Objective To investigate the correlation between thyroid hormone(TH)sensitivity and diabetic kidney disease(DKD)in patients with type 2 diabetes mellitus(T2DM).Methods A total of 949 T2DM patients with normal thyroid function were selected from the National Standardized Metabolic Disease Management Center database of our hospital between May 2020 and October 2024.All the patients were divided into DKD group(n=466)with urinary albumin/creatinine ratio(UACR)≥30 mg/g and simple T2DM group(n=483)with UACR<30 mg/g.Free triiodothyronine(FT3),free thyroxine(FT4),thyroid stimulating hormone(TSH),thyroid feedback quantification index(TFQI),thyroid stimulating hormone resistance index(TT4RI),thyroid stimulating hormone index(TSHI),FT3/FT4 were compared between the two groups.Results Body mass index(BMI),DM duration,subcutaneous fat area(SFA),blood urea nitrogen(BUN),serum creatinine(Scr),UACR,TSHI and FT4 were higher(P<0.05 or P<0.01),while FT3,TFQI was lower in DKD group than in T2DM group(P<0.05).Spearman correlation analysis showed that TT4RI was positively correlated with Scr(P<0.05),and FT3/FT4 was negatively correlated with UACR(P<0.05)in DKD group.TT4RI was positively correlated with UACR in T2DM group(P<0.05).Logistic regression analysis showed that FT3,BUN and BMI were influencing factors for DKD.The model formula was established as follows:DKD=0.711+0.102×BMI-0.002×SFA+0.138×BUN+0.007×Scr-0.578×FT3-0.089×FT4+0.750×TFQI-0.277×TSHI,which can forecasted the risk of DKD occurrence by 10%.The receiver operator characteristic curve evaluated the area under the curre of the above model formula as 0.705,the sensitivity was 49.1%,the specificity was 80.3%,and the cut-off value was 0.464.Conclusions With normal thyroid function,impaired central and peripheral TH sensitivity is correlated with T2DM combined with DKD,and elevated FT3 is a protective factor for T2DM combined with DKD.

Objective Based on the theory of"stomach disharmony leads to restlessness",the causal relationship between gastroesophageal reflux disease and insomnia was discussed by Mendel randomization method with two samples.Methods The data were collected from genome-wide association studies,the exposure factor was gastroesophageal reflux disease,and the outcome variable was insomnia.Mendel randomization analysis is realized by inverse variance weighted method,MR-Egger method,simple model method,weighted model method and weighted median method.Sensitivity analysis includes pleiotropic test,heterogeneity test and one-by-one elimination test,and is calculated by MR-Egger method,Cochran Q test and one-out-of-one method in turn.Results A total of 75 single nucleotide polymorphisms(SNPs)were screened.The inverse variance weighted method showed that gastroesophageal reflux disease increased the risk of insomnia(OR=1.255,95%CI:1.071-1.470,P<0.05).The weighted median method also confirmed that there was a positive causal relationship between gastroesophageal reflux disease and insomnia(OR=1.403,95%CI:1.117-1.762,P<0.05).Multiple sensitivity analysis indicated that there was no pleiotropy and heterogeneity in the results of Mendelian randomized analysis,which verified the stability of the research results.Conclusion There is a positive causal relationship between gastroesophageal reflux disease and insomnia,which enriches the theoretical connotation of"stomach disharmony leads to restlessness"from the genetic point of view and lays a foundation for further study.

