BACKGROUND:Although previous studies have reported associations between lipids and the risk of osteoporotic pathological fractures,the specific causal relationships between lipid level and osteoporotic pathological fractures remain unclear.OBJECTIVE:To elucidate the causal relationship between lipids and osteoporotic pathological fractures using a two-sample bidirectional Mendelian randomization analysis.METHODS:The data for 178 lipid metabolites were obtained from the IEU-GWAS database(developed by the MRC Integrative Epidemiology Unit at the University of Bristol,UK,which provides extensive summary data from genome-wide association studies),while osteoporotic pathological fracture data(from 173 619 European participants)were acquired from the FinnGen database(constructed by the Finnish national gene research program,focusing on investigating relationships between genomics and health/disease in the Finnish population).Osteoporotic pathological fracture data were used as the outcome variable,with lipids serving as exposures,for the bidirectional Mendelian randomization study to evaluate the causal effects of different lipids on osteoporotic pathological fractures.The UK Biobank database was employed as a validation set by switching the outcome variable to verify the findings horizontally.RESULTS AND CONCLUSION:(1)The inverse variance weighted analysis indicated that each unit increase in sterol ester(27∶1/20∶2)levels was associated with a 25.55％increase in the risk of osteoporotic pathological fractures(odds ratio=1.256,95％confidence interval:1.001-1.575,P=0.049),suggesting a significant positive correlation between elevated sterol ester levels and increased fracture risk.Reverse Mendelian randomization analysis revealed a significant negative association between osteoporotic pathological fractures and three types of phosphatidylcholine.Horizontal validation yielded consistent results,confirming sterol ester as a risk factor for osteoporotic pathological fractures.(2)The results indicate that sterol ester is a risk factor for osteoporotic pathological fractures,while phosphatidylcholine serves as a protective factor.These findings strengthen the evidence supporting the effect of lipids on the risk of osteoporotic pathological fractures.Although the GWAS data used in this study were derived from European populations,given the broad commonality of human genetics,the results provide valuable reference significance for improving osteoporosis in Chinese populations through lipid regulation.

BACKGROUND:Although previous studies have reported associations between lipids and the risk of osteoporotic pathological fractures,the specific causal relationships between lipid level and osteoporotic pathological fractures remain unclear.OBJECTIVE:To elucidate the causal relationship between lipids and osteoporotic pathological fractures using a two-sample bidirectional Mendelian randomization analysis.METHODS:The data for 178 lipid metabolites were obtained from the IEU-GWAS database(developed by the MRC Integrative Epidemiology Unit at the University of Bristol,UK,which provides extensive summary data from genome-wide association studies),while osteoporotic pathological fracture data(from 173 619 European participants)were acquired from the FinnGen database(constructed by the Finnish national gene research program,focusing on investigating relationships between genomics and health/disease in the Finnish population).Osteoporotic pathological fracture data were used as the outcome variable,with lipids serving as exposures,for the bidirectional Mendelian randomization study to evaluate the causal effects of different lipids on osteoporotic pathological fractures.The UK Biobank database was employed as a validation set by switching the outcome variable to verify the findings horizontally.RESULTS AND CONCLUSION:(1)The inverse variance weighted analysis indicated that each unit increase in sterol ester(27∶1/20∶2)levels was associated with a 25.55％increase in the risk of osteoporotic pathological fractures(odds ratio=1.256,95％confidence interval:1.001-1.575,P=0.049),suggesting a significant positive correlation between elevated sterol ester levels and increased fracture risk.Reverse Mendelian randomization analysis revealed a significant negative association between osteoporotic pathological fractures and three types of phosphatidylcholine.Horizontal validation yielded consistent results,confirming sterol ester as a risk factor for osteoporotic pathological fractures.(2)The results indicate that sterol ester is a risk factor for osteoporotic pathological fractures,while phosphatidylcholine serves as a protective factor.These findings strengthen the evidence supporting the effect of lipids on the risk of osteoporotic pathological fractures.Although the GWAS data used in this study were derived from European populations,given the broad commonality of human genetics,the results provide valuable reference significance for improving osteoporosis in Chinese populations through lipid regulation.

