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 A clinical comprehensive evaluation of five biologic targeted drugs for the treatment of severe eosinophilic asthma （SEA） was conducted to provide objective evidence for the rational selection of these medications in medical institutions. METHODS Using the evaluation methods from the Chinese Medical Institution Drug Evaluation and Selection Rapid Guide （ Third Edition ）， the effectiveness， safety， pharmaceutical characteristics， cost-effectiveness， and other attributes of five biologics targeting SEA （omalizumab， mepolizumab， benralizumab， dupilumab， and tezepelumab） already marketed in China were quantitatively scored across five dimensions， and their recommendation levels were categorized based on the scores. RESULTS The comprehensive scoring results showed that mepolizumab scored 81.29， making it a highly recommended variety； benralizumab scored 78.05， dupilumab scored 77.84 and omalizumab scored 70.14，all of which are recommended varieties； tezepelumab scored 67.77， considered weakly recommended variety. CONCLUSIONS Mepolizumab shows excellent performance in eosinophil clearance， good accessibility， and is more cost-effective than the others， making it more selective in SEA treatment； omalizumab has more advantages in the treatment of SEA patients with elevated immunoglobulin E levels； dupilumab can be used as the preferred treatment for SEA patients with chronic obstructive pulmonary disease.

OBJECTIVE A clinical comprehensive evaluation of five biologic targeted drugs for the treatment of severe eosinophilic asthma （SEA） was conducted to provide objective evidence for the rational selection of these medications in medical institutions. METHODS Using the evaluation methods from the Chinese Medical Institution Drug Evaluation and Selection Rapid Guide （ Third Edition ）， the effectiveness， safety， pharmaceutical characteristics， cost-effectiveness， and other attributes of five biologics targeting SEA （omalizumab， mepolizumab， benralizumab， dupilumab， and tezepelumab） already marketed in China were quantitatively scored across five dimensions， and their recommendation levels were categorized based on the scores. RESULTS The comprehensive scoring results showed that mepolizumab scored 81.29， making it a highly recommended variety； benralizumab scored 78.05， dupilumab scored 77.84 and omalizumab scored 70.14，all of which are recommended varieties； tezepelumab scored 67.77， considered weakly recommended variety. CONCLUSIONS Mepolizumab shows excellent performance in eosinophil clearance， good accessibility， and is more cost-effective than the others， making it more selective in SEA treatment； omalizumab has more advantages in the treatment of SEA patients with elevated immunoglobulin E levels； dupilumab can be used as the preferred treatment for SEA patients with chronic obstructive pulmonary disease.

Objective To investigate the effect of Remazolam(RZ)on intestinal injury in burn sepsis rats by regulating the Notch-1/hairy and enhancer of split homolog(Hes)signaling pathway.Methods Sixty SPF grade SD male rats were randomly separated into Normal group,Model group,low-dose RZ group(RZ-L group,3 mg/kg RZ),high-dose RZ group(RZ-H group,6 mg/kg RZ)and high-dose RZ+Notch-1 activator Jagged1 group(RZ-H+Jagged1 group,6 mg/kg RZ+0.67 mg/kg Jagged1),with 12 rats in each group.A burn sepsis model was prepared by establishing a 20%total surface area(TBSA)third-degree burn(burn)model on the back of rats,followed by injection of Pseudomonas aeruginosa.HE staining was applied to observe rat ileum tissue's pathological changes and assess intestinal mucosal damage score(Chiu's score).ELISA method was used to detect the levels of serum endotoxin,D-lactate,diamine oxidase(DAO),interleukin(IL-6),tumor necrosis factor-α(TNF-α)and myeloperoxidase(MPO)in rats.RT-qPCR method was applied to detect the expression of Notch-1 and Hes mRNA in rat ileum tissue,and Western Blot was used to detect the expression of Notch-1/Hes signaling pathway-related proteins in rat ileum tissue.Results Compared with the Normal group,the intestinal mucosal injury score(5.30±0.48 vs 1.00±0.52),serum endotoxin(135.69±16.24 pg/ml vs 62.48±3.23 pg/ml),D-lactate(1403.58±68.97 pg/ml vs 752.06±25.29 pg/ml)and DAO levels(137.55±12.37 pg/ml vs 58.52±4.43 pg/ml),ileal tissue IL-6(186.45±16.37 ng/ml vs 21.32±3.66 ng/ml),TNF-α(163.37±11.40 ng/ml vs 15.52±1.03 ng/ml)and MPO levels(8.94±0.92 U/ml vs 2.35±0.33 U/ml),Notch-1 mRNA(1.86±0.19 vs 1.00±0.10)and protein(0.79±0.08 vs 0.21±0.02),Hes-1 mRNA(2.13±0.21 vs 1.00±0.12)and protein(0.88±0.09,0.32±0.03)expression levels in the Model group were greatly increased,and the differences were statistically significant(t=14.294～47.368,all P<0.05).Compared with the Model group,the corresponding indicators of the RZ-L and RZ-H groups showed opposite changes,and the differences were statistically significant(tRZ-L=5.650～21.448,tRZ-H=4.435～42.403,all P<0.05).The Notch-1 activator Jagged1 weakened the therapeutic effect of RZ on intestinal injury in burn sepsis rats.Conclusion RZ may alleviate intestinal injury in burn sepsis model rats by inhibiting the Notch-1/Hes signaling pathway.