Objective Based on the theory of"stomach disharmony leads to restlessness",the causal relationship between gastroesophageal reflux disease and insomnia was discussed by Mendel randomization method with two samples.Methods The data were collected from genome-wide association studies,the exposure factor was gastroesophageal reflux disease,and the outcome variable was insomnia.Mendel randomization analysis is realized by inverse variance weighted method,MR-Egger method,simple model method,weighted model method and weighted median method.Sensitivity analysis includes pleiotropic test,heterogeneity test and one-by-one elimination test,and is calculated by MR-Egger method,Cochran Q test and one-out-of-one method in turn.Results A total of 75 single nucleotide polymorphisms(SNPs)were screened.The inverse variance weighted method showed that gastroesophageal reflux disease increased the risk of insomnia(OR=1.255,95%CI:1.071-1.470,P<0.05).The weighted median method also confirmed that there was a positive causal relationship between gastroesophageal reflux disease and insomnia(OR=1.403,95%CI:1.117-1.762,P<0.05).Multiple sensitivity analysis indicated that there was no pleiotropy and heterogeneity in the results of Mendelian randomized analysis,which verified the stability of the research results.Conclusion There is a positive causal relationship between gastroesophageal reflux disease and insomnia,which enriches the theoretical connotation of"stomach disharmony leads to restlessness"from the genetic point of view and lays a foundation for further study.

Objective To investigate the correlation between thyroid hormone(TH)sensitivity and diabetic kidney disease(DKD)in patients with type 2 diabetes mellitus(T2DM).Methods A total of 949 T2DM patients with normal thyroid function were selected from the National Standardized Metabolic Disease Management Center database of our hospital between May 2020 and October 2024.All the patients were divided into DKD group(n=466)with urinary albumin/creatinine ratio(UACR)≥30 mg/g and simple T2DM group(n=483)with UACR<30 mg/g.Free triiodothyronine(FT3),free thyroxine(FT4),thyroid stimulating hormone(TSH),thyroid feedback quantification index(TFQI),thyroid stimulating hormone resistance index(TT4RI),thyroid stimulating hormone index(TSHI),FT3/FT4 were compared between the two groups.Results Body mass index(BMI),DM duration,subcutaneous fat area(SFA),blood urea nitrogen(BUN),serum creatinine(Scr),UACR,TSHI and FT4 were higher(P<0.05 or P<0.01),while FT3,TFQI was lower in DKD group than in T2DM group(P<0.05).Spearman correlation analysis showed that TT4RI was positively correlated with Scr(P<0.05),and FT3/FT4 was negatively correlated with UACR(P<0.05)in DKD group.TT4RI was positively correlated with UACR in T2DM group(P<0.05).Logistic regression analysis showed that FT3,BUN and BMI were influencing factors for DKD.The model formula was established as follows:DKD=0.711+0.102×BMI-0.002×SFA+0.138×BUN+0.007×Scr-0.578×FT3-0.089×FT4+0.750×TFQI-0.277×TSHI,which can forecasted the risk of DKD occurrence by 10%.The receiver operator characteristic curve evaluated the area under the curre of the above model formula as 0.705,the sensitivity was 49.1%,the specificity was 80.3%,and the cut-off value was 0.464.Conclusions With normal thyroid function,impaired central and peripheral TH sensitivity is correlated with T2DM combined with DKD,and elevated FT3 is a protective factor for T2DM combined with DKD.

Objective To observe the value of PET/CT radiomics for predicting Ki-67 expression level of non-small cell lung carcinoma(NSCLC).Methods 18F-FDG PET/CT data of 139 NSCLC patients were retrospectively analyzed.The patients were divided into high-expression group(≥40%,n=75)and low-expression group(＜40%,n=64)according to Ki-67 expression level of NSCLC.CT,PET and PET/CT data were divided into training set and test set at a ratio of 7∶3 and make the distribution of Ki-67 expression levels balanced between sets,respectively.CT,PET and PET/CT radiomics features of NSCLC were extracted,and the optimal radiomics features were screened,then random forest(RF),categorical boosting(CatBoost)and extreme gradient boosting(XGBoost)algorithms were used to construct models,respectively.Receiver operating characteristic curve was plotted,and the area under the curve(AUC)was calculated to screen the radiomics model with the highest efficacy for predicting Ki-67 expression level of NSCLC.Results RF models had the highest performance among radiomics models constructed based on CT,PET and PET/CT.The efficacy of RFCT,RFPET and RFPET/CT models for predicting Ki-67 expression level of NSCLC in test set increased sequentially,with AUC of 0.830,0.870 and 0.940,respectively(all P＜0.05),and RFPET/CT was the best radiomics model.Conclusion PET/CT radiomics could be used to effectively predict Ki-67 expression level of NSCLC,and RFPET/CT model had the best performance.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

