Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

Objective:To analyze the effects of biodegradable-polymer sirolimus-eluting stents (BP-SES) and durable polymer sirolimus-eluting stents (DP-SES) implantation on serum endothelin 1 levels and the incidence of coronary restenosis in patients with coronary heart disease (CHD).Methods:A total of 114 patients with CHD admitted to the First People's Hospital of Xianyang in Shaanxi Province from May 2022 to January 2024 were selected. According to the principle of comparable baseline characteristics between groups, patients were divided into two groups by random number table method, with 57 cases in each group. After pretreatment of diseased vessels, DP-SES group underwent implantation of DP-SES with appropriate length and diameter, while BP-SES group underwent implantation of BP-SES with appropriate length and diameter. After implantation, non-compliant balloons were used for in-stent post-dilation. Comparisons of vascular endothelial function, levels of inflammatory factors and hemodynamic indicators before operation and at 6 months between groups were made postoperatively, also, the incidence rates of major adverse cardiovascular events (MACE) and coronary restenosis within 6 months were also compared. Measurement data with normal distribution was expressed as “xˉ±s”, independent sample t-test was used on comparison between groups, paired t-test was used for intra-group comparisons before and after treatment. Counting data was expressed as rate or composition ratio, χ2 test was used on comparison between groups. Results:At 6 months after surgery, the levels of endothelin 1 and VEGF were lower in BP-SES group compared to DP-SES group,[(72±5) ng/L vs. (77±7) ng/L, (147±25) ng/L vs. (157±27) ng/L, t=3.76, P<0.001, t=2.16, P=0.033]. The level of nitric oxide was higher in BP-SES group compared to DP-SES group [(79±7) μmol/L vs. (76±8) μmol/L, t=2.46, P<0.001]. At 6 months after surgery, the levels of TNF-α, IL-1 and CRP in DP-SES group were higher than those before surgery, and were all higher compared to BP-SES group[(81±5) ng/L vs. (75±5) ng/L, (159±18) ng/L vs. (151±16) ng/L, (31±4) mg/L vs. (29±3) mg/L, t=6.87, P<0.001, t=2.24, P=0.027, t=2.51, P=0.014]. At 6 months after surgery, the level of whole blood viscosity and plasma viscosity in both group were lower than those before surgery, and the level of Hct in BP-SES group was lower than those before surgery, the differences were statistically significant ( P<0.001), while the differences between groups were not statistically significant( P>0.05). The difference of incidence rates of MACE and coronary restenosis within 6 months between groups before surgery and 6 months after surgery were not statistically significant [7.0%(4/57) vs. 12.3%(7/57), χ2=0.91, P=0.341; 3.7%(2/57) vs. 8.3%(5/57), χ2=0.61, P=0.443]. Conclusion:Both BP-SES implantation and DP-SES implantation could effectively restore coronary blood supply, and are highly safe. However, the former can reduce damage to vascular wall and better improve endothelial function in patients.

Objective To investigate the factors influencing international normalized ratio (INR)>3.0 in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Methods A retrospective analysis was performed on the clinical data of patients who underwent mechanical heart valve replacement surgery and received warfarin anticoagulation therapy at West China Hospital of Sichuan University from January 1, 2011 to June 30, 2022. Based on the discharge INR values, patients were divided into two groups: an INR≤3.0 group and an INR>3.0 group. The factors associated with INR>3.0 at the time of discharge were analyzed. Results A total of 8901 patients were enrolled, including 3409 males and 5492 females, with a median age of 49.3 (43.5, 55.6) years. The gender, body mass index (BMI), New York Heart Association (NYHA) cardiac function grading, INR, glutamic oxaloacetic transaminase, and preoperative prothrombin time (PT) were statistically different between the two groups (P<0.05). Multivariate logistic regression analysis revealed that lower BMI, preoperative PT>15 s, and mitral valve replacement were independent risk factors for INR>3.0 at discharge (P<0.05). Conclusion BMI, preoperative PT, and surgical site are factors influencing INR>3.0 at discharge in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Special attention should be given to patients with lower BMI, longer preoperative PT, and mitral valve replacement to avoid excessive anticoagulation therapy.

