OBJECTIVE To analyze the selection and rationales of comparators for pharmaceutical enterprises in their medical insurance access application， so as to provide a reference for promoting communication and consensus between enterprises and medical insurance authorities in this process. METHODS The application materials for drugs outside the catalogue that passed formal review published by the National Healthcare Security Administration from 2021 to 2025 were extracted， and then content analysis was used to systematically sort out relevant information of the declared drugs and comparators； the specific situations and rationales of pharmaceutical enterprises’ selection of comparators were analyzed. RESULTS A total of 1 341 declared drug documents were collected. Data analysis showed that 1 035 （77.18%） were submitted with positive comparators and 306 （22.82%） used blank comparators； 58 drugs （4.33%） took combination therapy as the reference， and 5 drugs （0.37%） referred to non-pharmacological （or non-single pharmacological） treatment regimens. Among competitive drugs declared by multiple enterprises， 50.00% of the enterprises submitted different comparators. A total of 4 basic conditions and 39 additional conditions were extracted as the rationales for selecting positive comparators. For blank comparators， 12 drug-related factors， 2 administrative factors， and 1 other factor were identified. More than 10% of the drugs did not state the rationale for comparator selection， and over 44% of drugs using blank comparators provided only one justification. CONCLUSIONS Pharmaceutical enterprises mainly select comparators based on their own interests in the medical insurance access application， and there are deficiencies in the adequacy and standardization of their selection basis and reasoning. It is recommended that enterprises follow the principled requirements of medical insurance authorities， and fully and normatively explain the reasons for selecting comparators in combination with the characteristics of their own products. Meanwhile， it is advisable to change the current open-ended statement form of selection reasons into a closed-ended answering mode， so as to highlight the priority of selection， standardize the declaration behavior of enterprises， and reduce communication divergences between the two parties.

Objective To explore the number of peripheral blood regulatory T cells (Treg) in patients with chronic kidney disease (CKD) and its correlation with vascular calcification. Methods This was a single-center, cross-sectional, and observational study. Non-dialysis patients with CKD treated at Zhongshan Hospital, Fudan University from March 2021 to March 2022 were enrolled. Abdominal aortic calcification (AAC) was assessed using lateral abdominal X-ray. Number of Treg and cytokine levels were measured by flow cytometry. Logistic regression analysis was performed to evaluate the related factors for AAC in CKD patients. Results A total of 83 patients were included, aged 17–86 years, with 57 males (68.7%). The distribution of CKD stages was as follows: stage G1 in 7 patients (8.4%), stage G2 in 17 patients (20.5%), stage G3 in 21 patients (25.3%), stage G4 in 19 patients (22.9%), and stage G5 in 19 patients (22.9%). No AAC was observed in patients with stages G1 and G2, while the prevalence of AAC in patients with stages G3, G4, and G5 was 23.8%, 21.1%, and 26.3%, respectively. Compared with stage G1 patients, those with stages G3–5 showed decreased number of peripheral blood Treg and elevated levels of interleukin (IL)-6 and IL-17F (P＜0.05). The area under the receiver operating characteristic curve for number of peripheral blood Treg in predicting AAC in CKD patients was 0.766 (95%CI 0.652–0.879, P＝0.002). Logistic regression analysis showed that decreased number of Treg was related factor for AAC in CKD patients (OR＝0.957, 95%CI 0.922–0.992, P＝0.018). Conclusion As CKD progresses, number of peripheral blood Treg significantly decreases, which is correlated with AAC in CKD patients.