Objective:To investigate the predictive value of transabdominal uterine electromyography for pre-term labor after tocolysis in women with threatened preterm labor.Methods:A total of 48 pregnant women at 28-34 weeks of gestation diagnosed with threatened preterm labor and admitted to The Fourth Affiliated Hospital of Soo-chow University from January to September 2023 were included.According to the response to tocolysis and whether the pregnancy was prolonged for at least 48 h,women were divided into two groups:non-preterm birth within 48 h(n=35)and preterm birth within 48 h(n=13).Uterine electromyography parameters and difference were compared before and after tocolytic therapy in two groups.Univariate Logistic regression was performed to predict the related factors of preterm birth within 48 h after the using of tocolysis in pregnant women with threat-ened preterm birth by uterine electromyography,and receiver operating characteristic(ROC)curve was per-formed to evaluate their performance.Results:Compared to before treatment with tocolysis,after therapy,in the non-preterm birth within 48 h group,significant reductions in contraction frequency,area,duration and amplitude were observed(P<0.05).In the preterm birth within 48 h group,only contraction frequency decreased significant-ly(P<0.05).Univariate Logistic regression indicated that contraction frequency,contraction duration,and contrac-tion area were predictive factors for premature birth within 48 h after tocolysis(P<0.05).When the duration of u-terine contractions lasting for 104.55 s or more the sensitivity and specificity of predicting premature birth within 48 h are 92.3％and 68.6％,respectively.Conclusions:Uterine electromyography may predict the premature birth within 48 h after tocolytic treatment in preterm labor,which may provide reference for subsequent corticosteroid therapy or transfer of high-risk pregnant patients.

Objective:To investigate the predictive value of transabdominal uterine electromyography for pre-term labor after tocolysis in women with threatened preterm labor.Methods:A total of 48 pregnant women at 28-34 weeks of gestation diagnosed with threatened preterm labor and admitted to The Fourth Affiliated Hospital of Soo-chow University from January to September 2023 were included.According to the response to tocolysis and whether the pregnancy was prolonged for at least 48 h,women were divided into two groups:non-preterm birth within 48 h(n=35)and preterm birth within 48 h(n=13).Uterine electromyography parameters and difference were compared before and after tocolytic therapy in two groups.Univariate Logistic regression was performed to predict the related factors of preterm birth within 48 h after the using of tocolysis in pregnant women with threat-ened preterm birth by uterine electromyography,and receiver operating characteristic(ROC)curve was per-formed to evaluate their performance.Results:Compared to before treatment with tocolysis,after therapy,in the non-preterm birth within 48 h group,significant reductions in contraction frequency,area,duration and amplitude were observed(P<0.05).In the preterm birth within 48 h group,only contraction frequency decreased significant-ly(P<0.05).Univariate Logistic regression indicated that contraction frequency,contraction duration,and contrac-tion area were predictive factors for premature birth within 48 h after tocolysis(P<0.05).When the duration of u-terine contractions lasting for 104.55 s or more the sensitivity and specificity of predicting premature birth within 48 h are 92.3％and 68.6％,respectively.Conclusions:Uterine electromyography may predict the premature birth within 48 h after tocolytic treatment in preterm labor,which may provide reference for subsequent corticosteroid therapy or transfer of high-risk pregnant patients.

