ObjectiveTo investigate the protective effect of α-ketoglutarate （α-KG） on hepatic lipid deposition in offspring caused by arsenic exposure during pregnancy. Methods8-week-old institute of cancer research （ICR） mice were mated in a ratio of 2∶1 between females and males， and the detection of vaginal plugs confirmed pregnant. A total of 32 pregnant mice were randomly divided into four groups： control group， arsenic group， α-KG group， arsenic+α-KG group. On gestational day 0-16 （GD0-GD16）， the arsenic and arsenic+α-KG groups were exposed to sodium arsenite （NaAsO₂ ，15 mg/L） in drinking water everyday， and the α-KG and arsenic+α-KG groups were gavaged with α-KG （2 g/kg） everyday. On GD16， pregnant mice were euthanized to collect fetal liver， and fetal body weight and crown-rump length were measured. Gene expression differences between the control group and the arsenic group were analyzed by transcriptome. The total triglycerides （TGs） and subtypes in fetal liver were detected by liquid chromatography tandem mass spectrometry （LC-MS/MS）. Oil red O staining was used to observe the histopathological changes in the liver. Quantitative polymerase chain reaction （qPCR） was used to detect the expression level of genes related to lipid synthesis， transport， and degradation， and phosphatidylinositol 3' -kinase/ protein kinase B （PI3K/AKT） in the liver of fetus. ResultsTranscriptomics analysis showed that 2 144 genes were downregulated and 1 675 genes were upregulated in the arsenic exposed fetal liver； body weight and crown-rump length were reduced （P_TuKey<0.05）； the level of hepatic TGs was elevated in arsenic group （P_TuKey<0.05）； oil-red O staining showed a significant increase in lipid droplets in arsenic group （P_TuKey<0.01）； the expression of lipid synthesis-related genes were significantly upregulated （P_TuKey<0.05）； the expression of β-oxidation-related genes and lipid degradation-related genes were downregulated （P_TuKey<0.05）； the expression of PI3K， AKT decreased（P_TuKey<0.05）. Compared with the arsenic group， the body weight and crown-rump length of fetus increased in the arsenic+α-KG group （P_TuKey<0.05）； the level of hepatic TGs decreased in the arsenic+α-KG group （P_TuKey<0.05）； oil red O staining showed lipid droplets significantly decreased （P_TuKey<0.01）； the expression of lipid synthesis-related genes were downregulated （P_TuKey<0.05）， the expression of β-oxidation-related genes and lipid degradation-related genes were upregulated （P_TuKey<0.05）； the expression levels of PI3K and AKT increased （P_TuKey<0.05）. Conclusionα-KG alleviated hepatic lipid deposition in offspring exposed to arsenic during pregnancy through activating PI3K/AKT signaling pathway.

Elderly end-of-life patients often experience distress due to being caught in dilemmas of contemplation and decision-making. Narrative wills， grounded in life values and premised on respecting individual wishes and needs， present an individual’s unique life story through narrative forms， conveying their overall experience， interpretation of meaning， and understanding of life. They are preserved and passed on in a way that meets individual expectations， thereby promoting human exploration， reflection， and growth regarding the meaning of life through interpersonal interactions that transcend space and time. This paper explored the concept of narrative wills among elderly end-of-life patients， the ethical value and ethical principles of narrative wills， and the moral and ethical risks. It also provided specific ethical interpretations， assisting in the application and development of narrative wills in elderly end-of-life patients.

Objective: To explore the effects of Cldn14 gene knockout on renal metabolism and stone formation in rats，so as to provide reference for research in the field of urinary calium metabolism and stone formation. Methods: Cldn14 gene knockout homozygous rats and wild-type rats of the same age were randomly divided into 4 groups：wild-type control (WC) group，wild-type ethylene glycol (WE) group，gene knockout control (KC) group and gene knockout ethylene glycol (KE) group，with 10 rats in each group.The WE and KE groups were induced with ethylene glycol + ammonium chloride to form kidney stones，while the WC and KC groups received normal saline gavage.After 4 weeks of standard maintenance feeding，the urine samples were collected to detect the venous blood.The kidneys were collected for HE，Pizzolatto's staining and transmission electron microscopy.The protein in renal tissues was extracted to detect the expressions of Claudin16 and Claudin19. Results: Crystal deposition was observed in the renal tubular lumen of the WE and the KE groups，and more crystals were detected in the KE group.The WE group had a large number of intracytoplasmic black crystalline inclusions observed in renal tubular epithelial cells under transmission electron microscope，followed by the KE and KC groups.Compared with WC and WE groups，KC and KE groups had significantly decreased serum calcium and magnesium levels but significantly increased urinary calcium level.In addition，the urinary calcium level was higher in the WE group than in the WC group and higher in the KE group than in the KC group.The KE group had lower level of Claudin16，but there was no significant difference in the level of Claudin19 among the 4 groups(P>0.05). Conclusion: Knockout of Cldn14 gene alone cannot effectively reduce urinary calcium excretion or reduce the risk of stone formation in rats，which may be related to the decrease of Claudin16 level.

