ObjectiveTo investigate the effect and potential mechanism of caffeic acid （CA） on severe acute pancreatitis （SAP） induced by caerulein combined with lipopolysaccharide （LPS）， and to provide a basis for the research on novel drugs for the treatment of SAP. MethodsC57BL/6J mice， aged 6 weeks， were divided into control group， model group， CA group， and octreotide acetate （OA） group， with 6 mice in each group. The mice in the control group were given injection of normal saline， and those in the other groups were given intraperitoneal injection of caerulein combined with LPS to establish a mouse model of SAP. At 1 hour after the first injection of caerulein， the mice in the CA group and the OA group were given intraperitoneal injection of CA or subcutaneous injection of OA at an interval of 8 hours. The general status of the mice was observed after 24 hours of modeling， and serum， pancreas， lung， and colon samples were collected. HE staining was used to observe the histopathological changes of the pancreas and lungs， and the serum levels of α-amylase， lipase， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， alanine aminotransferase， aspartate aminotransferase， and creatinine were measured. RT-PCR was used to measure the expression of proinflammatory factors in the pancreas and lungs； myeloperoxidase （MPO） immunohistochemistry was used to observe the degree of neutrophil infiltration； Western blot was used to measure the activation of nuclear factor-kappa B （NF-κB） and the level of citrullinated histone H3 （CitH3）， a marker for the formation of neutrophil extracellular traps （NETs）， in the pancreas and lungs， as well as the expression level of ZO-1 in colon tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the Dunnett’s t-test was used for further comparison between two groups. ResultsCompared with the control group， the model group had severe injury in the pancreas and lungs and significant increases in the activity of serum α- amylase and lipase and the levels of the proinflammatory cytokines IL-6， interleukin-1β （IL-1β）， and TNF-α in serum and lung tissue （all P<0.05）， as well as significant increases in NF-κB activation， neutrophil infiltration， and the formation of NETs in the pancreas and lungs （all P<0.05）. Compared with the model group， the CA group had alleviated pathological injury of the pancreas and lungs and significant reductions in the activity of serum α-amylase and the levels of the proinflammatory cytokines IL-6， IL-1β， and TNF-α in serum and lung tissue （all P<0.05）， as well as significant reductions in NF-κB activation， neutrophil infiltration， and the formation of NETs in the pancreas and lungs （all P<0.05）. ConclusionCA can alleviate SAP induced by caerulein combined with LPS in mice， possibly by inhibiting neutrophil recruitment and the formation of NETs.

Palliative care is recognized as an effective measure to improve the quality of life for patients with end-stage diseases， and the significance and role of such patients participating in clinical trials to conquer major diseases has also become a broad consensus. However， due to the special physical， psychological， and social conditions of terminal trial participants， the ethical problems encountered in the trial process are more serious and complex. Drawing on ethical practice experience， these seemingly common phenomena and issues were deeply analyzed. Combined with the palliative care philosophy for end-stage patients， this paper proposed a series of improvement suggestions throughout the entire life cycle of clinical trials， hoping to promote the quality improvement of clinical research in which end-stage patients participate as subjects， while effectively protecting the safety and rights of the subjects and ensuring they receive appropriate palliative care during their participation in clinical trials or clinical-related scientific research.

The clinical data of a patient with Klinefelter syndrome (KS) complicated by partial androgen insensitivity syndrome (PAIS) was retrospectively analyzed.The patient, a 2-month-and-22-day-old baby, was admitted to Children′s Hospital Affiliated to Zhengzhou University due to abnormal external genitalia in October 2021.Upon birth, the patient exhibited abnormal external genitalia, manifested as clitoral hypertrophy.Hormonal examinations were consistent with those of peers, while chromosomal analysis revealed 47, XXY.Due to the severe undermasculinization, whole exome sequencing was conducted, indicating a heterozygous variant of the AR gene (c.1847G>A, p.Arg616His). The patient was diagnosed with PAIS, and her elder sister was diagnosed with complete androgen insensitivity syndrome.For further treatment, a multidisciplinary comprehensive evaluation is needed.This is a rare case of KS combined with PAIS, suggesting the possibility of AR gene mutations in KS children with severe undermasculinization.