OBJECTIVE To investigate the improvement effects and mechanism of astragaloside Ⅳ （AS- Ⅳ ） on lipopolysaccharide （LPS）-induced neuroinflammation. METHODS BV2 cells were divided into control group， LPS group， AS-Ⅳ groups at concentrations of 20 and 40 μmol/L， and dexamethasone group （2 μmol/L）. Except for control group， neuroinflammation model was established with LPS （1 μg/mL） in other groups after medication. The levels of inflammatory factors [interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， and nitric oxide （NO）] in cell supernatant were measured in each group. Mice were randomly divided into normal group， model group， positive control group （Aspirin enteric-coated tablet， 20 mg/kg）， AS-Ⅳ low- and high-dose groups （10， 20 mg/kg）， with 6 mice in each group. Mice in each group were administered the corresponding drug/normal saline via gavage/intraperitoneal injection， once a day， for 14 consecutive days. Except for normal group， other groups were intraperitoneally injected with LPS （250 μg/kg） 1 hour after daily administration of the drug/normal saline to establish neuroinflammation model. Serum levels of IL-6 and TNF-α were measured 2 h after the last medication； histopathological morphology of cerebral tissue in mice were observed； the co-localization of inducible nitric oxide synthase （iNOS）/ionized calcium binding adapter molecule 1 （Iba1） and CD206/Iba1 in the cerebral cortex region of mice was observed； the expressions of proteins related to the nuclear factor-κB （NF-κB）/mitogen-activated protein kinase （MAPK） signaling pathway in brain tissue of mice were also determined， including NF-κB p65， phosphorylated NF-κB p65（p-NF-κB p65）， p38 MAPK， phosphorylated p38 MAPK （p-p38 MAPK）， extracellular signal-regulated kinase （ERK）， and phosphorylated ERK （p-ERK）. RESULTS In the cell experiments， compared with control group， the levels of IL-6， TNF- α and NO in the cell supernatant of the LPS group were increased significantly （P＜0.05）； compared with LPS group， the levels of IL-6， TNF-α and NO were decreased significantly in the administration groups （P＜0.05）. In the animal experiments， compared with the normal group， the serum levels of IL-6 and TNF- α， the number of iNOS/Iba1 co-localization positive cells in the cerebral cortex， and the phosphorylation levels of p38 MAPK， NF- κB p65 and ERK proteins in brain tissue were all significantly increased/elevated in model group （P＜0.05）； the number of CD206/ Iba1 co-localization positive cells in the cerebral cortex region significantly decreased （P＜0.05）. The neurons in the cerebral cortex and the CA3 region of the hippocampus displayed a disordered arrangement. Compared with model group， above quantitative indexes of mice were all reversed significantly in administration groups （P＜0.05）； the neuronal cells in the cerebral cortex and the CA3 region of the hippocampus exhibited a relatively orderly arrangement. CONCLUSIONS AS-Ⅳ may inhibit the activation of the NF-κB/MAPK signaling pathway， promote the M2-type polarization of microglia， and thereby suppress neuroinflammatory responses.

Background Lead smelting workers are exposed to mixed heavy metals such as lead (Pb) and cadmium (Cd). However, the specific associations and molecular mechanisms by which their combined exposure induces genetic damage remain unclear. Objective To clarify the association between combined Pb-Cd exposure and genetic damage and to explore the possible biological mechanisms through occupational epidemiological investigations and animal experiments. Methods (1) Population study: A cross-sectional study was conducted on 374 lead smelting workers in northern China. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect urinary levels of 8 metals including Pb and Cd, and graphite furnace atomic absorption spectroscopy (GFAAS) was used to quantify blood levels of Pb and Cd. The cytokinesis-block micronucleus assay (CBMN) was used to assess genetic damage. Poisson regression was used to analyze the association between metal exposure and micronucleus rates. (2) In vivo experiment: Thirty SD rats were randomly assigned to five groups: control (pure water), Pb (300 mg·L⁻¹ lead acetate), Cd (50 mg·L⁻¹ cadmium chloride), combined exposure (Pb + Cd), and resveratrol intervention (Pb + Cd + 50 mg·L⁻¹ resveratrol). After 8 weeks of ad libitum drinking water exposure, liver pathology, oxidative stress indicators [reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)], genetic damage (Comet assay and γ-H2AX) were evaluated. Furthermore, cell cycle distribution, apoptosis rates, and mRNA expression of DNA damage response (DDR), DNA repair, and apoptosis-related genes were measured. Results (1) The geometric mean (GM, 95%CI) of urinary Pb and Cd were 14.69 (13.14, 16.51) µg·L⁻¹ and 2.11 (1.90, 2.33) µg·L⁻¹, respectively; the blood Pb and Cd levels were 117.10 (105.59, 129.87) µg·L⁻¹ and 4.55 (4.23, 4.89) µg·L⁻¹, respectively among the 374 workers. The mean micronucleus rate was (1.64±0.081) ‰, with significantly higher rates in males (1.65±0.083) ‰ than females (1.53±0.334) ‰ (U=4.166, P=0.041). All Pb and Cd biomarkers were positively correlated with micronucleus rate (FR>1, P<0.05), with a significant interaction effect observed between Pb and Cd (FR>1, P<0.05). (2) In rats, co-exposure to Pb and Cd caused liver tissue damage and inflammatory infiltration. Significant increases were observed in lymphocyte ROS; GSSG and MDA in lung tissue increased, while GSH and CAT activity decreased. Comet assay indicators and γ-H2AX levels were significantly elevated. Co-exposure induced S-phase arrest and increased apoptosis. mRNA levels of DDR (ATM, ATR, Chk2, and P53) and pro-apoptotic genes (Bax and Caspase-3) were upregulated, while the anti-apoptotic gene Bcl-2 and DNA repair genes (BRCA1, BRCA2, RAD51, RAD52, and CtIP) were downregulated. Two-way ANOVA confirmed synergistic effects on GSSG, Comet assay indicators, and ATR/Chk2 mRNA expression. Conclusion Occupational co-exposure to Pb and Cd synergistically induces genetic damage. This damage is mediated by oxidative stress and DNA damage, which activates the DDR pathway and inhibits the expression of DNA repair genes, ultimately leading to cell cycle arrest and apoptosis.