OBJECTIVE To analyze the characteristics of peripheral blood leukocyte morphology,scatterplot and leukocyte cell population data(CPD)in patients with severe fever and thrombocytopenia syndrome(SFTS),infec-tious mononucleosis(IM)and hemorrhagic fever with renal syndrome(HFRS),and to explore their differences.METHODS Blood routine examination data were collected,including microscopic cell images,scatter-plots and leukocyte CPD study parameters from 44 patients diagnosed with SFTS,17 with IM and 11 with HFRS at the First Affiliated Hospital with Nanjing Medical University from Mar.2023 to May 2024.These data were compared with those of healthy controls to explore specific differences in the characteristics of peripheral blood leu-kocyte.RESULTS All 3 viral infections exhibited a left shift in the nucleus under the microscope,yet the blood routine scatterplot and microscopic leukocyte characteristics differed.SFTS commonly presented with a plasmacy-toid reactive lymphocyte with scattered points appearing in the upper reactive lymphocyte area of the scatterplot.IM showed a predominant irregular fried-egg-like reactive lymphocyte under the microscope,with the scatterplot typically presenting a rocket-like shape,in patients with HFRS,there was a significant increase in im-mature granulocytes in peripheral blood and plasmacytoid reactive lymphocyte scatter points with blue immature granulocyte scatter points visible.The fluorescence distribution width(MO-WY)of monocytes in the SFTS group was lower than those in the IM,HFRS and healthy control groups(P＜0.05).Compared to SFTS,IM and healthy control groups,the lateral scattered light distribution width(NE-WX)and fluorescence distribution width(NE-WY)of neutrophils in the HFRS group were both increased(P＜0.05).CONCLUSIONS There are signifi-cant differences in the characteristics of peripheral blood leukocyte morphology,scatterplot and CPD study param-eters among three viral infection diseases SFTS,IM and HFRS.These differences can provide early clinical advice and assist in clinical differentiation.

Objective:To analyze the effect of joint management of type 2 diabetes mellitus (T2DM) between specialty and community under the model of National Diabetes Prevention and Control Center (DPCC).Methods:A total of 2 527 T2DM patients managed by DPCC Pingshan Center of Shenzhen from January 1, 2022 to December 31, 2024 were retrospectively included. After management, the rate of downturn, reexamination rate, blood pressure compliance rate, metabolic indicators (waist circumference, body mass index, fasting blood glucose, glycosylated hemoglobin, blood lipids) and screening rate of chronic complications of diabetes (atherosclerotic cardiovascular disease, microvascular disease, diabetic peripheral neuropathy) were analyzed. Those included 2022 ( n=564), 2023 ( n=1 477), and 2024 ( n=2 527). Results:The downturn rate in 2022, 2023 and 2024 increased year by year (22.8% vs 67.2% vs 89.9%, P<0.01), and the review rate (41.1% vs 62.2% vs 52.7%, P<0.01), complication screening rate (51.6% vs 85.3% vs 62.2%, P<0.01), blood pressure compliance rate (53.1% vs 78.0% vs 67.2%, P<0.01), body mass index compliance rate (13.2% vs 17.3% vs 28.6%, P<0.01), fasting blood glucose meeting rate (46.4% vs 60.2% vs 68.5%, P<0.01), glycated hemoglobin meeting rate (58.4% vs 63.2% vs 45.6%, P<0.01) were relatively improved. Waist circumference compliance rate (30.6% vs 27.7% vs 21.6%) and blood lipid compliance rate (33.6% vs 35.5% vs 31.9%) were not significantly improved, and the review rate, blood pressure compliance rate and complication screening rate in 2024 were lower than those in 2023 and higher than those in 2022. Conclusions:The combined management of type 2 diabetes under the DPCC model has significant effects on improving the down-conversion rate, rediagnosis rate, blood pressure compliance rate, metabolic index compliance rate and the screening rate of diabetes-related chronic complications in patients with diabetes. At the same time, it was also found that with the progress of hierarchical diagnosis and treatment, the review rate, complication screening rate, blood pressure, waist circumference, blood lipid and glycosylated hemoglobin reached the standard of patients decreased compared with the previous situation, which needs to be further analyzed and improved.

