Pelvic organ prolapse (POP), whose etiology is influenced by genetic and clinical risk factors, considerably impacts women's quality of life. However, the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored. This study constructed the first polygenic risk score (PRS) for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study. We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls. Results showed that the case group exhibited a significantly higher PRS than the control group. Moreover, the odds ratio of the top 10% risk group was 2.6 times higher than that of the bottom 10%. A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths. As far as we know, the integrated prediction model, which combined PRS and clinical risk factors, demonstrated better predictive accuracy than other existing PRS models. This combined risk assessment model serves as a robust tool for POP risk prediction and stratification, thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
Humans ; Female ; Pelvic Organ Prolapse/epidemiology* ; Middle Aged ; Risk Assessment/methods* ; China/epidemiology* ; Multifactorial Inheritance ; Aged ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Case-Control Studies ; Adult ; Polymorphism, Single Nucleotide ; Genetic Risk Score ; East Asian People

BACKGROUND:The asymmetrical biomechanical environment of adolescent idiopathic scoliosis can lead to further wedge deformation of the vertebral body,which may affect cardiopulmonary function and compress nerves in severe cases.Adolescent idiopathic scoliosis with different degrees of scoliosis should be treated with exercise,bracing,and surgery.However,the mechanical mechanism of selecting an orthopedic approach remains unclear due to the individual variability of patients.OBJECTIVE:To investigate the biomechanical mechanism of different orthopedic modalities for the treatment of adolescent idiopathic scoliosis to provide a basis for clinical selection of treatment modalities based on the spine model of adolescent idiopathic scoliosis patients.METHODS:Based on the CT images of an adolescent idiopathic scoliosis patient,a scoliosis model(C7-L5)was reconstructed in Mimics software in three dimensions,and lateral thrust force was applied at the T8/T9 thorax and vertical distraction force was applied over the C7 vertebra with the magnitude of 20,40,60,80,100,and 120 N.The intervertebral disc stress and vertebral displacement in concave and convex sides,and Cobb angle of the spine were analyzed under two orthopedic modalities.RESULTS AND CONCLUSION:(1)With lateral thrust,there was no significant change in the C7T1-T7T8 intervertebral disc.The concave and convex stress of T7T8-L4L5 segment decreased first and then increased with the increase of lateral thrust force.The correction effect of lateral thrust on the segment near T8T9 was obvious and weakened with the extension of the segment to the cephalic and caudal ends.At 120 N of lateral thrust,the thoracic Cobb angle changed from 53.2° to 32.5° and the lumbar Cobb angle changed from 50.2° to 43.9°.(2)With the vertical distraction,the thoracic intervertebral disc stresses first decreased and then increased,and all the lumbar disc stresses decreased.The C7 displacement was the most obvious,and the correction effect gradually diminished with the segment extended to the caudal end.At a vertical distraction force of 120 N,the thoracic Cobb angle changed from 53.2° to 39.4° and the lumbar Cobb angle changed from 50.2° to 47.6°.(3)It is concluded that both orthopedic modalities provide improvement in the degree of scoliosis,with the thoracic correction being greater than the lumbar correction.Also,the asymmetric stress distribution on the concave and convex sides is improved,which contributes to normal bone growth.A vertical distraction approach is appropriate for larger Cobb angles,and a lateral thrust approach is appropriate for smaller Cobb angles.The results of this study help to understand the mechanism of spinal orthosis and provide a theoretical basis for the choice of orthopedic approach.

This consensus was developed by the Orthodontic Society of the Chinese Stomatological Association to provide a systematic, scientific, and practical guideline for informed consent in orthodontic care. Orthodontic treatment is typically lengthy, highly individualized, and involves multiple factors such as growth and development, occlusal function, and facial esthetics. Rapid technological advances and diverse risk profiles make the traditional reliance on orthodontist experience or institutional templates insufficient to ensure patients′ full understanding and autonomous decision-making. To address this, the expert panel conducted extensive reviews of domestic and international guidelines, analyzed representative dispute cases, and performed multicenter patient-clinician surveys. Using a multi-round Delphi method, the group established a standardized informed consent framework covering the initial consultation, treatment, and retention phases. The consensus emphasizes that informed consent is not only a fundamental legal and ethical requirement but also a key step in building trust, improving patient compliance, and enhancing treatment satisfaction. Orthodontists should clearly and comprehensively explain treatment plans, potential risks, uncertainties, and associated costs, while respecting the autonomy of patients or guardians, and maintain continuous communication and dynamic evaluation throughout the treatment process. The release of this consensus provides unified and authoritative guidance for clinical orthodontics, helping to standardize informed consent, enhance its transparency, safeguard patient rights, reduce medical risks, and promote high-quality, sustainable development of orthodontic practice.