Background Lead smelting workers are exposed to mixed heavy metals such as lead (Pb) and cadmium (Cd). However, the specific associations and molecular mechanisms by which their combined exposure induces genetic damage remain unclear. Objective To clarify the association between combined Pb-Cd exposure and genetic damage and to explore the possible biological mechanisms through occupational epidemiological investigations and animal experiments. Methods (1) Population study: A cross-sectional study was conducted on 374 lead smelting workers in northern China. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect urinary levels of 8 metals including Pb and Cd, and graphite furnace atomic absorption spectroscopy (GFAAS) was used to quantify blood levels of Pb and Cd. The cytokinesis-block micronucleus assay (CBMN) was used to assess genetic damage. Poisson regression was used to analyze the association between metal exposure and micronucleus rates. (2) In vivo experiment: Thirty SD rats were randomly assigned to five groups: control (pure water), Pb (300 mg·L⁻¹ lead acetate), Cd (50 mg·L⁻¹ cadmium chloride), combined exposure (Pb + Cd), and resveratrol intervention (Pb + Cd + 50 mg·L⁻¹ resveratrol). After 8 weeks of ad libitum drinking water exposure, liver pathology, oxidative stress indicators [reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)], genetic damage (Comet assay and γ-H2AX) were evaluated. Furthermore, cell cycle distribution, apoptosis rates, and mRNA expression of DNA damage response (DDR), DNA repair, and apoptosis-related genes were measured. Results (1) The geometric mean (GM, 95%CI) of urinary Pb and Cd were 14.69 (13.14, 16.51) µg·L⁻¹ and 2.11 (1.90, 2.33) µg·L⁻¹, respectively; the blood Pb and Cd levels were 117.10 (105.59, 129.87) µg·L⁻¹ and 4.55 (4.23, 4.89) µg·L⁻¹, respectively among the 374 workers. The mean micronucleus rate was (1.64±0.081) ‰, with significantly higher rates in males (1.65±0.083) ‰ than females (1.53±0.334) ‰ (U=4.166, P=0.041). All Pb and Cd biomarkers were positively correlated with micronucleus rate (FR>1, P<0.05), with a significant interaction effect observed between Pb and Cd (FR>1, P<0.05). (2) In rats, co-exposure to Pb and Cd caused liver tissue damage and inflammatory infiltration. Significant increases were observed in lymphocyte ROS; GSSG and MDA in lung tissue increased, while GSH and CAT activity decreased. Comet assay indicators and γ-H2AX levels were significantly elevated. Co-exposure induced S-phase arrest and increased apoptosis. mRNA levels of DDR (ATM, ATR, Chk2, and P53) and pro-apoptotic genes (Bax and Caspase-3) were upregulated, while the anti-apoptotic gene Bcl-2 and DNA repair genes (BRCA1, BRCA2, RAD51, RAD52, and CtIP) were downregulated. Two-way ANOVA confirmed synergistic effects on GSSG, Comet assay indicators, and ATR/Chk2 mRNA expression. Conclusion Occupational co-exposure to Pb and Cd synergistically induces genetic damage. This damage is mediated by oxidative stress and DNA damage, which activates the DDR pathway and inhibits the expression of DNA repair genes, ultimately leading to cell cycle arrest and apoptosis.