BACKGROUND: Fibrosis of the connective tissue in the vaginal wall predominates in pelvic organ prolapse (POP), which is characterized by excessive fibroblast-to-myofibroblast differentiation and abnormal deposition of the extracellular matrix (ECM). Our study aimed to investigate the effect of ECM stiffness on vaginal fibroblasts and to explore the role of methyltransferase 3 (METTL3) in the development of POP. METHODS: Polyacrylamide hydrogels were applied to create an ECM microenvironment with variable stiffness to evaluate the effects of ECM stiffness on the proliferation, differentiation, and expression of ECM components in vaginal fibroblasts. METTL3 small interfering RNA and an overexpression vector were transfected into vaginal fibroblasts to evaluate the effects of METTL3 silencing and overexpression on matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the ECM. Both procedures were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining, Western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), and immunofluorescence (IF). RESULTS: Vaginal fibroblasts from POP patients exhibited increased proliferation ability, increased expression of α-smooth muscle actin (α-SMA), decreased expression of collagen I/III, and significantly decreased expression of tissue inhibitors of matrix metalloproteinases (TIMPs) in the stiff matrix ( P <0.05). Compared with those from non-POP patients, vaginal wall tissues from POP patients demonstrated a significant increase in METTL3 content ( P <0.05). However, silencing METTL3 expression in vaginal fibroblasts with high ECM stiffness resulted in decreased proliferation ability, decreased α-SMA expression, an increased ratio of collagen I/III, and increased TIMP1 and TIMP2 expression. Conversely, METTL3 overexpression significantly promoted the process of increased proliferation ability, increased α-SMA expression, decreased ratio of collagen I/III and decreased TIMP1 and TIMP2 expression in the soft matrix ( P <0.05). CONCLUSIONS Elevated ECM stiffness can promote excessive proliferation, differentiation, and abnormal ECM modulation, and the expression of METTL3 plays an important role in alleviating or aggravating matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal ECM modulation.
Humans ; Female ; Extracellular Matrix/metabolism* ; Cell Differentiation/genetics* ; Methyltransferases/metabolism* ; Pelvic Organ Prolapse/pathology* ; Fibroblasts/metabolism* ; Myofibroblasts/metabolism* ; Vagina/metabolism* ; Cell Proliferation/physiology* ; Cells, Cultured ; Middle Aged

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 assess the influencing factors of glycemic control among type 2 diabetes mellitus (T2DM) patients, in particular the correlations between peripheral blood eosinophils and metabolic indicators such as glucose, lipids, and uric acid (UA) in these patients.Methods:T2DM patients who were regularly followed up in the Intensive Diabetes Mellitus Clinic of Peking Union Medical College Hospital from January 2016 to September 2024 were prospectively selected as the research subjects. The clinical data of these patients at their first visit and at the 3rd, 6th, 9th, and 12th months of follow-up were collected. The potential correlations of peripheral blood eosinophils with blood glucose control, lipid metabolism, UA metabolism, and inflammation as well as their influencing factors were analyzed.Results:A total of 161 T2DM patients were included. The glycated hemoglobin A1c (HbA1c) compliance rate was significantly higher during the follow-up visits (3, 6, 9, and 12 months) than baseline (all P<0.05) but showed no significant correlation with the count or percentage of peripheral blood eosinophils. Spearman correlation analysis showed that the percentage of peripheral blood eosinophils was negatively correlated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) ( P=0.049) and high-density lipoprotein cholesterol (HDL-C) ( P=0.002) and positively with serum triglyceride (TG) ( P=0.034) and UA levels ( P<0.001). A further linear regression model analysis of these four variables and the percentage of eosinophils revealed that the percentage of peripheral blood eosinophils was only linearly correlated with serum UA level ( P<0.001). Conclusion:The percentage of peripheral blood eosinophils in T2DM patients is independently correlated with serum UA level, and monitoring serum UA level is important in T2DM management. Early identification and intervention of hyperuricemia can help provide more comprehensive and precise medical interventions for T2DM patients.

