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.

Since the International guidelines for groin hernia management were published in 2018,many new evidences have been published.In October 2023,the HerniaSurge Group published Update of the international HerniaSurge guidelines for groin hernia management.It updated eight chapters of the last guidelines,proposed 20 key questions,and 39 new statements and 32 recommendations,of which 16 were strong recommendations.This article combined clinical concerns to sort out and interpret the updated version.

Purpose To investigate the risk factors of severe hypocalcemia after ultrasound-guided thermal ablation for secondary hyperparathyroidism.Materials and Methods A retrospective case-control study was used to study 91 patients with uremia complicated with secondary hyperparathyroidism in the First People's Hospital of Yulin from May 2019 to May 2023.All patients underwent ultrasound-guided thermal ablation and were divided into severe hypocalcemia group(SH)and non-SH group according to postoperative blood calcium levels.The difference of clinical data between the two groups was compared,and the independent risk factors of SH were investigated by multivariate Logistic regression analysis.Results A total of 317 glands were ablated in 49 cases of microwave ablation and 42 cases of radiofrequency ablation.SH occurred in 57 cases(62.64%)after ablation.The comparison of clinical data between the two groups showed that there were significant differences in the preoperative intact parathyroid hormone(iPTH),decline rate of iPTH 1 d,preoperative serum alkaline phosphatase,the proportion of parathyroid glands≥4 and the total gland volume between the two groups(all P<0.05).Receiver operating characteristic curve analysis was used to obtain the best cut-off point of iPTH 1 d decline rate,the result was 74.59%,the area under the curve was 0.866(95%CI 0.787-0.945)(P<0.05),the sensitivity was 84.2%,and the specificity was 78.1%.Multivariate Logistic regression analysis showed that preoperative alkaline phosphatase(OR=1.015,95%CI 1.005-1.025,P=0.030)and decline rate of iPTH 1 d≥74.59%(OR=30.423,95%CI 5.938-155.858,P<0.001)and parathyroid glands≥4(OR=4.355,95%CI 1.027-18.469,P=0.046)were independent risk factors for postoperative SH(all P<0.05).Conclusion Preoperative alkaline phosphatase and decline rate of iPTH 1 d≥74.59%and the number of parathyroid glands≥4 are independent risk factors for SH after thermal ablation.

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.

Objective To observe the risk factors of recurrence after ultrasound-guided thermal ablation for treating uremia secondary hyperparathyroidism(SHPT).Methods Totally 59 patients with uremia SHPT who underwent ultrasound-guided thermal ablation were enrolled,including 23 cases with(relapse group)and 36 without SHPT recurrence(non relapsed group).Clinical data were compared between groups,univariate and multivariate logistic regression analysis were performed to screen independent risk factors of SHPT recurrence.Results There were significant differences of serum free thyroxine(FT4),urea,intact parathyroid hormone(iPTH)1 day after ablation,1 day decrease rate of iPTH,the maximum diameter of the largest nodule,ablation time,total ablation energy,energy to volume ratio and the proportion of 1 day decrease rate of iPTH≤90%between groups(all P＜0.05).Higher urea,lower energy to volume ratio and 1 day decrease rate of iPTH≤90%were all independent risk factors of SHPT recurrence(all P＜0.05).Conclusion Higher urea,lower energy to volume ratio and 1 day decrease rate of iPTH≤90%were independent risk factors of recurrence after ultrasound-guided thermal ablation for treating uremia SHPT.

Objective:To summarize the clinical experience of treating patients with severe acute organic fluorine poisoning using extracorporeal membrane oxygenation (ECMO).Methods:In January 2021, an acute mass organic fluorine gas poisoning incident occurred in Quzhou, Zhejiang Province. The clinical data of 4 severe patients with acute poisoning of organic fluorine treated by ECMO in our hospital were retrospectively analyzed, and the epidemiological characteristics, clinical symptoms, signs, the abnormal laboratory studies/examinations, and treatments of this kind poisoning patients, especially, the treatment pattern, support time, complications, and outcomes of ECMO were collected and analyzed.Results:All the 4 patients were male, with an average age of (52±9) years, and all of them came to the emergency department complaining chest tightness, cough and pharyngeal discomfort 6 h after exposure by inhalation. The patient’s condition progressed rapidly with severe acute respiratory failure and circulatory failure as the prominent manifestations. The mechanical ventilations were performed (13.0±4.8) h after poisoning, and ECMO treatment was performed (15.5±5.3) h after poisoning. Among them, 2 patients were treated using venoarterial (VA) ECMO, and 2 patients using venovenous (VV) ECMO, but 1 patient was converted to VA-ECMO 8 h later. The duration of ECMO support for the patients was (8.8±3.6) d. The duration of mechanical ventilation was (23.0±28.7) d and stay in intensive care unit was (42.0±55.4) d. Among them, one patient was transferred to a specialized rehabilitation hospital after the amputation surgery due to lower limb necrosis after VA-ECMO support, and the remaining 3 patients were discharged after recovery.Conclusions:ECMO support might have the irreplaceable value in the treatment of patients with severe acute organic fluorine poisoning, and should be considered as one of the reserves of regional health care system in dealing with public health emergencies.