Objective:The Capital′s Funds for Health Improvement and Research (referred to as ″CFH″), established to address clinical medical issues, have been operating for over a decade. This study aims to comprehensively evaluate the achievements of this fund and provide empirical support and recommendations for optimizing the operational model of the clinical research fund.Methods:An online questionnaire was used to investigate the following aspects of CFH: subject area, the person in charge, derived projects, theses, patents, transformation of results, and popularization and promotion.Results:A total of 745 projects were collected through the online survey, and after rechecking for outliers, 720 completed projects were ultimately included. The top three disciplinary domains, in terms of the number of completed projects, were oncology, cardiovascular diseases, and neurological disorders. The age distribution of project leaders exhibited a left-skewed pattern, with a median age of 45 years. 319 (44%) received support from other related projects subsequently. 95% of the projects resulted in paper publication. 211 (29%) projects applied for patents and copyrights, with 141 projects being granted patent authorization. 78 (11%) projects successfully achieved technology transfer, with transfer and licensing being the most common modes. 156 (22%) projects disseminated their outputs, often targeting secondary hospitals and community health institutions.Conclusions:CFH aligns with local needs, and the outputs are substantial. In the future, consideration can be given to establishing an evaluation mechanism, increasing efforts to promote high-quality outputs, strengthening the organizational model set by the project guidelines, and further improving the rolling support mechanism.

ObjectiveTo observe the effects of Sargassum and Glycyrrhizae Radix et Rhizoma incompatible pair with the Haizao Yuhutang （HYT） on oxidative stress in the liver of goiter rats under the condition of 2 times the dose limit of the Pharmacopoeia of the People's Republic of China 2020. MethodA total of 128 male Wistar rats were randomly divided into a blank group， a model group， a euthyrox group （20 μg·kg^-1）， a HYT group （12.06 g·kg^-1）， a HYT without Sargassum （HYT-H） group （9.90 g·kg^-1）， a HYT without Glycyrrhizae Radix et Rhizoma （HYT-G） group （10.26 g·kg^-1）， a HYT without Sargassum and Glycyrrhizae Radix et Rhizoma （HYT-HG） group （8.10 g·kg^-1）， and a Sargassum and Glycyrrhizae Radix et Rhizoma （HG） group （3.96 g·kg^-1）. The blank group was given deionized water by gavage， and the others were given propylthiouracil （PTU） to replicate the goiter pathological model. Euthyrox was taken as a positive control drug， and the rest of the Chinese medicine groups were given the corresponding decoction by gavage， the material was collected 12 hours after the last dose. The serum levels of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， alkaline phosphatase （ALP）， and the contents of superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px）， malondialdehyde （MDA）， reactive oxygen species （ROS） in liver tissue were detected in each group. The pathological changes in the liver were observed via hematoxylin-eosin （HE） staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was utilized to detect the mRNA expressions of Kelch-like Ech-associated protein 1 （Keap1）， nuclear factor E₂-related factor 2 （Nrf2）， heme oxygenase-1 （HO-1）， p53 and Caspase-3 in liver tissues. Western blot was adopted to detect the protein expressions of Nrf2 and HO-1 in liver tissues in oxidative stress-related signaling pathways. ResultCompared with control group， the model group showed significantly increased serum ALT level and contents of MDA and ROS in liver tissues （P<0.05， P<0.01）， significantly reduced activities of SOD and GSH-Px in the liver （P<0.01）， significantly increased mRNA expression of Keap1 （P<0.01）， and significantly decreased mRNA and protein expressions of Nrf2 and HO-1 （P<0.05， P<0.01）. Compared with the model group， the HYT group manifested significantly reduced serum levels of AST， ALT， and ALP （P<0.05， P<0.01）， significantly reduced contents of MDA and ROS in liver tissue （P<0.01）， significantly increased the activities of SOD and GSH-Px （P<0.01）， significantly decreased mRNA expressions of Keap1， p53， and Caspase-3 （P<0.01）， and significantly increased mRNA and protein expressions of Nrf2 and HO-1 （P<0.05， P<0.01）. ConclusionUnder the condition of 2 times the dose limit of the Pharmacopoeia of the People's Republic of China 2020， Sargassum and Glycyrrhizae Radix et Rhizoma incompatible pair with the HYT on oxidative stress in the liver of goiter rats had different effects. The HYT that contains Sargassum and Glycyrrhizae Radix et Rhizoma has a protective effect on the liver of goiter rats， and the effect is better than that of the HG group， the euthyrox group， and the incomplete groups. Its mechanism may be related to activating the Nrf2/HO-1 signaling pathway to alleviate liver oxidative stress and inhibiting the p53/Caspase-3 signaling pathway to reduce hepatocyte apoptosis.