Aging is comprehensively influenced by multiple fac-tors such as internal genes,cellular metabolism,external envi-ronment,and lifestyle habits.Among them,epigenetic regula-tion plays a core role.Epigenetic modifications,including DNA methylation,histone modification,heterochromatin remodeling,and non-coding RNA regulation,act in concert with the three-di-mensional genome architecture to precisely regulate gene expres-sion.This review elaborates on the factors influencing epigenetic regulation,as well as the mechanisms of how epigenetics affects the occurrence of organismal aging and the corresponding inter-vention strategies,providing relevant insights for uncovering the mechanisms of aging and preventing/treating aging-related disea-ses.

Objective To conduct preoperative simulations of three different osteotomy line design schemes under centric occlusion based on two distinct material assignment methods,evaluate biomechanical properties of the models,and explore which osteotomy line design schemes are more suitable for different types of mandibles.Methods Three types of mandibles were selected,and CT images were obtained for three-dimensional(3D)reconstruction.Material assignment was completed using the cortical/cancellous bone assignment method and the gray value assignment method.Osteotomy was simulated according to the three osteotomy line design schemes,followed by finite element analysis.Results In all simulation results of the mandibles,the maximum stress was 81.10 MPa,the maximum strain was 0.035 52,and the maximum displacement was 432.4 μm.The stress distributions obtained by the cortical/cancellous bone assignment method showed a larger stress distribution range than that that by the gray value assignment methods,but the maximum stress,strain,and displacement were generally lower.For the outflare type and common type mandibles,Scheme 1 showed lower maximum stress,strain,and displacement under both material assignment methods,but no clearly suitable scheme was found for the retracted type.Conclusions The outflare type and common type mandibles are more suitable for adopting the osteotomy line design scheme of Scheme 1.For the retracted type,other mandibular angle osteotomy plastic surgery methods may be considered to ensure better biomechanical characteristics.Whether choosing the osteotomy line design scheme or the modeling material assignment method,it is necessary to make the final decision based on the specific analysis objective and resource conditions.

Objective:To explore the activation pathway of CD4+CD28-T cells and their specific role in rheumatoid arthritis(RA).Methods:Peripheral blood mononuclear cells(PBMCs)were isolated from RA patients and healthy individuals.Flow cytome-try was used to detect the proportion and activation level of CD4+CD28-T cells,as well as the expressions of perforin and TNF-α,and to analyze the correlation between the proportion of CD4+CD28-T cells and age,C-reactive protein,anti-cyclic citrullinated peptide(CCP)antibodies,rheumatoid factors(RF)and erythrocyte sedimentation rate(ESR).The expression of Toll-like receptor(TLR)2 on CD4+CD28-T cells was detected by flow cytometry.Purified RA CD4+T cells were stimulated with anti-CD3 antibody and TLR2 agonist alone or in combination,and the activation level and cytokine secretion of CD4+CD28-T cells were detected by flow cytometry.Results:The proportion of CD4+CD28-T cells in RA patients was higher than that in healthy individuals(P<0.05),and was positively correlated with rheumatoid factors and erythrocyte sedimentation rate(r=0.554 1,P<0.01;r=0.363 4,P<0.01).Compared with CD4+CD28+T cells,CD25 expression was downregulate(P<0.01),but CD40L and TLR2 expressions were upregulated(P<0.01;P<0.000 1)in CD4+CD28-T cells from RA patients,and they secreted more perforin and TNF-α(P<0.001;P<0.001).After TLR2 ago-nist stimulation,there was no significant change in CD40L and CD25 expression,as well as perforin and TNF-α secretion in CD4+CD28-T cells from RA patients.Conclusion:The proportion of CD4+CD28-T cells is increased in RA patients,and they secrete a large amount of perforin and TNF-α,which may be involved in the inflammatory state and joint damage of RA,but TLR2 cannot re-place CD28 in activating CD4+CD28-T cells.