Objective:To assess the influencing factors of glycemic control among type 2 diabetes mellitus (T2DM) patients, in particular the correlations between peripheral blood eosinophils and metabolic indicators such as glucose, lipids, and uric acid (UA) in these patients.Methods:T2DM patients who were regularly followed up in the Intensive Diabetes Mellitus Clinic of Peking Union Medical College Hospital from January 2016 to September 2024 were prospectively selected as the research subjects. The clinical data of these patients at their first visit and at the 3rd, 6th, 9th, and 12th months of follow-up were collected. The potential correlations of peripheral blood eosinophils with blood glucose control, lipid metabolism, UA metabolism, and inflammation as well as their influencing factors were analyzed.Results:A total of 161 T2DM patients were included. The glycated hemoglobin A1c (HbA1c) compliance rate was significantly higher during the follow-up visits (3, 6, 9, and 12 months) than baseline (all P<0.05) but showed no significant correlation with the count or percentage of peripheral blood eosinophils. Spearman correlation analysis showed that the percentage of peripheral blood eosinophils was negatively correlated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) ( P=0.049) and high-density lipoprotein cholesterol (HDL-C) ( P=0.002) and positively with serum triglyceride (TG) ( P=0.034) and UA levels ( P<0.001). A further linear regression model analysis of these four variables and the percentage of eosinophils revealed that the percentage of peripheral blood eosinophils was only linearly correlated with serum UA level ( P<0.001). Conclusion:The percentage of peripheral blood eosinophils in T2DM patients is independently correlated with serum UA level, and monitoring serum UA level is important in T2DM management. Early identification and intervention of hyperuricemia can help provide more comprehensive and precise medical interventions for T2DM patients.

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 analyze the effects of biodegradable-polymer sirolimus-eluting stents (BP-SES) and durable polymer sirolimus-eluting stents (DP-SES) implantation on serum endothelin 1 levels and the incidence of coronary restenosis in patients with coronary heart disease (CHD).Methods:A total of 114 patients with CHD admitted to the First People's Hospital of Xianyang in Shaanxi Province from May 2022 to January 2024 were selected. According to the principle of comparable baseline characteristics between groups, patients were divided into two groups by random number table method, with 57 cases in each group. After pretreatment of diseased vessels, DP-SES group underwent implantation of DP-SES with appropriate length and diameter, while BP-SES group underwent implantation of BP-SES with appropriate length and diameter. After implantation, non-compliant balloons were used for in-stent post-dilation. Comparisons of vascular endothelial function, levels of inflammatory factors and hemodynamic indicators before operation and at 6 months between groups were made postoperatively, also, the incidence rates of major adverse cardiovascular events (MACE) and coronary restenosis within 6 months were also compared. Measurement data with normal distribution was expressed as “xˉ±s”, independent sample t-test was used on comparison between groups, paired t-test was used for intra-group comparisons before and after treatment. Counting data was expressed as rate or composition ratio, χ2 test was used on comparison between groups. Results:At 6 months after surgery, the levels of endothelin 1 and VEGF were lower in BP-SES group compared to DP-SES group,[(72±5) ng/L vs. (77±7) ng/L, (147±25) ng/L vs. (157±27) ng/L, t=3.76, P<0.001, t=2.16, P=0.033]. The level of nitric oxide was higher in BP-SES group compared to DP-SES group [(79±7) μmol/L vs. (76±8) μmol/L, t=2.46, P<0.001]. At 6 months after surgery, the levels of TNF-α, IL-1 and CRP in DP-SES group were higher than those before surgery, and were all higher compared to BP-SES group[(81±5) ng/L vs. (75±5) ng/L, (159±18) ng/L vs. (151±16) ng/L, (31±4) mg/L vs. (29±3) mg/L, t=6.87, P<0.001, t=2.24, P=0.027, t=2.51, P=0.014]. At 6 months after surgery, the level of whole blood viscosity and plasma viscosity in both group were lower than those before surgery, and the level of Hct in BP-SES group was lower than those before surgery, the differences were statistically significant ( P<0.001), while the differences between groups were not statistically significant( P>0.05). The difference of incidence rates of MACE and coronary restenosis within 6 months between groups before surgery and 6 months after surgery were not statistically significant [7.0%(4/57) vs. 12.3%(7/57), χ2=0.91, P=0.341; 3.7%(2/57) vs. 8.3%(5/57), χ2=0.61, P=0.443]. Conclusion:Both BP-SES implantation and DP-SES implantation could effectively restore coronary blood supply, and are highly safe. However, the former can reduce damage to vascular wall and better improve endothelial function in patients.