Objective:To explore the clinical features and genetic variants in three children suspected for β-ketothiolase deficiency (BKTD).Methods:Clinical manifestations, laboratory examination and genetic testing of three children suspected for BKTD at Henan Children′s Hospital between January 2018 and October 2022 were collected, and their clinical and genetic variants were retrospectively analyzed.Results:The children were all males with a age from 7 to 11 months. Their clinical manifestations have included poor spirit, shortness of breath, vomiting, convulsions after traumatic stress and/or infection. All of them had severe metabolic acidosis, elevated ketone bodies in blood and urine, hypoglycemia, with increased isoprenyl-carnitine and 3-hydroxyisovalyl-carnitine in the blood, and 2-methyl-3-hydroxybutyrate and methylprotaroyl glycine in the urine. All of them were found to harbor compound heterozygous variants of the ACAT1 gene, including c. 1183G>T and a large fragment deletion (11q22.3-11q23.1) in child 1, c. 121-3C>G and c. 826+ 5_826+ 9delGTGTT in child 2, and c. 928G>C and c. 1142T>C in child 3. The variants harbored by children 2 and 3 were known to be pathogenic or likely pathogenic. The heterozygous c. 1183G>T variant in child 1 was unreported previously and rated as a variant of unknown significance (PM2_Supporting+ PP3+ PP4) based on guidelines from the American College of Medical Genetics and Genomics. The large segment deletion in 11q22.3-11q23.1 has not been included in the DGV Database and was rated as a pathogenic copy number variation. Conclusion:The variants of the ACAT1 gene probably underlay the pathogenesis of BKTD in these three children.

Objective:The clinical and molecular genetic characteristics of 46, XY disorders of sex development caused by NR5A1 gene variants in 15 cases were analyzed to improve the understanding of this disease. Methods:The clinical data of children with NR5A1 gene variants diagnosed at the Children′s Hospital Affiliated to Zhengzhou University from March 2016 to December 2021 were retrospectively analyzed. Whole exome sequencing was performed to confirm the candidate sites, and Sanger sequencing was performed for validation. The patients were treated and followed up according to their disease characteristics. Results:At the initial diagnosis, 5 of the 15 cases were raised as females and 10 as males. The gonadal tissue was testis without residual Müllerian or ooticular structure, and all had various degrees of genital abnormalities. The average EMS masculinity score was 4.8 (1~9), including micropenis (100.0%), hypospadia (86.7%), unfused scrotum (46.7%), and abnormal testicular position (60.0%), in which the hypospadias was Ⅱ°~Ⅳ°. There was no skin pigmentation in 5 patients with growth retardation. Chromosomol karyotypes were 46, XY, adrenocorticotropin and cortisol levels were normal, electrolyte levels were normal, HCG stimulation test in 5 cases had normal response, 9 cases had low response. Anti-Müllerian hormone and statin B had decreased abnormally with age. A total of 14 NR5A1 variants were detected in the 15 children, most of which occurred in exon 4, of which 9 variant loci were not included in the HGMD database as of December 2022. Conclusion:The clinical phenotype of 46, XY abnormal sexual development caused by NR5A1 gene variants is extensive, with the external genitals showing varying degrees of insufficient masculinization. Adrenal involvement is rare.

Objective To construct an integrated pharmaceutical care model for chronic respiratory system disease patients,and to provide policy recommendations.Methods A field survey,a semi-structured interview,and a questionnaire survey were comprehensively used to investigate the effect of the reform and the status quo of pharmaceutical care for chronic respiratory diseases after the medicine consistency reform in the medical alliance of Chongqing.Subsequently,the rainbow model was used to assess the challenges in the macro,meso,micro,and supporting element's dimensions,and the integrated pharmaceutical care model was established as a consequence.Results The primary issues involved in the medical alliance were as followed:insufficient joint reformation for public health services,medical insurance,and medical production and circulation(JRPMM);deficient supporting policies;a dearth of information support;an inadequately list of medications;insufficient collaboration among chronic disease specialties;and unstandardized pharmaceutical care.Consequently,the following recommendations were:in the macro dimension,to strengthen the JRPMM to enhance the service capacity of primary hospitals and to develop suitable human resource coordination mechanisms.In the meso dimension,to intensify the reform of pharmaceutical care in the medical alliance and enhance specialty collaboration horizontally.In the micro dimension,to establish a pharmaceutical management committee in the medical alliance,to formulate pharmaceutical technical specifications for the hierarchical medical system,and to combine"talent and technology"training innovatively.In the supporting elements dimension,to bolster information support in the area and to develop suitable incentives and assessment institutions.Conclusion This paper reported an integrated pharmaceutical care model for chronic respiratory diseases,which could serve as a reference for standardizing the hierarchical medical system for chronic diseases.

