OBJECTIVES: To explore the predictive factors for hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants and to construct a nomogram prediction model for hsPDA occurrence in this population. METHODS: A retrospective analysis was conducted on the clinical data of preterm infants with gestational age <32 weeks diagnosed with patent ductus arteriosus (PDA) who were delivered at Nanjing Women and Children's Healthcare Hospital from January 2020 to December 2022. The subjects were divided into an hsPDA group (52 cases) and a non-hsPDA group (176 cases) based on the presence of hsPDA. Univariate analysis and multivariate logistic regression analysis were performed to screen predictive variables regarding the general information of the infants at birth, maternal pregnancy and delivery conditions, and relevant indicators during hospitalization. A nomogram prediction model for hsPDA occurrence was constructed using R software in preterm infants. Internal validation was performed using the Bootstrap method. Finally, the predictive model was evaluated for calibration, discrimination ability, and clinical utility. RESULTS: Multivariate regression analysis showed that the ratio of the left atrium to aorta diameter (LA/AO), mode of delivery (vaginal), and duration of mechanical ventilation were independent predictive factors for hsPDA in preterm infants (P<0.05). Based on the results of univariate analysis and multivariate logistic regression analysis, variables used to construct the nomogram prediction model for hsPDA risk included: LA/AO ratio, mode of delivery (vaginal), duration of mechanical ventilation, 5-minute Apgar score, and the presence of neonatal respiratory distress syndrome requiring surfactant therapy. The area under the receiver operating characteristic curve for this model was 0.876 (95%CI: 0.824-0.927), and the calibrated curve was close to the ideal reference line, indicating good calibration. The Hosmer-Lemeshow test demonstrated that the model fit well, and the clinical decision curve was above the extreme curves. CONCLUSIONS The nomogram prediction model, constructed using five variables (LA/AO ratio, vaginal delivery, duration of mechanical ventilation, 5-minute Apgar score, and the presence of neonatal respiratory distress syndrome requiring surfactant therapy), has reference significance for predicting the occurrence of hsPDA in preterm infants and provides valuable guidance for the early clinical identification of hsPDA.
Humans ; Ductus Arteriosus, Patent/etiology* ; Nomograms ; Female ; Infant, Newborn ; Infant, Premature ; Retrospective Studies ; Male ; Hemodynamics ; Logistic Models ; Pregnancy

Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

Objective To explore the evidence,urinary biomarkers,and partial mechanisms of hypercoagulability in the pathogenesis of IgA vasculitis(IgAV).Methods Differential expression of proteins in the urine of 10 healthy children and 10 children with IgAV was screened using high-performance liquid chromatography-tandem mass spectrometry,followed by Reactome pathway analysis.Protein-protein interaction(PPI)network analysis was conducted using STRING and Cytoscape software.In the validation cohort,15 healthy children and 25 children with IgAV were included,and the expression levels of differential urinary proteins were verified using enzyme-linked immunosorbent assay.Results A total of 772 differential proteins were identified between the IgAV group and the control group,with 768 upregulated and 4 downregulated.Reactome pathway enrichment results showed that neutrophil degranulation,platelet activation,and hemostasis pathways were involved in the pathogenesis of IgAV.Among the differential proteins,macrophage migration inhibitory factor(MIF)played a significant role in neutrophil degranulation and hemostasis,while thrombin was a key protein in platelet activation and hemostasis pathways.PPI analysis indicated that thrombin directly interacted with several proteins involved in inflammatory responses,and these interactions involved MIF.Validation results showed that compared to healthy children,children with IgAV had significantly higher urine thrombin/creatinine and urine MIF/creatinine levels(P<0.05).Conclusions Thrombin contributes to the pathogenesis of IgAV through interactions with inflammatory factors.Urinary thrombin and MIF can serve as biomarkers reflecting the hypercoagulable and inflammatory states in children with IgAV.

Objective To compare screw versus Kirschner wire fixation in the treatment of lateral humeral condyle frac-tures in children.Methods A systematic search was conducted in PubMed,Embase,the Cochrane library,Web of Science,China National Knowledge Internet(CNKI),Wanfang Datebase from in ception to February 2022.Studies comparing screws and Kirschner wire fixation in the treatment of lateral humeral condyle fractures in children were included.Outcome measures included and excluded by a set of inclusion and exclusion criteria and evaluated for their quality,their excellent and good rate of fracture healing,malunion,delayed union or nonunion,infection,limitation of elbow flexion or extension(＞10°)were ex-tracted and analyzed using software Rev Man 5.3.Results A total of 9 retrospective studies involving 647 patients were includ-ed,with 255 patients in the screw fixation group(including screw combined with Kirschner wire)and 392 patients in the Kirschner wire fixation group.Meta analysis showed the following:infection rate in the screw group was significantly lower than that in the Kirschner wire group[OR=0.22,95％CI(0.09,0.56),P=0.001].There were no significant differences between the 2 groups in excellent and good rate of fracture healing,malunion rate(P＞0.05).Subgroup analysis showed that infection rate in the screw-only group was significantly lower than that in the Kirschner wire group[OR=0.18,95％CI(0.05,0.65),P=0.009].Conclusion For lateral humeral condyle fractures,Screw fixation alone had a lower infection rate than kirschner wire fixation and screw combined with Kirschner wire fixation.There were no significant differences in the excellent and good rate of fracture healing,malunion.In terms of postoperative efficacy and safety of internal fixation,orthopaedic surgeons are more like-ly to recommend screws for fixation of lateral humeral condyle fractures in children.