Objective:To investigate the relationship between adenosine diphosphate (ADP) pathway-induced platelet dysfunction monitoring by thrombelastography with hospital mortality in patients with traumatic brain injury.Methods:The clinical data of 180 patients with traumatic brain injury in Zhejiang Quhua Hospital from January 2016 to December 2018 were retrospectively analyzed. The patients underwent thrombelastography examination. Among them, the ADP pathway-induced platelet inhibition rate (ADP inhibition rate) ≤ 60% was in 74 cases (non-ADP dysfunction group), and ADP inhibition rate > 60% was in 106 cases (ADP dysfunction group). Multiple Logistic regression analysis was used to analyze the independent influencing factors of patients′ hospital mortality. Logistic regression model was used to analyze the threshold of ADP inhibition rate to predict hospital mortality.Results:There were no statistical differences in the gender composition, age, prothrombin time, international standardized ratio, activated partial thromboplastin time, platelet count, systolic blood pressure, pulse, admission to thrombelastography examination time, Glasgow coma score, trauma severity score, simple trauma grading criteria and using of antiplatelet drugs before admission between 2 groups ( P>0.05). The intubation rate and in-hospital mortality in ADP dysfunction group were significantly higher than those in non-ADP dysfunction group: 69.8% (74/106) vs. 37.8% (28/74) and 32.1% (34/106) vs. 8.1% (6/74), and there were statistical differences ( P<0.01 or <0.05). The maximum amplitude and G value in ADP dysfunction group were significantly lower than those in non-ADP dysfunction group: (61 ± 9) mm vs. (65 ± 6) mm and (9 ± 4) kD/cm2 vs. (11 ± 3) kD/cm2, the ADP inhibition rate and arachidonic acid pathway-induced platelet inhibition rate were significantly higher than those in non-ADP dysfunction group: (76 ± 22)% vs. (45 ± 18)% and (75 ± 28)% vs. (35 ± 22)%, and there were statistical differences ( P<0.05). There were no statistical difference in the reaction time, blood clot formation time and angle between 2 groups ( P>0.05). Multiple Logistic regression analysis result showed that ADP inhibition rate >60% and trauma severity score were independent predictors of increased hospital mortality in patients with traumatic brain injury ( OR = 6.21 and 1.13, 95% CI 1.21 to 31.27 and 1.05 to 1.22, P<0.05). Logistic regression model analysis result showed that ADP inhibition rate >60% was the threshold for predicting the hospital mortality rate ( OR = 6.18, 95% CI 1.2 to 33.3). Conclusions:ADP inhibition rate of thrombelastography is related to the hospital mortality in patients with traumatic brain injury.

AIM:To explore the effects of PPARγon the elevated level of reactive oxygen species ( ROS) in-duced by high glucose and its mechanism .METHODS:Human umbilical vein endothelial cells ( HUVECs) were cultured with DMEM containing high glucose (33 mmol/L D-glucose), and DMEM containing lower glucose (5.5 mmol/L D-glu-cose) was used as control .Superoxide anion and nitric oxide fluorescence probes were used to observe the effects of PPAR γagonist on ROS and NO productions in the HUVECs .The uncoupling protein 2 (UCP2) protein level in the HUVECs was detected by Western blotting .RESULTS:PPARγagonist pioglitazone inhibited the ROS generation and prevented the de-crease in NO level under high glucose condition , and these effects were reversed by pretreatment with PPARγantagonist GW9662.The results of Western blotting indicated that PPARγagonist pioglitazone up-regulated the UCP2 expression un-der high glucose condition , and this effect was also blocked by GW 9662.Inhibition of UCP2 by genipin attenuated the effect of pioglotazone on the ROS production .CONCLUSION: Activation of PPARγinhibits ROS generation under high glucose condition , and this effect may mediate by up-regulation of UCP2.

Objective To investigate the risk factors and preventive strategies of patients with diffuse axonal injury(DAI) with deep veins thrombosis in lower limbs (LDVT).Methods One hundred and thirty cases of diffuse axonal injury patients with lower limb vascular were divided into LDVT group(22 cases) and non LDVT group(108 cases) based on ultrasound.The information including long-term bed,plasma fibrinogen level,varicose veins,hypertention,sex,age,smoking,alcohol drinking,diabetes,obesity,Glasgow Coma Scale (GCS) were collected.Results There were significant different between LDVT and non-LDVT group in terms of longterm bed time,hypertension,smoking,diabetes,high plasma fibrinogen,age,low GCS score correlated with LDVT (x2 =7.08,5.99,5.17,4.70,3.55,12.72,t =27.80,P ＜ 0.05).Gender,drinking,obesity,varicose vein factors had no correlation with LDVT(P ＞ 0.05).Conclusion Diffuse axonal injury in patients with LDVT is more common in patients with older age,hypertension,low GCS score,the higher the plasma fibrinogen.

Adielectrophoresis-basedmicrofluidicchipappliedtocellspatterningisdesignedandfabricated, and it demonstrates non-contact and batch manipulation of cells. The microfluidic chip employs a PDMS microchannel and two ITO electrodes, which are designed as astep shape. The distribution of electric field caused by the microelectrodes is simulated by finite element simulation software, COMSOL. The position of the maximum intensity of electric field is also determined. The ITO microelectrodes and the PDMS microchannel are fabricated using MEMS fabrication process. After oxygen plasma surface treatment, the PDMS microchannel and glass substrate with the ITO microelectrodes are aligned and bonded to form experimental microfluidic chip. Through DEP experiment with the varying frequencies, DEP response of yeast cells is examined, and the electric field frequency of the both positive and negative DEP responses are confirmed. The results showed that yeast cells in solution conductivity of 60 μS/cm had negative DEP movement at the frequency of 1 kHz to 10 kHz, positive DEP movement at the 500 kHz to 10 MHz, and no DEP movement at the 50 kHz. Under the condition of the sinusoidal potential of 8Vp-p and the electric field frequency of 5 MHz, the yeast cells were aligned into chains along the step edge of microelectrodes.