OBJECTIVE To observe the causal association between colorectal cancer and sepsis by means of bidirec-tional two-sample Mendelian randomization(MR).METHODS The Genome Wide Association Study(GWAS)datasets for colorectal cancer and sepsis were retrieved from the GWAS databases between its establishment and Feb.1,2024.MR was carried out for the colorectal cancer and sepsis interacting as exposure and outcome factors.The single nucleotide polymorhpism(SNPs)that were significantly associated with the exposure factors were screened out by setting P as less than 5.0× 10-8,r2 less than 0.001,the genetic distance 10,000 kb.The SNPs that were remarkably associated with the exposure factors were extracted from the GWAS datasets of the outcome variables,the instrumental variable were finally obtained,the inverse variance weighting(IVW)was taken as the main approach for the causal inference.The level pleiotropy was tested by using MR Egger method and MR-PRESSO,the heterogeneity was tested by IVW method and MR-Egger method,the sensitivity was analyzed by leave-one-out method,and the robustness of the result was tested.RESULTS A total of 30 SNPs were screed out by setting the colorectal cancer as exposure factor and the sepsis as outcome variable(F＞10);there was causal as-sociation between the colorectal cancer and the sepsis(OR=28.955,95％CI:1.215 to 690.052,P=0.037).Totally 14 SNPs were screened out by setting the sepsis as exposure factor and the colorectal cancer as treatment variable(F＞10),and there was no causal association between the colorectal cancer and the sepsis(OR=0.999,95％CI:0.997 to 1.002,P=0.674).There was no level pleiotropy in the instrumental variables during the two times of MR analysis;there was no heterogeneity in the instrumental variables,and the result of the MR analysis was robust.CONCLUSION There is causal association between the colorectal cancer and the increases of risk of sepsis.But there is no causal association between the sepsis and the increase of risk of colorectal cancer.

Background and purpose:Colorectal cancer(CRC),ranking as the third most common malignant tumor globally,continues to pose a significant public health challenge due to its high incidence and mortality rates.Chemotherapy remains a cornerstone treatment for advanced CRC.However,its efficacy is often severely limited by the emergence of multidrug resistance(MDR).The drug efflux mediated by ABCB1 is a key mechanism underlying chemotherapeutic failure.Although the non-steroidal anti-inflammatory drug tepoxalin exhibits potential antitumor activity,it remains unclear whether it influences CRC progression and chemoresistance by targeting ABCB1.This study aimed to elucidate the mechanism by which tepoxalin suppresses CRC cell growth and reverses chemoresistance through the regulation of ABCB1.Methods:This study employed a multifaceted research strategy:Bioinformatics analysis was conducted using the DepMap,The Cancer Genome Atlas(TCGA),Genotype-Tissue Expression(GTEx)and Human Protein Atlas(HPA)databases to analyze ABCB1 expression profiles and drug sensitivity.In vitro,the cell counting kit-8(CCK-8)assay was used to assess cell proliferation and chemosensitivity,and IC50 values were calculated.A subcutaneous xenograft model in nude mice was established to evaluate the antitumor efficacy in vivo.The drug affinity responsive target stability(DARTS)assay was performed to validate the direct binding between tepoxalin and ABCB1 protein.Transcriptome sequencing and gene set enrichment analysis(GSEA)were utilized to identify downstream signaling pathways.Western blot and immunohistochemistry were applied to detect the expression changes of key proteins.The PI3K-Akt pathway inhibitor copanlisib was used for reverse validation.Statistical analysis was performed using SPSS 20.0 software,and graphs were generated using GraphPad Prism 8.0.1.A value of P＜0.05 was considered statistically significant.Results:ABCB1 was significantly overexpressed in CRC tissues and cell lines(P＜0.05).Cells with high ABCB1 expression exhibited increased sensitivity to tepoxalin(R=-0.323,P＜0.001).Tepoxalin directly bound to the ABCB1 protein and promoted its proteasomal degradation.In vivo,tepoxalin significantly inhibited the growth of xenograft tumors(P＜0.01)and downregulated the expression of ABCB1 and Ki-67 proliferation index in tumor tissues.Transcriptomic analysis revealed that tepoxalin suppressed the PI3K-Akt signaling pathway[GSEA,false discovery rate(FDR)＜0.05],leading to reduced transcriptional expression of ABCB1.This effect was replicated using the PI3K-Akt pathway inhibitor copanlisib.Ultimately,tepoxalin synergistically enhanced the efficacy of 5-fluorouracil(5-FU)through the aforementioned actions.Conclusion:Tepoxalin targets ABCB1 through a dual-track mechanism:it directly binds to and destabilizes the ABCB1 protein while simultaneously downregulating its transcriptional expression via inhibition of the PI3K-Akt pathway.This coordinated action can synergistically inhibit CRC cell growth and effectively reverse chemoresistance,offering a novel potential therapeutic strategy for overcoming drug resistance in CRC.