Objective:To evaluate the diagnostic performance of artificial intelligence-assisted diagnostic systems in cervical cytopathological examination.Methods:Cervical cytology slide data were retrospectively collected from four hospitals for the external validation of the developed artificial intelligence-assisted diagnostic system. Subsequently, prospective data collection was conducted for human-machine assisted studies.Results:In the retrospective study, a total of 3 162 valid samples were collected as external validation data. The system showed an area under the curve (AUC) of 0.890 (95% CI: 0.878-0.902), accuracy of 0.885 (95% CI: 0.873-0.896), sensitivity of 0.928 (95% CI: 0.914-0.941), and specificity of 0.852 (95% CI: 0.834-0.867). In the prospective study, 212 valid samples were collected, and five junior cytologists participated in the human-machine assisted study. Without artificial intelligence assistance, the average AUC for the five cytologists was 0.686 (95% CI: 0.650-0.722), the accuracy was 0.699 (95% CI: 0.671-0.727), the sensitivity was 0.653 (95% CI: 0.599-0.703), the specificity was 0.719 (95% CI: 0.685-0.750), the Fleiss κ value was 0.510, and the reading time was 223 seconds. With artificial intelligence assistance, the AUC, accuracy, sensitivity, and specificity increased by 0.166, 0.143, 0.225, and 0.107, respectively. Additionally, Fleiss κ was 0.730 and the reading time decreased by 188 seconds. All differences were statistically significant (all P<0.001). Conclusions:Artificial intelligence-assisted diagnosis system shows excellent performance and good generalizability, significantly improving the diagnostic accuracy, consistency, and efficiency of junior cytologists. It can be an effective auxiliary tool for junior cytologists in clinical practice.

HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Objective: To understand the epidemiological and etiological characteristics of food poisoning event occurred in a school in Hangzhou, Zhejiang, so as to provide reference for the scientific management of related emergencies. Methods: By determining the nature of the event through epidemiological investigation, a case control study was carried out to spot suspicious food in May 2024. The hygienic investigation was conducted to find out possible pollution links and factors, patients and canteen practitioners anal swab, canteen retention samples, catering link daub and other specimens were collected ,for rapid pathogen screening. And the suspected pathogen Clostridium perfringens (CP) were isolated and identified according to the screening results, and toxin gene detection and whole genome sequencing and cluster analysis of CP isolated strains were carried out. Results: The incident resulted in 45 people experiencing gastrointestinal symptoms, such as diarrhea and abdominal pain. The suspicious food was tomato scrambled eggs and corn ribs provided by the student canteen for lunch on May 29. A hygiene investigation found that there was a risk of contamination in the food processing, preparation and storage. A total of 46 anal swabs and 10 canteen retention samples were positive for CP 16 S, 59 strains of CP were isolated from 27 samples, 10 cases and 1 practitioner isolate were positive for CPE ( cpe ) (F mode), and their whole genome evolution analysis was conducted based on the same source. Conclusions The food poisoning event is caused by CP infection carrying CPE ( cpe ) (F mode), and the possible sources of outbreak are the carriers of the CP by employees. It is recommended that cafeteria staff strengthen training on common foodborne diseases and conduct regular monitoring of pathogens.

Objective:To evaluate the diagnostic performance of artificial intelligence-assisted diagnostic systems in cervical cytopathological examination.Methods:Cervical cytology slide data were retrospectively collected from four hospitals for the external validation of the developed artificial intelligence-assisted diagnostic system. Subsequently, prospective data collection was conducted for human-machine assisted studies.Results:In the retrospective study, a total of 3 162 valid samples were collected as external validation data. The system showed an area under the curve (AUC) of 0.890 (95% CI: 0.878-0.902), accuracy of 0.885 (95% CI: 0.873-0.896), sensitivity of 0.928 (95% CI: 0.914-0.941), and specificity of 0.852 (95% CI: 0.834-0.867). In the prospective study, 212 valid samples were collected, and five junior cytologists participated in the human-machine assisted study. Without artificial intelligence assistance, the average AUC for the five cytologists was 0.686 (95% CI: 0.650-0.722), the accuracy was 0.699 (95% CI: 0.671-0.727), the sensitivity was 0.653 (95% CI: 0.599-0.703), the specificity was 0.719 (95% CI: 0.685-0.750), the Fleiss κ value was 0.510, and the reading time was 223 seconds. With artificial intelligence assistance, the AUC, accuracy, sensitivity, and specificity increased by 0.166, 0.143, 0.225, and 0.107, respectively. Additionally, Fleiss κ was 0.730 and the reading time decreased by 188 seconds. All differences were statistically significant (all P<0.001). Conclusions:Artificial intelligence-assisted diagnosis system shows excellent performance and good generalizability, significantly improving the diagnostic accuracy, consistency, and efficiency of junior cytologists. It can be an effective auxiliary tool for junior cytologists in clinical practice.

