OBJECTIVE To evaluate the cost-effectiveness of the first-line treatment using the combination therapy of sugemalimab and chemotherapy （hereinafter referred to as the “combination therapy”） for advanced esophageal squamous cell carcinoma （ESCC） with high programmed death-ligand 1 （PD-L1） expression from the perspective of the Chinese healthcare system. METHODS A partitioned survival model was constructed based on data from the GEMSTONE-304 study. The model cycle was set at 3 weeks， with a study duration of 10 years and a discount rate of 5%. The primary output parameters of the model included total costs， quality-adjusted life year （QALY）， incremental costs， and incremental cost-effectiveness ratio （ICER）. Cost- utility analysis was employed to assess the economic feasibility of the combination therapy compared to chemotherapy alone. The robustness of the base case analysis results was evaluated through univariate sensitivity analysis， probabilistic sensitivity analysis， and scenario analysis. RESULTS The ICER of the combination therapy compared to chemotherapy alone was 288 430.35 yuan/QALY， significantly exceeding the willingness-to-pay （WTP） threshold of 173 354.52 yuan/QALY which was set at 1.94 times the per capita gross domestic product （GDP） in 2023. The price of sugemalimab was the primary factor influencing the ICER. When the WTP threshold was set at 1.94 times the per capita GDP （173 354.52 yuan/QALY）， the probability of the combination therapy being cost-effective compared to chemotherapy alone was 0. The combination therapy only became cost-effective compared to chemotherapy alone when the price of the drug dropped to 6 107.41 yuan per box （600 mg）. CONCLUSIONS From the perspective of the Chinese healthcare system， the combination therapy for first-line treatment of advanced ESCC with high PD-L1 expression is not cost-effective； the combination therapy is cost-effective when the price of sugemalimab decreas by 50.65%.

Protein Engineering is a core compulsory course of biotechnology major, which is the first-class undergraduate major being constructed in Shanxi Province. In view of the problems of single teaching mode of Protein Engineering, such as insufficient students' participation, short teaching time, and expensive experiment cost, the course team carried out the reform and practice of teaching mode for this course, and put forward a new teaching strategy. Under the guidance of the "Golden Course" standard for advancement, innovation and challenge, the course team developed the materials for massive open online courses (MOOC), and carried out the online and offline mixed teaching of Protein Engineering based on BOPPPS+flipped classroom by using the Chao-Xing Fan-Ya network teaching platform. Through this, a comprehensive, systematic and dynamic new teaching system of Protein Engineering was developed. Using the teaching mode based on BOPPPS+flipped classroom, the offline classroom teaching was combined with students' online self-study and homework completion, chapter test and discussion, and this mixed teaching mode was fully integrated into the flipped classroom. After three rounds of teaching practice, the course team had developed a complete, reproducible, scientific and reasonable online and offline mixed teaching mode, which included course materials preparation, exploring experiment guidance, classroom discussion design and course performance evaluation. The online and offline mixed teaching mode of Protein Engineering based on BOPPPS+flipped classroom was helpful for students to improve their autonomous learning ability, to be deeply engaged in the whole teaching process, and to develop a comprehensive and profound understanding of Protein Engineering. This teaching mode improved the teaching quality of Protein Engineering, and facilitated students to learn other follow-up professional courses. Moreover, it provides a reference for the course teaching reform.
Humans ; Learning ; Students