Depression is a common mental dis-ease.At present,there are poor efficacy and drug-related safety problems in antidepressant treat-ment.Toludesvenlafaxine,as a new triple reuptake inhibitor(TRIs/SNDRIs),increases the inhibitory ef-fect of dopamine(DA)reuptake on the basis of se-rotonin(5-HT)and norepinephrine(NE),achieves multi-target synergistic therapy and reduces 5-HT/NE-related adverse drug reactions.This article re-views the basic introduction,preclinical research,clinical efficacy and safety of toludesvenlafaxine,in order to provide more ideas and options for the treatment of depression.

Objective:To explore the value of immature platelets and thromboelastography (TEG) in evaluating bleeding tendency in patients bitten by blood venomous snakes.Methods:In December 2023, a bleeding scoring system was used to grade the bleeding score and degree of bleeding in 147 patients with blood venomous snake bites. Immature platelets and TEG were also tested to analyze the correlation between the bleeding degree of patients and indicators such as TEG, immature platelet ratio (IPF), and absolute value of immature platelets (A-IPF). The measurement data were represented by Mean±SD, and ANOVA was used for comparison among groups. Statistical data were analyzed using χ2 test. Spearman correlation was used to analyze the correlation between bleeding degree and the platelet count (PLT), immature platelet and TEG. Pearson linear correlation was used to analyze the correlation of PLT, immature platelets and TEG. The indexes of immature platelets and TEG were analyzed by receiver operating characteristic curve. Results:The 147 patients were graded for bleeding severity based on their bleeding scores, and divided into mild (22 cases), moderate (119 cases), and severe groups (6 cases), and the clinical data such as age, gender and the time from bite to visit were compared among the three groups. The differences were not statistically significant ( P>0.05). The coagulation reaction time (R), clot formation time (K), and immature platelet parameters (IPF, A-IPF) in TEG parameters increased with the degree of bleeding. PLT decreased with the degree of bleeding, and the difference was statistically significant ( P<0.05). Blood venomous snake bite patients have a negative correlation between PLT and IPF ( r=-0.301, P=0.012), but no correlation with A-IPF ( r=0.072, P=0.461) ; PLT was positively correlated with coagulation Angle (αAngle) and maximum thrombus amplitude (MA) of TEG ( r=0.220、0.243, P=0.028、0.015), but negatively correlated with R value and K value ( r=-0.368、-0.362, P<0.001). IPF is positively correlated with R and K values ( r=303、271, P=0.0020、0.035) ; IPF is not correlated with MA value and Angle angle, while A-IPF is positively correlated with R value ( r=0.162, P<0.001). The degree of bleeding in patients is positively correlated with R value ( r=0.237, P<0.001), but not with K value, MA value, and Angle angle ( P>0.05) ; The degree of bleeding in patients is correlated with PLT ( r=-0.411, P<0.001). The ROC curve analysis results show that the R value, K value, and MA value are effective in evaluating the bleeding risk of blood venomous snake bites in patients, and the PLT combined with A-IPF has the best efficacy in evaluating the bleeding risk of blood venomous snake bites in patients. Conclusion:The combination of PLT and A-IPF, TEG's R value, K value, MA value indicators can accurately evaluate the bleeding risk of blood venomous snake bites, and can be widely used in clinical practice as an important prediction method for bleeding tendency in patients bitten by blood venomous snakes.