[Objective] To explore the clinical features of IgG4-related urinary diseases so as to provide reference for the diagnosis and treatment of such diseases. [Methods] The clinical data of 4 cases of IgG4-related urinary system diseases diagnosed and treated in Xijing Hospital of Air Force Medical University during Aug.2019 and Dec.2023 were retrospectively collected.Here, we report on the diagnosis and treatment of these patients, analysing their symptoms, serology, imaging and pathology as well as their treatment and outcomes. [Results] The patients included 2 male and 2 female.The lesions were involved with the retroperitoneum and urinary system.Three patients had symptoms of lumbar pain.The imaging manifestations were complex, including retroperitoneal mass involving urinary system organs in 2 cases, tabdense shadow of the right kidney in 1 case, and simple cystic mass of kidney in 1 case.Serum IgG4 value was not detected before surgery.All patients underwent radical surgical treatment.Postoperative pathology showed fibrous tissue hyperplasia with a large number of plasma cells, lymphocytes, a few neutrophil infiltrates, and lymphoid follicles and obliterated vasculitis in some specimens.The number of IgG4⁺ plasma cells was more than 10 in all tissues under high power microscope.After surgery, 3 patients had symptoms improved, and serum IgG4 value was within the normal range; 1 patient (patem 3) had elevated IgG4 value during follow-up, received subsequent hormone therapy, and the serum IgG 4 level remained stable. [Conclusion] The symptoms of IgG4-related diseases involving the urinary system are non-specific, and the imaging findings are various, easily confused with other diseases.Early detection of serum IgG4 and biopsy pathology can help clinicians make correct diagnosis in the early stage.

Objective To explore the effects and mechanism of calycosin-7-glucoside(CG)on lipopolysaccharide(LPS)-induced inflammatory injury in BV-2 cells and in a mouse model of neuroinflammation.Methods An in vitro neuroinflammation model was induced by LPS stimulation of BV-2 cells.BV-2 cells were divided into blank(CON),model(LPS),dexamethasone(DEX),and low-and high-dose CG(CG 10 μmol/L,CG 20 μmol/L,respectively)groups.The cell viability in each group was detected by Cell Counting Kit-8 assay,interleukin(IL)-6 and tumor necrosis factor(TNF)-α levels in the supernatant were detected by enzyme-linked immunosorbent assay(ELISA),and nitric oxide levels were detected using the Griess method.LPS was also used to induce neuroinflammation in mice in vivo.The mice were then divided randomly into blank(CON),model(LPS),aspirin,and low-and high-dose CG(CG 5 mg/kg,CG 10 mg/kg,respectively)groups.Pathological changes in the hippocampus were detected by hematoxylin/eosin staining.Serum levels of IL-6 and TNF-α were detected by ELISA,polarization of microglia was detected by immunofluorescence staining,and protein expression levels of Toll-like receptor 4(TLR4),myeloid differentiation primary response 88(MyD88),nuclear factor κB(NF-κB,P65)and phosphorylated-NF-κB(p-P65)in the cortex were detected by Western blot.Results CG alone or in combination with LPS in the concentration range of 2.5～160 μmol/L had no significant toxicity in BV-2 cells in vitro,compared with the CON group(P＞0.05).IL-6,TNF-α,and NO levels in the cell supernatant were increased in the LPS group compared with the CON group(P＜0.01),but were significantly reduced by CG(P＜0.05,P＜0.01).Hippocampal neurons were arranged loosely and disordered in the LPS group in vivo,compared with the CON group,and nuclear pyknosis was observed.Serum levels of IL-6 and TNF-α were increased(P＜0.05,P＜0.01).The number of ionized calcium binding adaptor molecule 1(Iba1)/inducible nitric oxide synthase(iNOS)cells was increased(P＜0.01),the number of CD206/Iba1 cells was decreased(P＜0.01),and expression levels of TLR4,MyD88,and p-P65 protein in the cortex were increased(P＜0.05).Compared with the LPS group,CG improved the pathological damage to the hippocampus and inhibited serum levels of IL-6 and TNF-α(P＜0.01).CG also decreased the number of iNOS/Iba1 cells,increased the number of CD206/Iba1 cells(P＜0.05,P＜0.01),and significantly down-regulated TLR4,MyD88,and p-P65 protein levels in the cortex(P＜0.05).Conclusions CG can ameliorate neuroinflammation in mice by suppressing the TLR4/MyD88/NF-κB pathway.