Objective:To compare the efficacy of different doses of tranexamic acid (TXA) for traumatic hemorrhagic shock (THS) in the early phase of trauma following acute exposure to high altitude in rabbits.Methods:Twenty-five healthy male New Zealand rabbits were randomly divided into plain control group ( n=5) and acute high-altitude THS group ( n=20) according to the random number table method. The plain control group did not undergo THS modeling throughout the experiment while the acute high-altitude THS group was raised in a hypoxia simulation chamber with a volume fraction of 10% for 3 days to establish the THS model. Based on the different doses of TXA administered intravenously at 30 minutes after THS modeling, the acute high-altitude THS group was further divided into four subgroups: acute high-altitude THS+0 mg/kg TXA subgroup, acute high-altitude THS+45 mg/kg TXA subgroup, acute high-altitude THS+90 mg/kg TXA subgroup and acute high-altitude THS+135 mg/kg TXA subgroup, with 5 rabbits in each. The vital signs [mean arterial pressure (MAP), heart rate, rectal temperature] and blood cell counts [red blood cell count (RBC), platelet count (PLT)], 4 coagulation parameters [fibrinogen (FIB), D-dimer, activated partial thromboplastin time (APTT), prothrombin time (PT)], thromboelastography [clotting reaction time (R value), clot formation time (K value), maximum amplitude (MA value)], syndecan-1, inflammatory factors [interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)], and plasminogen activator inhibitor-1 (PAI-1) were recorded before blood loss, at 30 minutes and 120 minutes after blood loss. At 6 hours after THS, the lungs, terminal ileum, and kidneys of the rabbits were collected to observe tissue damage, and the wet/dry weight ratio (W/D) and total water content (TLW) of the lung tissue were measured. Results:(1) Vital signs: Before blood loss, there were no significant differences in MAP, heart rate, or rectal temperature between the acute high-altitude THS subgroups and the plain control group ( P>0.05). At 30 minutes and 120 minutes after blood loss, the acute high-altitude THS subgroups exhibited significantly lower MAP, heart rate, and rectal temperature compared to those in the plain control group ( P<0.05). No significant differences were observed in MAP, heart rate or rectal temperature among the acute high-altitude THS subgroups at any time point ( P>0.05). In the acute high-altitude THS subgroups, MAP, heart rate and rectal temperature were significantly decreased at 30 minutes and 120 minutes after blood loss compared to those before blood loss ( P<0.05); At 120 minutes after blood loss, these parameters were further significantly decreased compared to those at 30 minutes after blood loss ( P<0.05). (2) Blood cell counts: Before blood loss, the RBC count was significantly higher in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), while the PLT was significantly lower ( P<0.05). At 30 minutes after blood loss, there was no significant difference in RBC count between the acute high-altitude THS subgroups and the plain control group ( P>0.05), but the PLT remained significantly lower in the acute high-altitude THS subgroups ( P<0.05). At 120 minutes after blood loss, the RBC count was significantly lower in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), with no significant differences among the acute high-altitude THS subgroups ( P>0.05). The PLT count was significantly lower in the acute high-altitude THS+0 mg/kg TXA subgroup compared to the other subgroups ( P<0.05). The PLT count in the acute high-altitude THS+45 mg/kg TXA subgroup was significantly lower than those in the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P<0.05), with no significant differences between the latter two subgroups ( P>0.05). (3) Four Coagulation parameters: Before blood loss, D-dimer level was significantly higher in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), while no significant difference was observed in FIB ( P>0.05). APTT and PT were significantly shortened in the acute high-altitude THS subgroups ( P<0.05). At 30 minutes after blood loss, D-dimer level remained significantly higher in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), while FIB was significantly lower ( P<0.05), with significant increase of APTT and PT compared to those before blood loss ( P<0.05). At 120 minutes after blood loss, the acute high-altitude THS+0 mg/kg TXA subgroup exhibited significantly higher D-dimer level compared to the other subgroups ( P<0.05), with significantly lower FIB and higher APTT and PT ( P<0.05). The acute high-altitude THS+45 mg/kg TXA subgroup also showed significantly higher D-dimer level compared to those in the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P<0.05), with significantly lower FIB and increased APTT and PT ( P<0.05). No significant differences were observed in D-dimer, FIB, APTT or PT between the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P>0.05). (4) Thromboelastography parameters: Before blood loss, the R value was significantly shorter in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), while no significant differences were observed in K value or MA value ( P>0.05). At 30 minutes after blood loss, both R value and K value were significantly shorter in the acute high-altitude THS subgroups compared to those in the plain control group ( P<0.05), with no significant differences in MA value ( P>0.05). At 120 minutes after blood loss, the acute high-altitude THS+0 mg/kg TXA subgroup exhibited significantly increased R value and K value compared to those in the other subgroups ( P<0.05), while MA value was significantly decreased ( P<0.05). The remaining acute high-altitude THS subgroups showed significant decrease of R value and K value compared to those in the plain control group ( P<0.05), while MA value was significantly lower ( P<0.05). The acute high-altitude THS+45 mg/kg TXA subgroup exhibited significantly lower R value and K value compared to those in the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P<0.05), with no significant differences in R value, K value and MA value between the later two groups ( P<0.05). (5) Changes in Syndecan-1, inflammatory factors and PAI-1: Before blood loss, syndecan-1 was significantly higher in the acute high-altitude THS subgroups compared to that in the plain control group ( P<0.05), while no significant differences were observed in IL-6, TNF-α, or PAI-1 ( P>0.05). At 30 minutes after blood loss, syndecan-1, IL-6, TNF-α, and PAI-1 were significantly higher in the acute high-altitude THS subgroups compared to those in the plain control group ( P<0.05). At 120 minutes after blood loss, syndecan-1, IL-6, TNF-α, and PAI-1 were significantly higher in the acute high-altitude THS subgroups compared to those in the plain control group ( P<0.05). Among them, the acute high-altitude THS+0 mg/kg TXA group exhibited significantly higher levels of syndecan-1, IL-6, TNF-α, and PAI-1 compared to the other acute high-altitude THS subgroups ( P<0.05). The acute high-altitude THS+45 mg/kg TXA subgroup had significantly higher syndecan-1, IL-6, and TNF-α compared to those in the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P<0.05), with no significant difference in PAI-1 ( P>0.05). No significant differences were observed in syndecan-1, IL-6, TNF-α or PAI-1 between the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA subgroups ( P>0.05). (6) Tissue injury: At 6 hours after THS, acute high-altitude THS+0 mg/kg TXA group exhibited significant interstitial thickening of the lung with extensive inflammatory cell infiltration, localized loss of intestinal brush border accompanied by cellular disruption, and marked structural disruption of renal corpuscles with focal cellular injury and necrosis. At 6 hours after THS, the acute high-altitude THS+0 mg/kg TXA subgroup exhibited significantly higher lung injury scores, Chiu′s intestinal injury scores, and kidney injury scores compared to those of the other subgroups ( P<0.05). No significant differences were observed in the tissue injury scores of the lungs, intestines and kidneys among the other subgroups ( P>0.05). The acute high-altitude THS+0 mg/kg TXA subgroup also had significantly higher lung W/D and TLW compared to those in the other subgroups ( P<0.05). At 6 hours after THS, the acute high-altitude THS+45 mg/kg TXA group exhibited significantly higher W/D and TLW of the lung tissues compared to those in the acute high-altitude THS+90 mg/kg TXA and acute high-altitude THS+135 mg/kg TXA groups ( P<0.05), with no significant differences between the latter two subgroups ( P>0.05). Conclusions:At 3 days after acute exposure to high altitude, rabbits show a hypercoagulable state of the blood, accompanied by endothelial barrier dysfunction. At 30 minutes after the induction of acute high-altitude THS, a single slow intravenous bolus injection of TXA at doses of 90 mg/kg and 135 mg/kg is more effective in improving coagulation and fibrinolysis function, inflammatory response, endothelial injury, and reduced the risk of pulmonary edema than that at a dose of 45 mg/kg.

