Epidermal growth factor receptor-tyrosine kinase inhibitor （EGFR-TKI） represent a class of small-molecule targeted therapeutics for oncology treatment， and serve as first-line therapy for advanced non-small cell lung cancer （NSCLC） with EGFR- sensitive mutations， with representative agents including gefitinib， dacomitinib， and osimertinib. In clinical practice， dose adjustment of EGFR-TKI may be required for cancer patients under special circumstances such as drug combinations or hepatic/ renal impairment. Physiologically-based pharmacokinetic （PBPK） model， capable of predicting pharmacokinetic （PK） processes in humans， has emerged as a vital tool for clinical dose optimization. This article sorts the modeling methodologies， workflows， and commonly used software tools for PBPK model， and summarizes the current applications of PBPK model in EGFR-TKI precision therapy as of June 30， 2024. Findings demonstrate that PBPK modeling methods commonly employ the “bottom-up” approach and the middle-out approach. The process typically involves four steps： parameter collection， compartment selection， model validation， and model application. Commonly used software for modeling includes Simcyp， GastroPlus， and open-source software such as PK- Sim. PBPK model can be utilized for predicting drug-drug interactions of EGFR-TKI co-administered with metabolic enzyme inducers or inhibitors， acid-suppressive drugs， or traditional Chinese and Western medicines. It can also adjust dosages in conjunction with genomics， predict PK processes in special populations （such as patients with liver or kidney dysfunction， pediatric patients）， evaluate the efficacy and safety of drugs， and extrapolate PK predictions from animal models to humans.

BACKGROUND:Repetitive trans-spinal magnetic stimulation(rTSMS)can inhibit inflammatory responses following spinal cord injury.rTSMS applies magnetic field stimulation to the spinal cord region to modulate neuronal excitability and synaptic transmission,thereby promoting plasticity and repair of the nervous system. OBJECTIVE:To observe the effects of rTSMS on the Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB/NLRP3 signaling pathway after spinal cord injury and explore its mechanism in promoting motor function recovery. METHODS:Male C57BL/6J mice,SPF grade,were randomly divided into sham surgery group,spinal cord injury group,and rTSMS group.The latter two groups of mice were anesthetized and the T9 vertebral plate was removed using rongeur forceps to expose the spinal cord,and the spinal cord was clamped using a small aneurysm clip for 20 seconds to establish the spinal cord injury model.Mice in the rTSMS group underwent a 21-day rTSMS intervention starting on day 1 after spinal cord injury.The stimulation lasted 10 minutes per day,5 days per week with an interval of 2 days.Basso Mouse Scale scores were used to assess motor function recovery in mice after spinal cord injury at 1,3,7,14,and 21 days after spinal cord injury.Western blot was employed to detect the expression of AQP4,apoptotic factors Bax,Bcl-2,CL-Caspase-3,inflammatory factors tumor necrosis factor-α,interferon-γ,interleukin-6,interleukin-4,and the TLR4/NF-κB/NLRP3 signaling pathway related proteins in the injured spinal cord.Oxidative stress assay kit was used to measure the activity of superoxide dismutase,glutathione peroxidase,and malondialdehyde content at the site of spinal cord injury.Immunofluorescence staining was performed to detect the expression of neuronal nuclei(NeuN). RESULTS AND CONCLUSION:The Basso Mouse Scale score in the rTSMS group was significantly higher than that in the spinal cord injury group(P<0.05).Compared with the spinal cord injury group,the rTSMS group showed a reduction in spinal cord water content.The expression of AQP4 protein,malondialdehyde content,and expression of Bax,Bcl-2,CL-Caspase-3,tumor necrosis factor-α,interferon-γ,interleukin-6,and TLR4/NF-κB/NLRP3 signaling pathway related proteins were all decreased in the rTSMS group,while the activities of superoxide dismutase and glutathione peroxidase,as well as the expression of Bcl-2,interleukin-4,and NeuN,were all increased(P<0.05).These results suggest that rTSMS downregulates the expression of proteins related to the TLR4/NF-κB/NLRP3 signaling pathway,alleviating symptoms after spinal cord injury such as spinal cord edema,oxidative stress,apoptosis,and inflammation,exerting neuroprotective effects,and thereby promoting the recovery of hindlimb motor function after spinal cord injury.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

