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.

ObjectiveTo investigate the therapeutic effects of direct-acting antiviral agents (DAAs) combined regimens for hepatitis C virus (HCV) patients in Dehong Prefecture, Yunnan Province from 2022 to 2024, to analyze the characteristics of treatment failure patients, so as to provide a basis for discovering more effective treatment regimens in the future. MethodsData on HCV prevention and treatment in Dehong Prefecture was extracted from the China Disease Control and Prevention Information System. A total of 617 patients with HCV antiviral therapy were included, and the differences in variable characteristics among patients with different genotypes were analyzed using comparative statistical tests, including basic socio-demographic characteristics, biochemical testing indicators, and information on previous treatment and current treatment. In addition, the cure rate of HCV patients with diverse characteristics was compared, and the potential causes of treatment failure were explored simultaneously. ResultsThe cure rate of HCV was 96.8%, and statistically significant differences were observed in aspartate transaminase (AST) and alanine transaminase (ALT) levels, previous antiviral therapy history and initial treatment regimens among patients with different HCV genotypes (all P<0.05). Among the multi-type combination regimens, the cure rate of sofosbuvir (SOF)-containing regimens was 97.00%, that of velpatasvir (VEL)-containing regimens was 95.45%, and the cure rate of other treatment regimens, including the regimens with ribavirin (RIB) intervention, was 93.10%. Among the patients with treatment failure, 45.00% had genotype 3, 40.00% had abnormal abdominal ultrasound results, and all presented with elevated baseline AST test levels. ConclusionThe clinical treatment of HCV patients should consider the differences in genotype and biochemical test results. DAAs combined regimens for HCV have achieved a high cure rate in Dehong Prefecture and are applicable to HCV patients with diverse clinical characteristics, providing research evidence for wider application.

BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer (LACC), but there are still many patients who suffer tumor recurrence. However, valuable predictors of treatment outcomes remain limited. This study aimed to assess the value of the serum immune biomarkers to predict the prognosis. METHODS: We reviewed cervical cancer patients treated with CCRT between January 2014 and May 2018 at Peking Union Medical College Hospital. The systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and lactate dehydrogenase (LDH) were calculated using blood samples. The relationship between immune markers and the treatment outcome was analyzed. The area under the receiver operating characteristic (ROC) curve was used to evaluate the predictive efficiency. The Cox proportional hazards model and log-rank were used to predict overall survival (OS) and disease-free survival (DFS). RESULTS: This study included 667 patients. Among them, 195 (29.2%) patients were defined as treatment failure, including 127 (19.0%) patients with pelvic failure, 94 (14.1%) distant failure, and 25 (3.7%) concurrent pelvic and distant failure. It revealed that the tumor stage, size, metastatic lymph nodes (MLNs), and serum immune biomarkers, such as SII, SIRI, and LDH, were significantly related to treatment outcomes. We demonstrated that the optimal cut-off of the SII, SIRI, and LDH were 970.4 × 10 9 /L, 1.3 × 10 9 /L, and 207.52 U/L, respectively. Importantly, this study presented that LDH level had the highest OR (OR = 4.2; 95% CI [2.3-10.8]). Furthermore, the OS and DFS for patients with pre-SII ≥970.5 × 10 9 /L were significantly worse than those with pre-SII <970.5 × 10 9 /L. Similarly, pre-SIRI ≥1.25 × 10 9 /L and pre-LDH ≥207.5 U/L were related to poor survival outcomes. CONCLUSIONS This study demonstrated that the baseline SII, SIRI, and LDH levels can be used to accurately and effectively predict the treatment outcomes after CCRT and long-term prognosis. Our results may offer additional prognostic information in clinical, which helps to detect the potential recurrent metastasis in time.
Humans ; Female ; Uterine Cervical Neoplasms/drug therapy* ; Middle Aged ; Adult ; Aged ; Chemoradiotherapy/methods* ; L-Lactate Dehydrogenase/blood* ; Treatment Outcome ; Disease-Free Survival ; Prognosis ; ROC Curve ; Biomarkers, Tumor/blood* ; Proportional Hazards Models

Objective To analyze the colorectal cancer screening of community residents in Pudong New Area in Shanghai and provide reference for the promotion and strategy optimization of colorectal cancer screening programs. Methods Residents aged 50-74 years in the colorectal cancer screening project of Pudong New Area in Shanghai from 2013 to 2023 were recruited in this analysis. The situation of primary screening and colonoscopy in the community was described, and results of different age groups in primary screening and colonoscopy surveys were evaluated. Chi-square test was used to determine differences between groups. Results From 2013 to 2023, 907 030 residents were screened in Pudong New Area, of which 183 724 residents were positive, and the positive rate was 20.3%. The positive rate was the lowest in the 50-54 age group and the highest in the 70-74 age group. The positive rate was higher in men than in women. The overall colonoscopy rate was 27.1%, with the highest rates in the 50-54 age group in men and the 55-59 age group in women, respectively. The participation rate of colonoscopy increased with the increase of the year. A total of 19 094 cases of intestinal lesions were found by colonoscopy. Among these lesions, 1 147 cases were colorectal cancer, accounting for 6.0%, and the population detection rate was 126.5/100 000. In addition, 4 751 cases of precancerous lesions were found, accounting for 24.9%, and the detection rate was 523.8/100 000. Conclusion Colorectal cancer screening improves the detection rate of precancerous lesions and early cancer and is of great significance for reducing the incidence and mortality of colon cancer. Measures should be taken to optimize the screening strategy based on age differences and increase the participation rate of primary screening and colonoscopy to achieve the best effect of local colorectal cancer prevention and treatment.