This consensus was developed by the Orthodontic Society of the Chinese Stomatological Association to provide a systematic, scientific, and practical guideline for informed consent in orthodontic care. Orthodontic treatment is typically lengthy, highly individualized, and involves multiple factors such as growth and development, occlusal function, and facial esthetics. Rapid technological advances and diverse risk profiles make the traditional reliance on orthodontist experience or institutional templates insufficient to ensure patients′ full understanding and autonomous decision-making. To address this, the expert panel conducted extensive reviews of domestic and international guidelines, analyzed representative dispute cases, and performed multicenter patient-clinician surveys. Using a multi-round Delphi method, the group established a standardized informed consent framework covering the initial consultation, treatment, and retention phases. The consensus emphasizes that informed consent is not only a fundamental legal and ethical requirement but also a key step in building trust, improving patient compliance, and enhancing treatment satisfaction. Orthodontists should clearly and comprehensively explain treatment plans, potential risks, uncertainties, and associated costs, while respecting the autonomy of patients or guardians, and maintain continuous communication and dynamic evaluation throughout the treatment process. The release of this consensus provides unified and authoritative guidance for clinical orthodontics, helping to standardize informed consent, enhance its transparency, safeguard patient rights, reduce medical risks, and promote high-quality, sustainable development of orthodontic practice.

BACKGROUND:The asymmetrical biomechanical environment of adolescent idiopathic scoliosis can lead to further wedge deformation of the vertebral body,which may affect cardiopulmonary function and compress nerves in severe cases.Adolescent idiopathic scoliosis with different degrees of scoliosis should be treated with exercise,bracing,and surgery.However,the mechanical mechanism of selecting an orthopedic approach remains unclear due to the individual variability of patients.OBJECTIVE:To investigate the biomechanical mechanism of different orthopedic modalities for the treatment of adolescent idiopathic scoliosis to provide a basis for clinical selection of treatment modalities based on the spine model of adolescent idiopathic scoliosis patients.METHODS:Based on the CT images of an adolescent idiopathic scoliosis patient,a scoliosis model(C7-L5)was reconstructed in Mimics software in three dimensions,and lateral thrust force was applied at the T8/T9 thorax and vertical distraction force was applied over the C7 vertebra with the magnitude of 20,40,60,80,100,and 120 N.The intervertebral disc stress and vertebral displacement in concave and convex sides,and Cobb angle of the spine were analyzed under two orthopedic modalities.RESULTS AND CONCLUSION:(1)With lateral thrust,there was no significant change in the C7T1-T7T8 intervertebral disc.The concave and convex stress of T7T8-L4L5 segment decreased first and then increased with the increase of lateral thrust force.The correction effect of lateral thrust on the segment near T8T9 was obvious and weakened with the extension of the segment to the cephalic and caudal ends.At 120 N of lateral thrust,the thoracic Cobb angle changed from 53.2° to 32.5° and the lumbar Cobb angle changed from 50.2° to 43.9°.(2)With the vertical distraction,the thoracic intervertebral disc stresses first decreased and then increased,and all the lumbar disc stresses decreased.The C7 displacement was the most obvious,and the correction effect gradually diminished with the segment extended to the caudal end.At a vertical distraction force of 120 N,the thoracic Cobb angle changed from 53.2° to 39.4° and the lumbar Cobb angle changed from 50.2° to 47.6°.(3)It is concluded that both orthopedic modalities provide improvement in the degree of scoliosis,with the thoracic correction being greater than the lumbar correction.Also,the asymmetric stress distribution on the concave and convex sides is improved,which contributes to normal bone growth.A vertical distraction approach is appropriate for larger Cobb angles,and a lateral thrust approach is appropriate for smaller Cobb angles.The results of this study help to understand the mechanism of spinal orthosis and provide a theoretical basis for the choice of orthopedic approach.