Objective:To explore the protective effect of miR-346 up-regulated by crocin on myocardial ischemia reperfusion injury in rats.Methods:The rat model of myocardial ischemia reperfusion was constructed by open-chest ligation of the left anterior descending coronary artery followed by reperfusion. Fifty male SD rats were randomly divided into the sham operation group, model group, crocin group, miR-346 negative control (miR-NC) group, and miR-346 inhibitor group with 10 rats in each group. Rats in the sham operation group were only received thoracotomy without ligation. Rats in the miR-NC group and miR-346 inhibitor group were injected with miR-NC or miR-346 inhibitor through the tail vein 48 h prior to ligation of the left anterior descending coronary artery ligation. The crocetin reagent for gastric lavage was prepared by dissolving 8 mg of crocetin in 100 ml of physiological saline. Rats in the crocetin group, miR-NC group, and miR-346 inhibitor group were gavaged with crocetin reagent at 80 mg/kg. Rats in the sham operation group and model group were gavaged with saline at 5 ml/kg. The crocetin reagent and saline were gavaged once a day for 15 days. Serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were detected by enzyme-linked immunosorbent assay (ELISA). The miR-346 expression level was detected by real-time fluorescence quantitative PCR (qRT-PCR). The pathological changes in cardiac muscle tissues were detected by HE staining. Cardiomyocyte apoptosis rate was detected by TUNEL staining. The expression levels of apoptosis-related proteins were detected by Western Blot.Results:Compared with the sham operation group, the serum levels of CK-MB and LDH, pathological scores, cardiomyocyte apoptosis rate and expression of cleaved cysteinyl aspartate specific proteinase-3 (cleaved Caspase-3) and B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) were increased in the model group (all P < 0.05), and the miR-346 expression level and Bcl-2 levels in myocardial tissues were decreased (all P < 0.05). Compared with the model group, serum CK-MB and LDH levels, pathological scores, cardiomyocyte apoptosis rate, and cleaved Caspase-3 and Bax expression levels were decreased in the crocin group (all P < 0.05), and miR-346 expression level and Bcl-2 levels in the myocardial tissues were increased (all P < 0.05). Compared with the miR-NC group, the serum levels of CK-MB, LDH, pathological scores, cardiomyocyte apoptosis rate, and cleaved Caspase-3 and Bax expression levels were decreased in the miR-346 inhibitor group (all P < 0.05), and miR-346 expression level and Bcl-2 level were increased in myocardial tissues (all P < 0.05). Conclusions:Crocin can reduce myocardial tissue injury and attenuate cardiomyocyte apoptosis in myocardial ischemia-reperfusion rats by up-regulating miR-346.

Objective:To establish a general method for the simultaneous determination of hydroxyphenyl esters and quaternary ammonium bacteriostatic agents in eye drops.Methods:The chromatographic analysis was per-formed on an Agilent C18 column(4.6 mm ×250 mm,5 μm)with 1％triethylamine solution(pH adjusted to 5.0 with phosphoric acid)as mobile phase A and methanol as mobile phase B.Gradient elution was performed at col-umn temperature of 40 ℃.The detection wavelength was 214 nm,the flow rate was 1 mL·min-1,and the injec-tion volume was 20 μL.Results:Methylparaben,ethylparaben,propylparaben,butylparaben,benzalkonium chlo-ride and benzalkonium bromide were 0.11-559.0,0.10-513.0,0.10-258.8,0.11-270.5,1.07-537.0 and 1.03-512.8 μg·mL-1,respectively.The linear range was good(r＞0.999).The average recoveries of meth-ylparaben,benzalkonium bromide and benzalkonium chloride were 104.7％(RSD=1.3％),102.6％(RSD=1.1％)and 100.9％(RSD=1.1％),respectively.The contents of bacteriostatic agent in 100 batches of eye drops from 36 varieties of 12 enterprises were determined,and the accurate results were obtained.Conclusion:This meth-od provides a reference for the content quality control and safety evaluation of bacteriostatic agents in eye drops.

This article introduces the connotation of feedback-seeking behavior, analyzes the influencing factors of feedback-seeking behavior of medical students from personal factors, feedback provider situation, hospital organizational environment and social culture and summarizes intervention strategies for feedback-seeking behavior from the perspectives of medical students, teachers and society, so as to provide a basis and guidance for constructing feedback-training programs for medical students, thereby ensuring medical quality and patient safety.

Objective To investigate the value of electrocardiogra(ECG)P-wave parameters com-bined with serum adiponectin and visfatin(VF)in predicting recurrence of atrial fibrillation(AF)after radiofrequency ablation.Methods A total of 120 AF patients(AF group)admitted to our hospital from March 2021 to March 2023 were enrolled,and divided into a recurrence group(39 cases)and a non-recurrence group(81 cases)according to the postoperative condition.Another 120 healthy individuals who took physical examination in the same period were enrolled and served as control group.All subjects underwent ECG.ELISA was used to detect adiponectin and VF levels.Logistic regression analysis was used to identify the influencing factors of postoperative recur-rence in AF patients.ROC curve was plotted to analyze the predictive value of P-wave parameters combined with serum adiponectin and VF for postoperative recurrence in AF patients.The P-wave parameters included P-wave duration(PWD),maximum PWD(Pmax),minimum PWD,and P-wave dispersion(Pd).Results PWD,Pmax and Pd were significantly decreased in AF patients after operation(P＜0.01).Serum adiponectin level was obviously lower and that of VF was nota-bly higher in the AF group than the control group(6.15±1.58 μg/L vs 11.43±2.26 μg/L,12.05±2.30 μg/L vs 6.23±1.02 μg/L,P＜0.01).The recurrence group had remarkably higher preopera-tive PWD,Pmax and Pd,and lower adiponectin and higher VF levels than the non-recurrence group(P＜0.01).Multivariate logistic regression analysis showed that PWD,Pmax,Pd,and VF were risk factors,and adiponectin was a protective factor for postoperative recurrence in AF pa-tients(P＜0.05,P＜0.01).ROC curve analysis indicated that PWD,Pmax,Pd,adiponectin and VF combined together to detect postoperative recurrence in AF patients had an AUC value of 0.972,which was higher than that of above indicators alone(Z=2.574,Z=2.567,Z=2.543,Z=2.554,Z=2.586,P＜0.05).Conclusion ECG P-wave parameters as well as elevated serum VF and re-duced serum adiponectin are influencing factors for postoperative recurrence in AF patients,and their combined detection may promote the predictive value for postoperative recurrence in them.