Bisphenol A (BPA) is widely used to produce epoxy resin and polycarbonate plastic products. In severe cases, these plastics may release BPA, which then infiltrates into the environment. Various concentrations of BPA have been found in most biological fluid. Its presence has been well shown to be closely related to many chronic diseases, including chronic kidney disease (CKD). However, little is known regarding the adverse effects of BPA exposure and its succedent cellular events on CKD. Hence, in the current in vivo study, we aimed to assess the effects of chronic exposure to BPA on animal nephrotoxicity through investigating oxidative stress and apoptosis. Upon exposure to BPA at 0.01, 0.1, and 1 mg/L via drinking water for four weeks, the mated and pregnant females were continuously exposed to BPA until weaning. Subsequently, three weeks old F1-male neonates were also orally challenged with the same three doses of BPA for ten weeks. The results showed that the kidneys of 0.1 and 1 mg/L BPA-treated mice were seriously damaged; the contents of serum renal function indexes and lipid peroxidation products were significantly increased, including urea nitrogen, creatinine, uric acid, and thiobarbituric acid reactive substances; the morphological structure of mouse kidneys was impaired; the expressions of antioxidant-related genes at mRNA and protein levels from mouse kidneys were markedly diminished, including glutathione-S-transferase, superoxide dismutase, and catalase; the expressions of genes and proteins related to apoptosis index (ratio of Bax/Bcl-1 and Caspase-3) were significantly enhanced. The data manifested that cumulative oxidative stress and apoptosis might play an essential role in the animal nephrotoxicity induced by chronic exposure to BPA.
Female ; Male ; Mice ; Animals ; Oxidative Stress ; Antioxidants ; Apoptosis ; Renal Insufficiency, Chronic

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
Humans ; Aspergillosis, Allergic Bronchopulmonary/complications* ; Aspergillus fumigatus/genetics* ; Asthma/genetics* ; Aspergillus ; Mutation/genetics* ; CARD Signaling Adaptor Proteins/genetics*

Objective: To investigate psychological and behavioral responses and the prevalence of acute stress disorder (ASD) among the injured from a serious road traffic accident. Methods: The injured persons at ages of 7 years and older from a serious road traffic accident were enrolled, and individuals with severe injury were exclude. Participants' gender, age, educational level, marital status, injury severity, family member's injury and death during the accident and psychological and behavioral status were collected. The prevalence of ASD was estimated using a semi-structured interview and the ASD Scale, and the factors affecting the development of ASD were identified using a multivariable logistic regression model. Results: A total of 132 survivors participated in psychological crisis assessment, including 82 men (62.12%) and 50 women (37.88%) and with a mean age of (46.50±18.57) years. There were 6 participants without obvious trauma (4.54%), 113 with mild injury (85.61%) and 13 with moderate injury (9.85%), and there were 6 participants with death of their family members during this accident. Insomnia, anxiety, flashback and fear were predominant psychological and behavioral responses, with prevalence rates of 42.42%, 35.58%, 26.52% and 23.48%, respectively. The prevalence of ASD was 30.30% among participants, and a higher rate of ASD was detected among women than among men (52.00% vs. 17.07%; χ2=17.940, P<0.001). The detection of ASD was higher among participants with death of their family members than among those without death of their family members (83.33% vs. 26.98%; χ2=8.370, P=0.004), and a higher detection rate of ASD was seen among participants with moderate injury (61.54%; χ2=6.786, P=0.034). Multivariable logistic regression analysis showed a higher risk of ASD among females (OR=7.764, 95%CI: 3.187-18.915) and those with a high educational level (high school/technical secondary school, OR=6.896, 95%CI: 1.030-46.152; diploma and above, OR=71.583, 95%CI: 4.145-1 236.270). Conclusions Insomnia and anxiety are predominant psychological and behavioral responses following serious road traffic accidents, and women and individuals with a high educational level present a high risk of ASD, which requires to be given timely psychological crisis interventions.

Food allergy(FA)is a global health problem that affects a large population,and thus effective treatment is highly desirable.Oral immunotherapy(OIT)has been showing reasonable efficacy and favorable safety in most FA subjects.Dependable biomarkers are needed for treatment assessment and outcome prediction during OIT.Several immunological indicators have been used as biomarkers in OIT,such as skin prick tests,basophil and mast cell reactivity,T cell and B cell responses,allergen-specific antibody levels,and cytokines.Other novel indicators also could be potential biomarkers.In this review,we discuss and assess the application of various immunological indicators as biomarkers for OIT.

The theories of pathophysiology come from experimental research,and experimental teaching is an important part of pathophysiology course.Experimental teaching can cultivate the abilities of independent thinking and comprehensive analysis in students,improve their practical skills,and enhance their understanding and application of theoretical knowledge.However,teaching reform should be carried out due to the drawbacks of current pathophysiological experimental teaching.With the teaching idea centered on learning,the quality of pathophysiological experimental teaching can be enhanced by rational arrangement of experimental courses,optimization of teaching contents,and comprehensive application of various teaching models,so as to effectively improve the level of theoretical knowledge and comprehensive practical ability among students.