OBJECTIVE To investigate the effects of CYP3A5 gene polymorphism and Wuzhi capsule （WZ） on early postoperative tacrolimus exposure and adverse reactions in renal transplant patients. METHODS A total of 132 patients who underwent renal transplantation and received tacrolimus + mycophenolic acids + prednisone after operation in our hospital from September 2021 to September 2023 were selected and divided into four groups according to genotypes （CYP3A5*1 or CYP3A5*3/*3） and with or without WZ （“ +WZ” meant drug combination， “ +NO WZ” meant without combination）. The blood trough concentration/daily dose （c0/D） values of the four groups were analyzed on the 14th day， 1 month and 3 months after renal transplantation. The incidence of acute rejection and the incidence of tacrolimus-related adverse reactions within 3 months after transplantation were compared among 4 groups. RESULTS On the 14th day， 1 month and 3 months after surgery （except for the CYP3A5*1+WZ group）， c0/D values of CYP3A5*1 genotype patients were significantly lower than those of CYP3A5*3/*3 genotype patients regardless of whether they were treated with WZ additionally （P＜0.05）. Within 3 months after surgery， although there was no significant difference in the incidence of acute rejection and tacrolimus-related adverse reactions among the four groups （P＞ 0.05）， the incidence of hyperglycemia in patients with CYP3A5*3/*3 was higher （41.67%）. CONCLUSIONS CYP3A5 gene polymorphism is significantly related to tacrolimus c0/D in kidney transplant patients. Under the premise of c0 monitoring of tacrolimus， patients with CYP3A5*1 genotype should be given WZ as soon as possible after surgery to accelerate tacrolimus to reach the therapeutic concentration range， while CYP3A5*3/*3 genotype is not recommended to be given WZ because of the higher risk of hyperglycemia.

The preparation edge of the tooth in oral restoration has always been the hot concern for dentists,and the improper preparation edge may lead to such diseases as caries and periodontitis,and ultimately lead to the restoration failure.The application of biologically oriented preparation technique has been proven to restore good periodontal soft and hard tissue morphology,which is expected to replace the traditional dental preparation methods.This article aims to comprehensively discuss the application of biologically oriented preparation technique in veneers,full crown and implantation.

Objective To study the application value of CAD/CAM technology in the teaching of inlay manufacturing.Methods A total of 60 undergraduates interned in the Department of Stomatology,Yan'an Hospital,Kunming Medical University were randomly divided into an experimental group(n=30)and a control group(n=30).We selected appropriate clinical cases for students to prepare for mandibular molar's proximal occlusal inlays.The instructor guided the results of the first preparation in different ways,and the students made the second modification and preparation,and the assessment team scored and evaluated the five aspects of the final preparation,the shape of the preparation,the shape of the occlusal surface,the dovetail retention,and the adjacent surface.Results The scores of all detection indexes in the experimental group were higher than those in the control group(P<0.05).Conclusion The application of CAD/CAM technology in inlay manufacturing teaching can effectively improve students'clinical hands-on ability and achieve better teaching effects than traditional teaching methods.

Objective To develop deep learning-based auxiliary diagnostic models for diverse pulmonary diffuse cystic diseases,and subsequently evaluate their classification performance to identify the optimal model for clinical diagnosis.Methods A total of 288 patients diagnosed with idiopathic pulmonary fibrosis(IPF),pulmonary lymphangioleiomyomatosis(PLAM),and pulmonary Langerhans cell histiocytosis(PLCH)were prospectively enrolled from the First Affiliated Hospital of Guangzhou Medical University between January 2010 and October 2022,comprising 76 cases of IPF,179 cases of PLAM,and 33 cases of PLCH.A total of 877 CT cases were collected,comprising 232 cases of IPF,557 cases of PLAM,and 88 cases of pulmonary PLCH.Based on the cutoff date of December 31,2019,the CT scans were divided into two datasets:dataset A consisted of 500 CT scans including 185 IPF cases,265 PLAM cases,and 50 PLCH cases;while dataset B comprised 377 CT scans with a distribution of 47 IPFcases,292 PLAMcases,and 38 PLCH cases.The Dataset A was randomly partitioned into training set,validation set,and test set in a ratio of 7∶1∶2.Subsequently,six distinct deep learning neural networks were employed for training after preprocessing and data augmentation.Receiver operating characteristic curves were generated to assess the model performance using metrics such as area under the curve(AUC),accuracy,sensitivity,specificity,and F1 score in order to identify the optimal model.Furthermore,a test set B comprising 30 randomly selected cases from dataset B for each disease type was utilized to evaluate the trained optimal model by employing the same aforementioned metrics.Results In test A,six well-established diagnostic models demonstrated superior classification performance for IPF and LAM,with an AUC greater than 0.9.For LCH,EfficientNet exhibited low classification efficiency with an AUC between 0.6 and 0.7,while Vgg11 showed an AUC between 0.8 and 0.9;the other four models displayed excellent classification efficiency with an AUC greater than 0.9.Except for Inception V3,the remaining five diagnostic models performed poorly in identifying and classifying LCH lesions.Considering multiple indicators,the InceptionV3 model showcased optimal comprehensive performance among the six models,achieving high evaluation parameters such as overall accuracy(94.90%),precision(93.49%),recall(90.84%),and specificity(96.91%).TestB was conducted using the trained InceptionV3 model resulting in an accuracy of 81%,precision of 82%,recall of 81%,and specificity of 90%.Conclusions Six recognition and classification models,developed using deep learning technology in conjunction with pulmonary CT images,demonstrate effective discrimination between LAM,LCH,and IPF.Notably,the model constructed utilizing the InceptionV3 neural network exhibits superior efficiency in accurately recognizing and classifying IPF and LAM.