Quantitative systems pharmacology (QSP) modeling is an emerging computational medicine approach with growing applications and significance in modern drug development. QSP models are generally formulated based on multiscale disease mechanisms and drug-target interactions, which makes them capable of integrating multimodal data from the preclinical and clinical space. This also enables them to generate quantitative characterization of the dynamic disease progression as well as high-throughput predictions of drug-induced efficacy and toxicity signals. Therefore, QSP modeling and model-based virtual clinical trials have been widely implemented to guide drug development, in scenarios such as target identification and assessment, clinical trial design, evaluation of combination therapy and biomarkers, and personalized medicine. In US and Europe, QSP modeling has been developing rapidly in the past 10 years and is now an integral part of the model-informed drug development paradigm; however, in China it is still a nascent field. Here we will present a comprehensive review of the recent advancements of QSP and its impact in modern drug development through a number of case studies. This review will provide guidance for the future drug development efforts and the growth of QSP practice in China.

Objective:To study influence of exercise rehabilitation based on medical treatment combination model on patients with chronic heart failure(CHF).Methods:A total of 110 CHF patients treated in our hospital were ran-domly and equally divided into routine nursing group and exercise rehabilitation group(received exercise rehabilita-tion on the basis of medical treatment combination model based on routine nursing group).Both groups were inter-vened for 12 week.s Peak oxygen uptake(Peak VO2),Peak work rate(Peak WR),anaerobic threshold(AT),ratio of peak VO2 to heart rate(Peak VO2/HR),score of Minnesota living with heart failure questionnaire(MLHFQ)and 6min walking distance(6MWD)before and after intervention and incidence rate of major adverse cardiovascular events(MACE)were compared between two groups.Results:There were three cases lost during intervention in each group.Compared with routine nursing group,after intervention,there were significant rise in Peak VO2[(13.92±0.88)ml·min-1·kg-1 vs.(16.00±0.84)ml·min-1·kg-1],Peak VO2/HR[(8.92±0.81)ml/beat vs.(9.83±0.79)ml/beat],AT[(684.10±74.11)ml/min vs.(827.38±98.56)ml/min]and 6MWD[(470.12±42.76)m vs.(502.21±26.54)m],and sig-nificant reductions in Peak WR[(79.85±6.10)W vs.(72.65±5.48)W]and MLHFQ score[(49.17±3.96)scores vs.(36.38±3.57)scores]in exercise rehabilitation group(P=0.001 all).Incidence rate of MACE in exercise rehabili-tation group was significantly lower than that of routine nursing group(0.36%vs.15.38%,P=0.046).Conclusion:Ex-ercise rehabilitation based on medical treatment combination model can significantly improve cardiopulmonary function and exercise endurance,reduce incidence rate of adverse cardiovascular events and improve short-term quality of life in pa-tients with chronic heart failure.

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/β-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knock-down.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/β-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alle-viated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.