Objective:To explore the effect of Chaibei Zhixian Decoction on intestinal flora and T helper 17/regulatory T cell(Th17/Treg)immune balance in epileptic rats by regulating mammalian target of rapamycin/hypoxia-inducible factor-1α(mTOR/HIF-1α)pathway.Methods:Sixty rats were randomly divided into Sham group,Model group,low-dose Chaibei Zhixian Decoction group(CBZXD-Low)and high-dose Chaibei Zhixian Decoction group(CBZXD-High),with 15 rats in each group.Lateral ventricular injec-tion 1 μl kainic acid(1.5 μg/μl)was used to prepare epileptic rat model,Sham group was injected with an equal amount of physiological saline.CBZXD-Low group and CBZXD-High group were given Chaibei Zhixian Decoction by gavage daily(8.48 g/kg,16.96 g/kg),while Sham group and model group were given an equal amount of physiological saline by gavage.After continuous gavage for 4 weeks,HE staining and Nissl staining were used to detect pathological damage in hippocampal tissue;RT-qPCR was used to detect Th17/Treg related marker mRNA levels in spleen tissue and mTOR,HIF-1α mRNA levels in hippocampus tissue;flow cytometry was used to de-tect Th17/Treg cell ratio in spleen tissue;16S rRNA sequencing of feces in colon segment was performed;Western blot was used to de-tect mTOR and HIF-1α protein levels in hippocampal tissue.Results:Compared with Sham group,Model group rats suffered from spontaneous epilepsy,the arrangement of hippocampal neurons was disordered and severely lacking,intracellular Nissl bodies was de-creased,RORγt,IL-17A mRNA levels in spleen tissue were increased,Foxp3,CTLA-4 and GITR mRNA levels were decreased,the proportion of Th17 cells and Th17/Treg were increased,the proportion of Treg cell was decreased,intestinal flora α/β diversity were decreased,the proportion of harmful bacteria such as Cronobacter and Heliobacillus were increased,the proportion of beneficial bacte-ria such as Bacteroides,Lactobacillus,Prevotella and Akkermansia were decreased;mTOR and HIF-1α mRNA levels,p-mTOR/mTOR,HIF-1α protein levelsin hippocampal tissue were increased(P<0.05);compared with Model group,the seizures of rats in CBZXD-Low group and CBZXD-High group were significantly reduced,and the damage to hippocampal neurons was alleviated,RORγt,IL-17A mRNA levels in spleen tissue were decreased,Foxp3,CTLA-4 and GITR mRNA levels were increased,the propor-tion of Th17 cells and Th17/Treg were decreased,the proportion of Treg cell was increased,intestinal flora α/β diversity were in-creased,the proportion of harmful bacteria such as Cronobacter and Heliobacillus were decreased,the proportion of beneficial bacte-ria,such as Bacteroides,Lactobacillus,Prevotella,and Akkermansia were increased;mTOR and HIF-1α mRNA levels,p-mTOR/mTOR,HIF-1α protein levels in hippocampal tissue were decreased(P<0.05);and it showed a dose-dependent effect of Chaibei Zhixian Decoction(P<0.05).Conclusion:Chaibei Zhixian Decoction can restore intestinal flora and Th17/Treg cell immune balance in epileptic rats,it possibly plays a role by regulating mTOR/HIF-1α pathway.

Objective:To assess the core competencies of internal medicine residents undergoing standardized residency training and to explore the effectiveness of core competency evaluation on mobile devices.Methods:The mobile formative evaluation module was developed based on the "Xueyiku" teaching management platform. From January to December 2023, clinical teachers were asked to evaluate 150 internal medicine residents based on the "Resident Core Competency Milestone Evaluation System in China Consortium of Elite Teaching Hospitals", and the results were analyzed using non-parametric tests.Results:Among the six core competencies of internal medicine residents, professionalism received the highest score, whereas teaching skill received a lower score (97.50 vs. 90.00; H=167.31, P<0.001). Second-year residents had significantly higher scores than first-year residents (93.00 vs. 90.00; P<0.001), but similar scores to third-year residents (93.00 vs. 93.00; P>0.05). In addition, there was no significant difference in score among residents with different medical education backgrounds ( P>0.05). Conclusions:More emphasis should be placed on improving the teaching skills of internal medicine residents, along with the implementation of tiered progressive training. The mobile core competency evaluation is an effective means for assessing the comprehensive skills of residents in a timely manner.

Bone tissue engineering(BTE)is expected to be used as an autologous bone graft substitute for bone defects,and in the se-lection of BTE scaffold materials,collagen(Col)and hydroxyapatite(HA)have attracted attention due to their unique biomimetic ad-vantages.Collagen/hydroxyapatite(CHA)composite scaffolds made by combining the two have been shown to have excellent biocompat-ibility and bone-enhancing potential in various in vitro,in vivo,and clinical studies.With the development of three-dimensional(3D)printing technology in the field of tissue engineering,bone scaffolds constructed using 3D printing methods have been shown to possess superior clinical potential.This review describes new advances in 3D printed CHA composite scaffolds and introduces the application of 3D printed CHA scaffolds in oral and maxillofacial bone regenerative repair.