BackgroundPrevious investigations have illuminated the correlation between smoking and C-reactive protein （CRP）， but previous research findings may be influenced by other confounding factors. The causal relationship of CRP in smoking-related pathological process requires further exploration. ObjectiveTo investigate the causal relationship between smoking behavior and CRP by utilizing the cumulative statistical data from existing genome-wide association studies （GWAS）， so as to provide references for formulating relevant public health policies and smoking intervention measures. MethodsThis research utilized the GWAS summary statistics for CRP and four smoking phenotypes： age of initiation of regular smoking， smoking initiation， smoking cessation and cigarettes per day-selecting independent genetic loci correlated with smoking and CRP as instrumental variables. The study employed the inverse variance weighted method （IVW） and the weighted median approach for two-sample Mendelian randomization （MR） analysis to explore the bidirectional causal relationship between smoking and CRP. The Cochran's Q test was applied to assess heterogeneity among single nucleotide polymorphisms （SNPs）. MR pleiotropy residual sum and outlier was used to detect SNP outliers. MR-Egger intercept test examined the horizontal pleiotropy of SNPs. Leave-one-out sensitivity analysis assessed the impact of individual SNP on the Mendelian randomization results. ResultsThe MR analysis revealed a bidirectional causal relationship between CRP and smoking initiation （β=0.170， P=0.01） （with smoking initiationas the exposure）， （β=0.040， P=0.001） （with CRP as the exposure）. ConclusionSmoking may lead to alterations in CRP levels， while changes in CRP levels could also influence individual's propensity to initiate smoking.

Objective To investigate the correlations of serum calcium, 25-hydroxyvitamin D and uric acid levels with benign paroxysmal positional vertigo (BPPV). Methods A total of 96 patients with BPPV were enrolled in vertigo group and further divided into mild vertigo (30 cases), moderate vertigo (42 cases), and severe vertigo (24 cases) groups based on the severity of vertigo symptoms. Additionally, 63 healthy people undergoing physical examination without BPPV were recruited as control group. Serum calcium, 25-hydroxyvitamin D, and uric acid levels were compared among groups, and their correlations with the severity of vertigo in BPPV patients were analyzed. Follow-up was conducted for 3 months to record the recurrence rate of BPPV. Results The serum calcium and 25-hydroxyvitamin D levels in the moderate and severe vertigo groups were significantly lower, while uric acid levels, total score of Dizziness Handicap Inventory (DHI) as well as functional, emotional, and physical scores were significantly higher than those in the mild vertigo group and control group (P < 0.05). Moreover, the severe vertigo group exhibited lower serum calcium and 25-hydroxyvitamin D levels and higher uric acid level, DHI total score and functional, emotional, as well as physical scores (P < 0.05). No significant differences were observed in serum calcium, 25-hydroxyvitamin D, uric acid levels, or DHI scores between the mild vertigo group and the control group (P>0.05). The severity of vertigo in BPPV patients was negatively correlated with serum calcium (r=-0.557, P < 0.05) and 25-hydroxyvitamin D levels (r=-0.467, P < 0.05), and positively correlated with uric acid levels (r=0.504, P < 0.05). The 3-month recurrence rate of BPPV was 8.33%(8/96). Compared to patients with serum calcium ≥2.11 mmol/L, 25-hydroxyvitamin D ≥30 ng/mL, and uric acid ≤428 μmol/L, those with serum calcium < 2.11 mmol/L, 25-hydroxyvitamin D < 30 ng/mL, and uric acid >428 μmol/L had significantly higher BPPV recurrence rates (P < 0.05). Conclusion BPPV patients exhibit abnormally lower serum calcium and 25-hydroxyvitamin D levels and abnormally higher uric acid levels. The severity of vertigo in BPPV patients is negatively correlated with serum calcium and 25-hydroxyvitamin D levels and positively correlated with uric acid levels.