Background and purpose:Colorectal cancer(CRC),ranking as the third most common malignant tumor globally,continues to pose a significant public health challenge due to its high incidence and mortality rates.Chemotherapy remains a cornerstone treatment for advanced CRC.However,its efficacy is often severely limited by the emergence of multidrug resistance(MDR).The drug efflux mediated by ABCB1 is a key mechanism underlying chemotherapeutic failure.Although the non-steroidal anti-inflammatory drug tepoxalin exhibits potential antitumor activity,it remains unclear whether it influences CRC progression and chemoresistance by targeting ABCB1.This study aimed to elucidate the mechanism by which tepoxalin suppresses CRC cell growth and reverses chemoresistance through the regulation of ABCB1.Methods:This study employed a multifaceted research strategy:Bioinformatics analysis was conducted using the DepMap,The Cancer Genome Atlas(TCGA),Genotype-Tissue Expression(GTEx)and Human Protein Atlas(HPA)databases to analyze ABCB1 expression profiles and drug sensitivity.In vitro,the cell counting kit-8(CCK-8)assay was used to assess cell proliferation and chemosensitivity,and IC50 values were calculated.A subcutaneous xenograft model in nude mice was established to evaluate the antitumor efficacy in vivo.The drug affinity responsive target stability(DARTS)assay was performed to validate the direct binding between tepoxalin and ABCB1 protein.Transcriptome sequencing and gene set enrichment analysis(GSEA)were utilized to identify downstream signaling pathways.Western blot and immunohistochemistry were applied to detect the expression changes of key proteins.The PI3K-Akt pathway inhibitor copanlisib was used for reverse validation.Statistical analysis was performed using SPSS 20.0 software,and graphs were generated using GraphPad Prism 8.0.1.A value of P＜0.05 was considered statistically significant.Results:ABCB1 was significantly overexpressed in CRC tissues and cell lines(P＜0.05).Cells with high ABCB1 expression exhibited increased sensitivity to tepoxalin(R=-0.323,P＜0.001).Tepoxalin directly bound to the ABCB1 protein and promoted its proteasomal degradation.In vivo,tepoxalin significantly inhibited the growth of xenograft tumors(P＜0.01)and downregulated the expression of ABCB1 and Ki-67 proliferation index in tumor tissues.Transcriptomic analysis revealed that tepoxalin suppressed the PI3K-Akt signaling pathway[GSEA,false discovery rate(FDR)＜0.05],leading to reduced transcriptional expression of ABCB1.This effect was replicated using the PI3K-Akt pathway inhibitor copanlisib.Ultimately,tepoxalin synergistically enhanced the efficacy of 5-fluorouracil(5-FU)through the aforementioned actions.Conclusion:Tepoxalin targets ABCB1 through a dual-track mechanism:it directly binds to and destabilizes the ABCB1 protein while simultaneously downregulating its transcriptional expression via inhibition of the PI3K-Akt pathway.This coordinated action can synergistically inhibit CRC cell growth and effectively reverse chemoresistance,offering a novel potential therapeutic strategy for overcoming drug resistance in CRC.