Objective To conduct a rapid health technology assessment(rHTA)of the efficacy,safety,and cost-effectiveness of tirzepatide for the treatment of type 2 diabetes mellitus(T2DM),and to provide evidence for clinical medication.Methods PubMed,Web of Science,Embase,Cochrane Library,WanFang Data,CNKI databases,and health technology assessment(HTA)websites were searched to collect systematic reviews/Meta-analysis,pharmacoecomic literature and HTA reports of tirzepatide in the treatment of T2DM from inception to February 28,2025.Two researchers independently conducted literature screening,data extraction,and quality assessment,and then summarized and analyzed the results.Results A total of 13 articles were included,comprising 2 HTA reports,8 systematic reviews/Meta-analyses,and 3 pharmacoeconomic studies.In terms of efficacy,tirzepatide outperformed placebo or other antidiabetic drugs in reducing glycated hemoglobin(HbA1c),increasing the rate of HbA1c＜7％,lowering blood glucose,and reducing weight.The antihyperglycemic and weight-loss effects of tirzepatide were dose-dependent,and it also had certain advantages in reducing the risk of cardiovascular events and renal composite endpoint events.Regarding safety,the incidence of gastrointestinal adverse events in the tirzepatide group was higher than that in the placebo group and the insulin group,mainly manifested as diarrhea,nausea,and vomiting.However,it did not increase the risk of serious gastrointestinal adverse events,nor did it increase the risk of hypoglycemia and pancreatitis.In terms of cost-effectiveness,tirzepatide had cost-utility and cost-effectiveness advantages compared with semaglutide and other antidiabetic drugs.Conclusion Compared with other antidiabetic drugs,tirzepatide has better efficacy,safety,and cost-effectiveness in the treatment of T2DM.