Objective:To investigate the short-term efficacy and safety of rituximab (RTX) in children with calcineurin inhibitor (CNI) resistant steroid resistant nephrotic syndrome (SRNS).Methods:A retrospective case analysis was conducted. Thirteen children with CNI resistant SRNS who were regularly treated with RTX (375 mg/m 2 per dose (maximum dose 500 mg), 1 dose per week, a total of 4 doses) in Department of Nephrology, Children′s Hospital of Fudan University from January 2016 to December 2023 were enrolled. The general data, disease related information, urinary protein/creatinine, serum albumin, blood creatinine before RTX treatment, immunosuppressants, adverse events, and monthly urinary protein/creatinine, serum albumin, and blood creatinine indexes within 6 months after RTX treatment were collected. The changes of urinary protein/creatinine, serum albumin and estimated glomerular filtration rate (eGFR) before and after RTX at 3 and 6 months were analyzed by using paired sample t test and Wilcoxon signed-rank test. Results:Among the 13 patients, 8 were male and 5 were female. The age of disease onset was 4.0 (2.9, 6.8) years and the age of RTX treatment was 9.8 (5.9, 13.6) years. There were 8 cases of focal segmental glomerulosclerosis, 3 cases of minimal change disease and 2 cases of mesangial proliferative glomerulonephritis. No clinically significant gene variation was detected in 12 cases and the other one did not receive gene test. Before RTX treatment, 11 cases were in chronic kidney disease stage G1, and 1 case each was in stage G2 and stage G3. Ten children completed 4 doses of RTX treatment, 1 patient completed 3 doses, and 2 patients completed 2 doses. Urinary protein/creatinine in 13 children at 3 and 6 months after RTX treatment was significantly lower than baseline (0.60 (0.13, 2.04), 0.49 (0.28, 1.10) vs. 1.44 (0.76, 4.11) mg/mg, Z=-2.34, -2.34, both P<0.05), and serum albumin was significantly higher than baseline ((35±8), (34±7) vs. (30±6) g/L, t=2.30, 2.60, both P<0.05). The eGFR at 6 months after RTX treatment was not significantly different from the baseline ((110±32) vs. (113±35) ml/(min·1.73 m 2), t=-0.76, P>0.05)). No serious adverse reactions occurred in this study. Conclusion:RTX could reduce urinary protein and increase serum albumin in short-term treatment in children with CNI resistant SRNS without significant side effects.

Molecular editing around privileged scaffolds, also known as periphery editing, is a commonly used strategy in contemporary drug discovery and development. Tranylcypromine (TCP) is a widely acknowledged scaffold with diverse pharmacological activities. TCP-derived compounds target different enzymes and cellular receptors such as amine oxidase, platelet P2Y₁₂ receptor, and cytochrome P450 superfamily. These compounds have demonstrated various effects including antidepressant, anticancer, antiviral properties, involvement in prostaglandin synthesis, and mediation of drug metabolism. Notably, the first reversible oral P2Y₁₂ receptor antagonist, ticagrelor, is currently used to prevent future myocardial infarction, stroke, and cardiovascular death. Several TCP-based lysine demethylase 1 (LSD1) inhibitors are currently undergoing clinical assessment. MIV-150, a third-generation non-nucleoside reverse transcriptase inhibitor, has progressed to the clinical stage for treating human immunodeficiency virus type 1 (HIV-1) seronegative patients suffering from acute coronary syndrome. This review aims to explore the target landscape of TCPs, highlight key structure-activity relationships (SARs), and emphasize the therapeutic potential of TCPs for treating various diseases. Finally, the lessons learned from our medicinal chemistry practice, challenges and future directions of TCP-based drug discovery are briefly discussed.