Objective: To investigate the value of Cytomegalovirus(CMV) DNA real-time quantitative-polymerase chain reaction(RT-PCR) in different body fluids for diagnosing CMV pneumonia in immunocompetent infants. Methods: The clinical data of immunocompetent infants with CMV pneumonia who were treated in Pediatric Intensive Care Unit of Guangdong Women and Children′s Hospital from January 1^st, 2016 to February 5^th, 2018 were retrospectively analyzed.The clinical data included CMV DNA load of bronchoalveolar lavage fluid(BALF), urine, blood and cerebrospinal fluid(CSF); blood immunoglobulin(Ig)M CMV, alanine aminotransferase (ALT), X-ray and CT test of chest, combined infection, clinical manifestation and treatment. Results: Nine hundred and twenty-six infants received bronchoalveolar lavage by bronchoscope, and 34 cases were diagnosed as immunocompetent with CMV pneumonia.The infants with CMV pneumonia: the positive percentage of urine CMV DNA, blood CMV DNA, blood IgM CMV and ALT elevation were 100.0%(34/34 cases), 61.8%(21/34 cases), 52.9%(18/34 cases) and 20.6%(7/34 cases), respectively.There was no difference in positive percentage between blood CMV DNA and blood IgM CMV (χ²=0.5, P>0.05). Both the positive percentages of blood CMV DNA and blood IgM CMV were lower than those in the urine CMV DNA, and the differences were statistically significant (χ²=16.1, 20.9, all P<0.05). The positive percentages of ALT elevation were lower than those in the positive percentage of urine CMV DNA, blood CMV DNA and blood IgM CMV, and the differences were statistically significant (χ²=44.8, 11.9, 7.7, all P<0.05). Ten patients′ CSF CMV DNA were tested, and they were all negative.The median load of CMV DNA in BALF, urine and blood was 170.0×10⁵ copies/L, 130.0×10⁵ copies/L and 6.0×10⁵ copies/L.There was no difference in median load between BALF and urine (U=561, P>0.05). BALF CMV DNA load and blood CMV DNA load had a weak positive correlation (r=0.35, P<0.05), BALF CMV DNA load and age had a negative correlation (r=-0.42, P<0.05), and urine CMV DNA load and blood CMV DNA load had a positive correlation (r=0.52, P<0.05). No matter whether blood IgM CMV was positive, BALF CMV DNA load had no differences (U=92, P>0.05). The main radiographic signs were pulmonary interstitial lesions.Thirty-four immunocompetent infants with CMV pneumonia, 18 patients (52.9%) with symptoms lasted for over 2 weeks, 20 patients (58.8%) had complicated infections.They all received inductive treatment of Ganciclovir, 55.9%(19/34 cases) patients′ urine CMV DNA turned to be negative.When patients got combined infections by bacteria or mycoplasma, antibiotics were used.All discharged patients had symptoms relieved and signs improved. Conclusions BALF RT-PCR is instant, sensitive and distinctive method to diagnose CMV pneumonia.Urine RT-PCR gets specimens conveniently and safely, its positive percentage and DNA load are present well according to BALF, and is suitable for screening and monitoring CMV infection.Blood CMV DNA load and blood IgM CMV indicate viral dissemination and immunocompetence, but it is not recommended for diagnosing CMV pneumonia solely.