OBJECTIVE: To compare the long-term follow-up effect and complications of ceramic on ceramic (CoC) interface and ceramic on polyethyleneon ceramic (CoP) interface in primary total hip arthroplasty, and provide clinical evidence. METHODS: Search PubMed, EMBase, the CoChrane Library databases, Web of science, Wanfang database, and CNKI from January 2000 to September 2021, screening and inclusion of randomized controlled trials (RCTs) comparing the long-term efficacy and complications of CoC interface and CoP interface in total hip arthroplasty. Literature screening, quality evaluation and data extraction were carried out according to the inclusion and exclusion criteria, using Review Manager 5.3 statistical software. The software was used to perform statistical analysis on joint function, revision, prosthesis fracture, abnormal joint noise, and prosthesis wear rate after CoC or CoP. RESULTS: Seven RCTs studies were included, including 390 cases of hips with CoC artificial joints and 384 cases of hips with CoP artificial joints. The long-term joint function improvement of CoC and CoP artificial joints was similar and there was no significant differences, with an average difference was MD=0.63, 95%CI=(-1.81, 3.07), P=0.61. About the postoperative complications, CoC artificial joints have higher incidence rate of abnormal joint noise, with odds ratio (OR)=11.05, 95%CI=(2.04, 59.84), P=0.005. CoP artificial joints wear faster, with an average MD=-87.11, 95%CI=(-114.40, -59.82), P<0.000 1. There was no significant difference between the two groups in the replacement-related complications such as joint dislocation, prosthesis loosening, osteolysis, and the rate of prosthesis revision caused by various reasons. CONCLUSION The clinical function results and complications of CoC artificial joints are comparable to those of CoP artificial joints. Although CoP artificial joint prosthesis has a faster wear rate, it does not affect joint function and increase complications, and there is no abnormal joint noise. CoC is expensive and the long-term efficacy is equivalent to CoP. Clinicians should consider cost performance when choosing CoC.
Humans ; Arthroplasty, Replacement, Hip/methods* ; Hip Prosthesis ; Follow-Up Studies ; Prosthesis Design ; Polyethylene ; Prosthesis Failure ; Reoperation ; Ceramics ; Treatment Outcome

OBJECTIVE: To assess the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) for treatment of type 2 diabetes in a randomized, double-blind, placebo-controlled multicenter clinical trial. METHODS: A total of 200 patients were randomized to receive SZ-A (n=100) or placebo (n=100) for 16 weeks. The data analysis system for electronic data capture clinical trial central randomization system was used for randomization and dispensing of drugs. The primary outcome was the change in glycosylated hemoglobin (HbA1c) level. The secondary outcome included the proportions of cases with HbA1c <7.0% and HbA1c <6.5%, fasting blood glucose (FBG), postprandial blood glucose (PBG), area under curve for the PBG (AUC_0-2h), body weight, and body mass index (BMI). Adverse events (AEs), severe adverse events (SAEs), treatment-related adverse events (TAEs), gastrointestinal disorders (GDs), blood pressure, routine blood tests, and liver and kidney function were monitored. RESULTS: Compared with baseline, the change of HbA1c at week 16 was -0.80% (95% CI: -0.98% to -0.62%) and -0.09% (95% CI: -0.27% to 0.09%) in SZ-A group and placebo group, respectively. The proportion of patients with HbA1c <7% and <6.5% was higher in the SZ-A group than in the placebo group (46.8% vs. 21.6% and 29.9% vs. 10.8%). The observed values and changes in FBG, 1 h-PBG, 2 h-PBG, and AUC_0-2h differed significantly between groups (P<0.001), but differences were not significant in body weight and BMI (P>0.05). The incidence rates of AEs, TAEs, and GDs differed significantly between groups (P=0.010, P=0.005, and P=0.006, respectively), whereas the incidence rates of SAEs showed no significant differences between groups (P=1.000). CONCLUSION SZ-A are effective and safe for treatment of type 2 diabetes. The protocol was registered in http://www.chictr.org.cn/showproj.aspx?proj=60117 (ChiCTR2000038550).
Alkaloids ; Blood Glucose ; Diabetes Mellitus, Type 2/drug therapy* ; Double-Blind Method ; Glycated Hemoglobin A ; Humans ; Hypoglycemic Agents/therapeutic use* ; Morus ; Tablets/therapeutic use* ; Treatment Outcome

The onset of prostate cancer (PCa) is often hidden, and recurrence and metastasis are more likely to occur due to chemotherapy resistance. Herein, we identified downregulated long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) in PCa that was associated with metastasis and paclitaxel resistance. GAS5 acted as a tumor suppressor in suppressing the proliferation and metastasis of paclitaxel-resistant PCa cells. GAS5 overexpression in vivo inhibited the tumor growth of xenografts and elevated PCa sensitivity to paclitaxel. Combination of GAS5 and paclitaxel treatment showed great potential in PCa treatment. Moreover, mechanistic analysis revealed a novel regulatory network of GAS5/miR-18a-5p/serine/threonine kinase 4 (STK4) that inhibits epithelial-to-mesenchymal transition (EMT) and enhances tumor stem cell-like-mediated sensitivity to paclitaxel in PCa. These findings provide a novel direction for the development of a potential adjunct to cancer chemotherapy that aims to improve the sensitivity of chemotherapy drugs in PCa.
Humans ; Male ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Gene Expression Regulation, Neoplastic ; MicroRNAs/metabolism* ; Neoplastic Stem Cells ; Paclitaxel/therapeutic use* ; Prostatic Neoplasms/genetics* ; Protein Serine-Threonine Kinases/metabolism* ; RNA, Long Noncoding/metabolism* ; Epithelial-Mesenchymal Transition