OBJECTIVE To explore the effects of trichloroisocyanuric acid(TCCA)on the prolifera-tion of spermatogonia by inducing oxidative stress and ferroptosis.METHODS GC-1 cells were cultured in DMEM-F12 medium,and cell proliferation was plotted according to the growth curve.GC-1 cells were treated with TCCA at concentrations of 0(cell control),97,194,and 387 μmol·L-1 for 24 h.Cell viability was detected using the CCK-8 method,apoptosis cells were stained with Hoechst 33342,cell cycle was examined by PI staining method,RT-qPCR was performed to measure the mRNA expres-sion levels of apoptosis-related genes Bax,Fas,oxidative stress-related genes superoxide dismutase 2(SOD2),glutathione peroxidase 4(GPX4),nuclear factor erythroid 2-related factor 2(Nrf2),solute carrier family 7 member 11(SLC7A11),dihydroorotate dehydrogenase(DHODH),DNA methyltransferase 3A(DNMT3A),and DNA methyltransferase 3L(DNMT3L).The Griess method was used to determine the nitric oxide(NO)content,colorimetric method for the malondialdehyde(MDA)level,DCFH-DA fluores-cence probe method for the reactive oxygen species(ROS)level,DNTB colorimetric method for the reduced glutathione(GSH)content,and WST-8 method for the reduced coenzymeⅡ(NADPH)content.RESULTS Compared with the cell control group,the cell survival rates in the TCCA 194 and 387 μmol·L-1 groups decreased significantly(P<0.01),accompanied by nuclear condensation and fragmentation,a significant increase in apoptosis rate(P<0.01),and cell arrest in the G2/M phase(P<0.05).Additionally,in the TCCA 387 μmol·L-1 group,the levels of NO,MDA and ROS increased(P<0.01),while the levels of GSH and NADPH decreased(P<0.01).Moreover,the mRNA expressions of SOD2,GPX4,Nrf2,SLC7A11,and DHODH decreased(P<0.05,P<0.01),while the expressions of Bax,Fas,DNMT3L,and DNMT3A increased(P<0.05,P<0.01).CONCLUSION TCCA exposure reduces the viability of GC-1 cells,inhibits cell proliferation,induces apoptosis of GC-1 cells.The mechanism may be related to the ability of TCCA to enhance oxidate stress,induce ferroptosis,and interfere with the methylation of GC-1 cells.

Objective:To establish a nomogram for preoperative differentiating intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC) based on clinical, ultrasound, and contrast-enhanced ultrasound (CEUS) data.Methods:A retrospective analysis was conducted on ultrasound and CEUS data of 462 patients who underwent hepatectomy in Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2016 to December 2023, including 262 cases of HCC (56.7%) and 200 cases of ICC (43.3%). The data were randomly divided into training set ( n=324) and validation set ( n=138) in a 7∶3 ratio. Univariate analysis was used to initially screen for variables with statistically significant differences between HCC and ICC groups in the training set, and LASSO regression was performed to select the variables with higher coefficients. Logistic regression analyses were then used to predict independent risk factors for ICC. A nomogram was drawn using R software. The performance of the nomogram was then validated using ROC curve, calibration curve, and decision curve analysis (DCA). Results:Univariate analysis showed that there were significant differences in age, gender, liver cirrhosis, HBsAg (+ ), ALP >185 U/L, CA19-9 >27 kU/L, CA242>10 kU/L, irregular shape, border, cholangiectasis, portal vein tumor thrombus, enhanced pattern in arterial phase, clearance time <60 s, intra-tumoral vein between ICC and HCC groups (all P<0.05). The top 10 features were selected for LASSO regression analysis. Logistic regression analysis revealed that gender, cirrhosis, CA19-9>27 kU/L, CA242>10 kU/L, cholangiectasis, clearance time <60 s, intra-tumoral vein and enhanced pattern in arterial phase were risk factors for ICC (all P<0.05). The area under the ROC curve in the training and validation groups were 0.963 and 0.914, respectively. In the training group, the specificity and sensitivity of the nomogram were 0.926 and 0.917, respectively, and in the validation group, they were 0.875 and 0.871, respectively. The calibration curve showed that the prediction effect of the model was in good agreement with the actual situation. DCA showed that the nomogram could increase the net benefit to the different diagnosis of ICC in patients. Conclusions:The nomogram based on clinical, ultrasound and CEUS features has a good predictive value for preoperative identification of ICC and provides reliable evidence for clinical practice.