1)％,and the mean lesion length was(16.8±5.7)mm.The mean normal distal and proximal lumen diameter of the stenosed blood vessel were(5.1±0.5)mm and(8.1±0.8)mm,respectively.One patient had a type Ⅰ aortic arch,8 patients had type Ⅱ,and 1 patient had type Ⅲ.Among the 8 patients with right ICA stenosis,4 underwent direct catheterization of the right common carotid artery using a glidewire,while the other 4 required exchange technique for guide catheter placement.Both left-sided lesions were treated using exchange technique.Guide catheter placement and stent deployment were successful in all cases.No difficulties were encountered in embolic protection device retrieval.The mean residual stenosis rate was(21.6±6.7)％.(3)The mean postoperative hospital stay was(1.8±0.9)days.No puncture site bleeding or symptomatic radial artery occlusion occurred.One patient experienced a cerebrovascular event due to a pontine perforator artery infarction,presenting with diplopia and impaired left eye adduction,likely caused by postoperative hypotension and hypoperfusion.This patient had an immediate postoperative mRS score of 2 at discharge,which improved to 0 at 6 months.The other 9 patients showed no change in mRS scores compared to preoperative assessments,and no new cerebral infarctions were detected within 72 hours after surgery.At 12-month follow-up,carotid color Doppler ultrasound revealed no in-stent restenosis in any patient.Conclusions CAS performed via TRA using single-layer braided microporous dense mesh stents appears to be feasible and safe.However,this study is a single-center,retrospective analysis with a small sample size.Larger prospective randomized controlled trials are needed to validate these findings.

Objective:To identify the gene mutation types of 4 suspected β-thalassemia patients in Yunnan Province,and to analyze the genotypes and hematological phenotypes.Methods:Whole genome sequencing was performed on the samples of 4 suspected β-thalassemia patients from the Dai ethnic group in a thalassemia endemic area of Yunnan Province,whose hematological phenotypes were not consistent with the results of common thalassemia gene mutations.The mutations of β-globin gene clusters were confirmed by polymerase chain reaction(PCR)and Sanger DNA sequencing technology.Results:The 3.5 kb deletion in β-globin gene cluster(NC_000011.10:g.5224302-5227791 del3490bp)was detected in 4 patients'samples,of which 1 case was also detected with HbE mutation and 1 case with CD17 mutation.These 2 patients displayed moderate anemia phenotype,while the two patients with only the 3.5 kb deletion presented with other mild anemia phenotype.Conclusion:Heterozygous carriers with rare 3.5 kb deletion of the β-globin gene cluster may develop mild anemia,compound mutations of the 3.5 kb deletion with other mutations may led to intermediate thalasemia with moderate to sever anemia.In areas with a high incidence of thalassemia,suspected patients should undergo genetic testing to avoid missing or misdiagnosing rare mutations.

The research focus of diabetes, a common chronic metabolic disease, has shifted from individual factors to environmental factors at the population level. Epidemiological studies suggest an association between exposure to environmental pollutants and the risk of diabetes. Major environmental pollutants include organochlorine pesticides, polychlorinated biphenyls, phthalates and their metabolites, and arsenics, which primarily enter the human body through the skin, respiratory tract, and digestive system. Long-term exposure to these pollutants can affect the pathology of diabetes through various mechanisms, such as promoting insulin resistance, causing insulin secretion deficiencies, inducing oxidative stress-induced glucose metabolism disorders, and affecting DNA methylation. However, the potential damaging mechanism of the impact of environmental pollutants on diabetes remain unclear. Limitations such as insufficient sample sizes, uncertainties regarding exposure time and dosage, and differences between single and co-exposures. In the future, it is necessary to focus on exploring and analyzing the mechanisms of environmental pollutant exposure on diabetes to develop effective prevention strategies, control and reduce the incidence and development of diabetes, and provide new insights into its diagnosis and treatment.