OBJECTIVE To observe the causal association between colorectal cancer and sepsis by means of bidirec-tional two-sample Mendelian randomization(MR).METHODS The Genome Wide Association Study(GWAS)datasets for colorectal cancer and sepsis were retrieved from the GWAS databases between its establishment and Feb.1,2024.MR was carried out for the colorectal cancer and sepsis interacting as exposure and outcome factors.The single nucleotide polymorhpism(SNPs)that were significantly associated with the exposure factors were screened out by setting P as less than 5.0× 10-8,r2 less than 0.001,the genetic distance 10,000 kb.The SNPs that were remarkably associated with the exposure factors were extracted from the GWAS datasets of the outcome variables,the instrumental variable were finally obtained,the inverse variance weighting(IVW)was taken as the main approach for the causal inference.The level pleiotropy was tested by using MR Egger method and MR-PRESSO,the heterogeneity was tested by IVW method and MR-Egger method,the sensitivity was analyzed by leave-one-out method,and the robustness of the result was tested.RESULTS A total of 30 SNPs were screed out by setting the colorectal cancer as exposure factor and the sepsis as outcome variable(F＞10);there was causal as-sociation between the colorectal cancer and the sepsis(OR=28.955,95％CI:1.215 to 690.052,P=0.037).Totally 14 SNPs were screened out by setting the sepsis as exposure factor and the colorectal cancer as treatment variable(F＞10),and there was no causal association between the colorectal cancer and the sepsis(OR=0.999,95％CI:0.997 to 1.002,P=0.674).There was no level pleiotropy in the instrumental variables during the two times of MR analysis;there was no heterogeneity in the instrumental variables,and the result of the MR analysis was robust.CONCLUSION There is causal association between the colorectal cancer and the increases of risk of sepsis.But there is no causal association between the sepsis and the increase of risk of colorectal cancer.

[Objective] To determine the feasibility of preparing plasminogen (Pg) with Fraction Ⅲ precipitation (hereinafter referred to as FⅢ-P) from low-temperature ethanol process by full chromatography (hereinafter referred to as FⅢ-P process). [Methods] The FⅢ-P was diluted with dissolution buffer at different dilution times and stirring time. The potency and antigen concentration of Pg in dissolution sample were detected and the dissolution and clarification conditions were determined. Pre-treatment of loading sample and pre-experiment of affinity chromatography were carried out on the FⅢ-P dissolution sample to judge whether the loading sample had an impact on the chromatography by observing the performance of the affinity chromatography column and to evaluate whether the affinity chromatography could achieve the purpose of purifying Pg by detecting the plasma protein antigen concentration and Pg potency of the samples in the process. Two batches of FⅢ-P process were studied step by step, and the specific activity, steps and total recovery, and the output of Pg per ton of plasma were calculated. The feasibility of preparing Pg by FⅢ-P process was evaluated by comparing with the data of full chromatography process using plasma as raw material (hereinafter referred to as plasma process). [Results] The FⅢ-P was dissolved with 10 times of dissolution buffer, stirred for 1 hour, centrifuged at room temperature of 10 000×g for 15 minutes. The supernatant was first filtered with a screen, then clarified with an 8/0.8 μm filter, and finally filtered with a 0.45/0.2 μm filter and loaded. Pre-test showed that from clarification and filtration to Pg affinity chromatography, the step recovery of activity and antigen was 39.51% and 108.64%, respectively, the antigen concentration of Pg increased by 31.16 times and the activity increased by 11.39 times after affinity chromatography, which reaching the effect of affinity chromatography purification of Pg. The results of 2 batches of step-by-step scale-up FⅢ-P process showed that the total recoveries of antigen and activity from plasma to SP chromatography of FⅢ-P process were (45.76±1.10)% and (24.15±0.59)%, respectively, which had a total loss of about 1/3 of antigen and about 2/3 of activity compared to the plasma process. The Pg specific activity of SP chromatography eluent was (4.68±0.25) U/mg, which was about half of that of plasma process, but meeted the internal standard of > 4 U/mg. The output of Pg antigen per ton of plasma in the FⅢ-P process was 68.73% of that in the plasma process, and the output of Pg activity per ton of plasma in the plasma process was 29.82% of that in the plasma process, which basically achieved the purpose of waste utilization of FⅢ-P. [Conclusion] The technical route of preparing Pg from FⅢ-P by full chromatography is feasible.