Objective To identify microbiome biomarkers in patients with inflammatory bowel disease ( IBD) in different regions and establish predictive models , and to explore the various gut microbiota function in IBD patients .Methods The 16 srRNA gene sequences of 1510 IBD patients and 496 healthy controls were collected from China , the United States ( RISK and PRISM cohort ), Germany, India and Lithuania cohort.QIIME ( v1.9.1) was used to analyze microbiota data.LEfSe was used to identify biomarkers for IBD.Random forest method was used to establish the prediction model to distinguish IBD from HC.PICRUSt was used to predict the functional changes of gut microbiota in IBD patients .Resultsɑdiversity of gut microbial in IBD patients was significantly lower than in HC (Wilcoxon,P<0.05).The gut microbiota of IBD patients was different from HC significantly ( Adonis,P<0.05) in all of the cohort study but Indian.LEfSe analysis showed that the IBD patients from China and the U .S.cohort harbored similar dysbiosis patterns , while those from Lithuania , Germany and India have highly localized dysbiosis patterns.Generally, enterococcus was significantly increased in IBD patients in China , the U.S.and Germany cohort.Enterobacteriaceae was significantly increased in IBD patients in China and the U .S. cohort.Ruminococcus was significantly decreased in the intestines of IBD patients in China , the U.S.and India cohort.When predicting IBD status using machine learning models built on local population , the area under the curve ( AUC) was 86.48％ ±4.91％.Meanwhile, when predicting IBD status using machine learning models built on other populations , China and the U.S.had a relatively high AUC for cross-predicting, whilethe other pairs were failed when cross-applied to each other.The model established based on all samples was used to predict each population ,which showed that China , the United States ( RISK and PRISM cohort ), Germany, Lithuania and India cohorts having AUCs of 90.1％, 82.3％, 79.6％, 61.9％, 65.5％and 54.2％respectively.For functional analysis, in China, the United States (RISK and PRISM cohort ) and India cohort , glutathione metabolism and quinones biosynthesis was significantly increased in IBD patients.In China, Germany and Lithuania cohort , flagella assembly and bacterial motility proteins functions were significantly decreased in the IBD patients .Conclusions The intestinal microbiota of IBD patients from different countries could have consistent dysbiosis patterns , but geographical factors still exert a great effect on the microbiota , which needs to be further explored in subsequent studies .

Objective To explore the application of double-parameter three-dimension arterial spin labeling (3D-ASL) in evaluating collateral circulation in patients with unilateral chronic middle cerebral artery (MCA) occlusion.Methods From May 2015 to November 2017,24 patients with unilateral chronic MCA occlusion were scanned in Yantaishan Hospital by conventional MRI,DWI,3D-TOF-MRA and 3D-ASL (post-labeling delays:1.5 s and 2.5 s respectively) using a 3.0 T MR scanner.The cerebral blood flow (CBF) values were measured in region of interest in the occlusive cortical area and in the contralateral normal cerebral area.The differences in CBF value measured by 3D-ASL (PLD=1.5 s and PLD=2.5 s) were analyzed by statistical methods.Results All the patients (n=24) on 3D-ASL (PLD=1.5 s) presented with apparent hypoperfusion in the MCA occlusion territory;but 3D-ASL (PLD=2.5 s) demonstrated the basically same perfusion in bilateral MCA territories,without apparent hypoperfusion in one cerebral hemisphere.The subtraction images of 3D-ASL (PLD 2.5 s-PLD 1.5 s)presented laminated high signal areas in the cortical region of MCA occlusion.There was no statistically significant difference in CBF value of the contralateral normal cerebral area between measurements by 3D-ASL (PLD=1.5 s) and by 3D-ASL (PLD=2.5 s) (6.39±5.01 mL/100 g·min versus 55.87±6.89 mL/100 g· min) (P＞0.05).The CBF value of region of interest in the occluded cortical area (23.34±4.53 mL/100 g· min) was significantly lower than that in the contralateral normal cerebral area (55.87±6.89 mL/100 g·min) by 3D-ASL (PLD=1.5 s) (P＜0.05).The CBF value of region of interest in the occluded cortical area (53.93±8.59 mL/100 g·min) by 3D-ASL (PLD=2.5 s) was significantly higher than that by 3D-ASL (PLD=1.5 s) (23.34±4.53 mL/100 g·min) (P＜0.05).There was no statistically significant difference between the CBF value of region of interest in the occluded cortical area and that in the contralateral normal cerebral area by 3D-ASL (PLD=2.5 s) (P＞0.05).Conclusions 3D-ASL (PLD=1.5 s and PLD=2.5 s) can noninvasively and intuitively demonstrate the collateral circulation compensation in patients with chronic MCA occlusion.3D-ASL (PLD=1.5 s) can reflect the first-order collateral circulation compensation while 3D-ASL (PLD=2.5 s) can reflect accurately the secondary collateral circulation compensation.