Objective:To analyze the clinical characteristics and genetic profile of patients with 46, XY Disorders of sex development (DSD) and a female phenotype in order to provide insights for the diagnosis and management of similar cases.Methods:A retrospective analysis was conducted on 36 children with 46, XY DSD and a female phenotype who were treated at the Department of Endocrinology, Genetics and Metabolism of Henan Children′s Hospital between March 1, 2016, and June 30, 2024. The evaluations included external genitalia scoring using the Prader scale and External Masculinization Score (EMS), imaging studies to assess gonadal development, and assessments of adrenal and gonadal function via adrenal hormone levels, sex hormone levels, and human chorionic gonadotropin (hCG) stimulation testing. Gender role behavior was assessed using gender role scales and sandplay therapy. Whole exome sequencing and Sanger sequencing were used to identify and validate genetic variants. A multidisciplinary team (MDT) comprehensively determined gender rearing based on molecular genetic diagnosis. This study was approved by the Medical Ethics Committee of Henan Children′s Hospital (Ethics No.: 2024-K-105).Results:The median age at initial consultation was 3 years and 1 month (range: 7 days to 16 years). Common symptoms included primary amenorrhea, clitoromegaly, and inguinal hernia. Fully feminized external genitalia were observed in 52.7% of the cases, and 80.5% had absence of the uterus. Internal gonads included absent gonads (5.6%), ovotestes (8.3%), streak gonads (5.6%), cryptorchidism (75.0%), and normally positioned testes (5.6%). At initial diagnosis, median luteinizing hormone (LH) was 1.305 IU/L, with elevated LH in 14 cases. Median follicle-stimulating hormone (FSH) was 4.87 IU/L, with elevated FSH in 17 cases. Median testosterone was 0.025 ng/mL. Median dihydrotestosterone (DHT) was 36.90 pg/mL. After hCG stimulation, median testosterone was 0.984 ng/mL and median DHT was 71.69 pg/mL. The testosterone/DHT ratio was elevated in one case (35.7). Testosterone levels remained below 1 ng/mL after hCG stimulation in 18 cases. Anti-Müllerian hormone (AMH) was decreased in 15 cases and increased in 3 cases. Inhibin B (InhB) was increased in 7 cases and decreased in 4 cases. Pathogenic variants were detected in 88.9% of the patients, involving AR (11 cases), CYP17A1 (4 cases), GATA4 (1 case), NR0B1 (1 case), NR5A1 (7 cases), SRD5A2 (1 case), WT1 (2 cases), STAR (4 cases), and LHCGR (1 case), totaling 34 variant sites. Among these, 9 variants were de novo, and 23 were inherited from parents. Sixteen variant sites were previously unreported. Gender assignment was male in 11 cases (30.6%) and female in 25 cases (69.4%). Conclusion:Common symptoms in 46, XY DSD patients with a female phenotype include primary amenorrhea, clitoromegaly, and inguinal hernia. Elevated FSH, androgen deficiency, and decreased AMH and InhB may indicate testicular dysgenesis or impaired androgen synthesis. Adrenal insufficiency should raise suspicion for defects in steroid hormone synthesis pathway enzymes.

Purpose To investigate the clinicopathological features,differential diagnosis and prognosis of atypical fibroxanthoma(AFX).Methods Pathological features of 15 cases of AFX and 3 cases of pleomorphic dermal sarcoma(PDS)misdiagnosed as AFX were retrospectively analyzed by hematoxylin and eosin staining and immunohistochemical EnVision staining technology.Clinical information was collected and analyzed,and the relevant literatures were re-viewed.Results The age of the 15 patients with AFX ranged from 18 to 78 years,with an average age of 57 years.4 cases occurred in the head and neck,and 11 cases occurred in the trunk and limbs.3 patients with PDS misdiagnosed as AFX were aged from 56 to 60 years,with an average age of 58 years.The tumors were located in the trunk and limbs.Microscopically,15 cases of AFX and 3 cases of PDS misdiagnosed as AFX were composed of proliferative pleo-morphic and atypical spindle cells interspersed with a varying number of multinucleated cells.15 cases of AFX tumors were superficial and located in the dermis.In 3 cases of PDS misdiagnosed as AFX,1 case was located in subcutane-ous adipose tissue,1 case had superficial subcutaneous extension,and the third case had positive basal margin.Immu-nohistochemically,the immunophenotypes of the two groups were consistent.CD10 was expressed in all cases,CD68 was positive in most cases,SMA was expressed in a few cases,desmin was focal expressed in a very few cases,and S-100,SOX10,CD34,HMB-45,Melan A,STAT6 and CK(AE1/AE3)were not expressed in all cases.Ki67 prolifera-tion index ranged from 2％to 30％.15 patients with AFX were followed up from 12 to 108 months.One patient had tumor recurrence 1 year and 3 years after operation due to positive basal margin.Most of the other patients underwent extended resection after diagnosis and were in good condition without tumor recurrence and metastasis.3 cases of PDS misdiagnosed as AFX were followed up for 31 to 78 months.One patient had lung metastasis after 2 years,one patient recurred 4 times after operation,and the other patient died after 4 times of recurrence.Conclusion AFX is a rare dis-ease with similar pathological characteristics and immunophenotype to PDS.AFX can be diagnosed only when the tumor is small and completely confined to the dermis.When the maximum diameter of the tumor is more than 3 cm,or the presence of any form of subcutaneous extension requires a high level of vigilance for PDS.Careful differentiation and correct classification of AFX and PDS are very important for the treatment and prognosis of the disease.