Objective To elucidate the effects of miR-616 on the malignant biological processes of osteosarcoma and to preliminarily explore its potential mechanisms.Methods In situ hybridization(ISH)was employed to analyze miR-616 expression in 11 paraffin-embedded osteosarcoma specimens collected in our department during January 2018 to December 2019.Quantitative real-time PCR(qRT-PCR)was used to compare the mRNA expression level of miR-616 in the osteoblast cell line hFOB1.19 and osteosarcoma cell lines 143B and HOS.Stable cell lines with miR-616 knockdown or overexpression were established via lentiviral transfection in 143B and HOS cells.Cell proliferation and apoptosis were detected by flow cytometry,while cell invasion and migration were assessed using Transwell and colony formation assays,respectively.To evaluate the effect of miR-616 on tumor growth in vivo,10 female nude mice(4 weeks old,weighing 18～20 g)were randomized into a control group and a miR-616 overexpression group.After the xenograft tumor model was constructed,the growth of subcutaneous tumors was monitored.Finally,next-generation sequencing and a dual-luciferase reporter assay were performed to identify the target genes of miR-616.Results ISH results showed that miR-616 expression was up-regulated in osteosarcoma tissues than adjacent tissues,and primarily localized in the cytoplasm.qRT-PCR confirmed that miR-616 level was significantly higher in 143B and HOS cells than hFOB1.19 cells(P<0.05).In vitro experiments revealed that miR-616 overexpression enhanced the proliferation,migration and invasion,while suppressing apoptosis in 143B and HOS cells(P<0.01).Conversely,miR-616 knockdown weakened these malignant phenotypes(P<0.05),with miR-616-3p showing a stronger effect on apoptosis than miR-616-5p.Animal experiments demonstrated that the tumor weight in the miR-616 overexpression group was significantly greater than that of the control group(98.00±17.22 vs 33.60±8.08 mg,P<0.01).Furthermore,KLF2 was identified and confirmed as a direct target of miR-616.Conclusion MiR-616 promotes malignant biological behaviors in osteosarcoma,and its expression level indicates that it may serve as a potential therapeutic target.

Ursodeoxycholic acid(UDCA)is a naturally occurring,low-toxicity,and hydrophilic bile acid(BA)in the human body that is converted by intestinal flora using primary BA.Solute carrier family 7 member 11(SLC7A11)functions to uptake extracellular cystine in exchange for glutamate,and is highly expressed in a variety of human cancers.Retroperitoneal liposarcoma(RLPS)refers to liposarcoma originating from the retroperitoneal area.Lipidomics analysis revealed that UDCA was one of the most significantly down-regulated metabolites in sera of RIPS patients compared with healthy subjects.The augmentation of UDCA concentration(≥25 μg/mL)demonstrated a suppressive effect on the proliferation of liposarcoma cells.[15N2]-cystine and[13Cs]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione(GSH)synthesis.Mechanistically,UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis,leading to reactive oxygen species(ROS)accumulation and mitochondrial oxidative damage.Furthermore,UDCA can promote the anti-cancer effects of ferroptosis inducers(Erastin,RSL3),the murine double minute 2(MDM2)inhibitors(Nutlin 3a,RG7112),cyclin dependent kinase 4(CDK4)inhibitor(Abemaciclib),and glutaminase inhibitor(CB839).Together,UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity,and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA.More importantly,in combination with other antitumor chemotherapy or physiotherapy treatments,UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.