Sucrose synthase plays a crucial role in the plant sugar metabolism pathway by catalyzing the production of uridine diphosphate (UDP)-glucose, which serves as a bioactive glycosyl donor for various metabolic processes. In this study, a sucrose synthase gene named CtSus was cloned from Cistanche tubulosa, a traditional Chinese medicine known for its rich content of diverse glycosides, based on transcriptome analysis results. The open reading frame of CtSus was 2 418 bp long encoding 805 amino acids. Sequence analysis revealed conserved domains associated with the plant sucrose synthase family at both the N-terminal and C-terminal regions of CtSus protein. Phylogenetic analysis demonstrated that CtSus shares a close evolutionary relationship with sucrose synthases from other plants within the same order. Functional identification of CtSus was performed through whole-cell catalysis coupling with UGT71BD1, a characterized glycosyltransferase enzyme. The results showed that the introduction of CtSus significantly enhanced the conversion rate of glycosylation catalyzed by UGT71BD1. The soluble expression of CtSus in Escherichia coli was further achieved using the pCold^TM TF expression vector. In vitro enzymatic assay indicated the activity of CtSus to catalyze the formation of UDP-glucose in the presence of sucrose and UDP. Real-time quantitative-polymerase chain reaction results showed that the expression patterns of CtSus gene in different parts of C. tubulosa and the suspension cell cultures of C. tubulosa under drought stress correlated with the accumulation patterns observed for phenylethanol glycosides, respectively. Furthermore, key amino acids and their interactions between enzyme and substrate were explored based on protein structure prediction and molecular docking results. Overall, our findings identify a sucrose synthase CtSus responsible for the supply of the active glycosyl donor UDP-glucose during the biosynthesis of glycoside products in C. tubulosa and have also provided a gene element that can be utilized in engineering strain construction for glycoside products production.

Objective To analyze the clinical characteristics and prognosis of patients with coronary slow flow(CSF)or no reflow(CNR)after emergency PCI.Methods A total of 443 elderly STEMI patients who underwent emergency PCI in Department of Cardiology of the First Affilia-ted Hospital of Tsinghua University from January 2017 to August 2023 were recruited,and ac-cording to thrombolysis in myocardial infarction(TIMI)flow grading after operation,they were divided into CSF/CNR group(TIMI grade≤2 flow,n=40)and normal flow(NCF)group(TIMI grade 3 flow,n=403).Logistic regression analysis was used to analyze the risk factors for CSF/CNR in STEMI patients after PCI.The prognosis was analyzed in the two groups.Results The CSF/CNR group had advanced age,longer durations from onset to admission and from onset to balloon opening,higher mortality rate,and larger proportions of chronic heart failure(CHF),type 2 diabetes mellitus(T2DM),pulse rate＞100 times/min,SBP＜100 mm Hg(1 mm Hg=0.133 kPa),Killip grade＞1,left anterior descending artery disease,LVEF＜50％,and using glycopro-tein Ⅱb/Ⅲa inhibitors and intraaortic balloon counterpulsation,but lower male ratio and DBP when compared with the control group(P＜0.05,P＜0.01).Multiple logistic regression analysis revealed that T2DM(OR=1.320,95％CI:0.618-2.123,P=0.046),mean SBP(OR=1.239,95％CI:0.752-1.525,P=0.04)and SBP＜100 mm Hg(OR=1.330,95％CI:0.836-1.675,P=0.013)were independent risk factors,while male was a protective factor(OR=-1.755,95％CI:-2.338--1.171,P=0.002)for CSF/CNR in STEMI patients after PCI.Conclusion T2DM and lower SBP are independent risk factors,while male is a protective factor for CSF/CNR in STEMI patients after emergency PCI.

There are few clinical reports on the diagnosis and treatment of upper urinary tract stones secondary to urinary diversion. This study included 30 patients with upper urinary tract stones secondary to urinary diversion, and all of which were successfully managed. The individualized treatment with the ureteroscopy and/or percutaneous nephrolithotripsy with antegrade, retrograde, or a combination of antegrade and retrograde is safe and feasible.