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 analyze the clinical characteristics and genetic profile of patients with 46,XY Disorders of sex development (DSD) and a female phenotype in order to provide insights for the diagnosis and management of similar cases. METHODS: A retrospective analysis was conducted on 36 children with 46,XY DSD and a female phenotype who were treated at the Department of Endocrinology, Genetics and Metabolism of Henan Children's Hospital between March 1, 2016, and June 30, 2024. The evaluations included external genitalia scoring using the Prader scale and External Masculinization Score (EMS), imaging studies to assess gonadal development, and assessments of adrenal and gonadal function via adrenal hormone levels, sex hormone levels, and human chorionic gonadotropin (hCG) stimulation testing. Gender role behavior was assessed using gender role scales and sandplay therapy. Whole exome sequencing and Sanger sequencing were used to identify and validate genetic variants. A multidisciplinary team (MDT) comprehensively determined gender rearing based on molecular genetic diagnosis. This study was approved by the Medical Ethics Committee of Henan Children's Hospital (Ethics No.: 2024-K-105). RESULTS: The median age at initial consultation was 3 years and 1 month (range: 7 days to 16 years). Common symptoms included primary amenorrhea, clitoromegaly, and inguinal hernia. Fully feminized external genitalia were observed in 52.7% of the cases, and 80.5% had absence of the uterus. Internal gonads included absent gonads (5.6%), ovotestes (8.3%), streak gonads (5.6%), cryptorchidism (75.0%), and normally positioned testes (5.6%). At initial diagnosis, median luteinizing hormone (LH) was 1.305 IU/L, with elevated LH in 14 cases. Median follicle-stimulating hormone (FSH) was 4.87 IU/L, with elevated FSH in 17 cases. Median testosterone was 0.025 ng/mL. Median dihydrotestosterone (DHT) was 36.90 pg/mL. After hCG stimulation, median testosterone was 0.984 ng/mL and median DHT was 71.69 pg/mL. The testosterone/DHT ratio was elevated in one case (35.7). Testosterone levels remained below 1 ng/mL after hCG stimulation in 18 cases. Anti-Müllerian hormone (AMH) was decreased in 15 cases and increased in 3 cases. Inhibin B (InhB) was increased in 7 cases and decreased in 4 cases. Pathogenic variants were detected in 88.9% of the patients, involving AR (11 cases), CYP17A1 (4 cases), GATA4 (1 case), NR0B1 (1 case), NR5A1 (7 cases), SRD5A2 (1 case), WT1 (2 cases), STAR (4 cases), and LHCGR (1 case), totaling 34 variant sites. Among these, 9 variants were de novo, and 23 were inherited from parents. Sixteen variant sites were previously unreported. Gender assignment was male in 11 cases (30.6%) and female in 25 cases (69.4%). CONCLUSION Common symptoms in 46,XY DSD patients with a female phenotype include primary amenorrhea, clitoromegaly, and inguinal hernia. Elevated FSH, androgen deficiency, and decreased AMH and InhB may indicate testicular dysgenesis or impaired androgen synthesis. Adrenal insufficiency should raise suspicion for defects in steroid hormone synthesis pathway enzymes.
Humans ; Female ; Disorder of Sex Development, 46,XY/diagnosis* ; Child ; Male ; Phenotype ; Child, Preschool ; Retrospective Studies ; Adolescent ; Infant