OBJECTIVE To establish a multi-dimensional value assessment framework for new antidiabetic drugs based on multi-criteria decision analysis theory， thus providing a theoretical framework and methodology for evidence-informed medical insurance decision-making. METHODS Firstly， multi-dimensional evidence was searched and obtained to provide reliable data for the establishment of the framework. Secondly， in terms of the obtained evidence， the value assessment framework was preliminarily constructed. Its structure， main core criteria， and contextual criteria were determined through focus group discussion. Finally， the criteria and sub-criteria of the framework and their weights were further determined， reasons for inclusion of sub-criteria and the reasonableness of rating scores were evaluated， and methods of assessment were optimized through expert consultation. RESULTS The multi-dimensional value assessment framework for new antidiabetic drugs was composed of core criteria and contextualized criteria， which could be used for quantitative and qualitative value assessment of new drugs， respectively. The core criteria consisted of five dimensions， with affordability （6.31） having the highest weighting score， followed by comparative effectiveness （6.20）， comparative safety （6.01）， cost-effectiveness （5.89）， and quality of evidence （5.46）. After the normalization of weight within sub-criteria， the budget impact on medical insurance had the highest standardized weight， followed by the control of glycated hemoglobin and patient affordability. The contextual criteria included two dimensions， i. e.， innovation and equity. CONCLUSIONS The assessment framework integrates evidence， stakeholders’ values， and decision contexts to enable a multi- dimensional and evidence-based assessment of the value of new antidiabetic drugs.

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome

The regulatory processes in developmental biology research are significantly influenced by long non-coding RNAs (lncRNAs). However, the dynamics of lncRNA expression during human tooth development remain poorly understood. In this research, we examined the lncRNAs present in the dental epithelium (DE) and dental mesenchyme (DM) at the late bud, cap, and early bell stages of human fetal tooth development through bulk RNA sequencing. Developmental regulators co-expressed with neighboring lncRNAs were significantly enriched in odontogenesis. Specific lncRNAs expressed in the DE and DM, such as PANCR, MIR205HG, DLX6-AS1, and DNM3OS, were identified through a combination of bulk RNA sequencing and single-cell analysis. Further subcluster analysis revealed lncRNAs specifically expressed in important regions of the tooth germ, such as the inner enamel epithelium and coronal dental papilla (CDP). Functionally, we demonstrated that CDP-specific DLX6-AS1 enhanced odontoblastic differentiation in human tooth germ mesenchymal cells and dental pulp stem cells. These findings suggest that lncRNAs could serve as valuable cell markers for tooth development and potential therapeutic targets for tooth regeneration.
Humans ; RNA, Long Noncoding/metabolism* ; Odontogenesis/genetics* ; Tooth Germ/embryology* ; Cell Differentiation ; Gene Expression Regulation, Developmental ; Mesoderm/metabolism* ; Tooth/embryology* ; Gene Expression Profiling ; Sequence Analysis, RNA ; Dental Pulp/cytology*

Objective:To explore the genetic etiology of a fetus with cryptophthalmos detected by prenatal ultrasonography.Methods:A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy.Results:The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c. 4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+ PM2_Supporting+ PM5+ PP3+ PP4; PM2_Supporting+ PM3+ PP3+ PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype. Conclusion:The FREM2: c. 4537G>A and c. 7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.

Objective:To summarize the clinical characteristics of patients with end-stage heart failure who receive heart transplant under extracorporeal membrane oxygenation (ECMO) support.Methods:The clinical data of 12 pediatric patients who received heart transplant with ECMO support in the Seventh Medical Center of Chinese People′s Liberation Army General Hospital and Guangdong Provincial People′s Hospital, from January 2019 to December 2023 was collected. The data included sex, age, weight, diagnosis, pre-ECMO lactate level, left ventricular ejection fraction (LVEF), vasoactive-inotropic score (VIS), and preoperative ECMO running time. Surgical data included cold ischemia time of the donor heart, cardiopulmonary bypass time, intraoperative use of immunosuppressant, postoperative use of ECMO, duration of postoperative ECMO, rate of successful weaning from ECMO, and survival discharge rate. The paired t-test was performed to compare cardiac function indices before and after left ventricular decompression. Results:The 12 patients ranged in age from 1.1 to 15.8 years, and weighted from 8 to 63 kg. Ten children were diagnosed with dilated cardiomyopathy, one with myocardial underdensification, and one with a novel heterozygous mutation of the SCN5A gene causing overlap syndrome complicated by fatal arrhythmia. Before ECMO, the lactate ranged from 0.6 to>15.0 mmol/L, the LVEF from 6.5% to 43%, and VIS from 3 to 108. Four patients underwent left ventricular decompression supported by preoperative ECMO, and their pulse pressure was significantly increased after decompression ((17.8±2.1) vs. (9.8±1.5) mmHg, 1 mmHg=0.133 kPa, t=11.31, P=0.001), while there was no apparent change in LVEF ((26.8±4.4)% vs. (24.9±4.9)%, t=1.75, P=0.178). A total of 7 children received a second run of ECMO after surgery and 3 of them successfully weaned off ECMO and survived to discharge. In the entire cohort, 10 were successfully weaned from ECMO and 8 survived to discharge. Conclusions:For children with end-stage heart failure supported by ECMO, left ventricular decompression can significantly improve pulse pressure. These patients will eventually require heart transplantation.

Objective To study the changes of blood glutathione peroxidase (GSH-px),superoxide dis-mutase (SOD),malondialdehyde (MDA) and pathological tissues in the rat contrast-induced nephropathy (CIN) model,and to determine the role of oxidation mechanism in CIN.Methods A total of 40 adult male SD rats were selected and divided into three big groups and five small groups.After constructing the model,six rats with good status were taken from each group for conducting the experiment.The serum GSH-px,SOD and MDA levels were measured,the renal tissue biopsy was performed and the morphological changes of kid-ney cells were compared.Results There was no statistically significant difference in the baseline data among the blank control group,the control group and the experimental group (P>0.05).There was no statistically significant difference in serum GSH-px,SOD and MDA levels before model construction,at 24,48 h after model construction between the blank control group and the control group (P>0.05).There were statistical-ly significant differences in serum GSH-px,SOD and MDA levels of the experimental group between before model construction and after model construction (P<0.05).There was no statistically significant difference in serum GSH-px,SOD and MDA level in the experimental group between at 24 h after modelling and 48 h af-ter modeling (P>0.05).There was no statistically significant difference in serum GSH-px,SOD and MDA levels at 24 h after modeling among the three groups (P>0.05).There were statistically significant differ-ences in serum GSH-px,SOD and MDA levels at 48 h after modeling among the three groups and their pairs (P<0.05).The pathological sections of the blank control group and control group showed no obvious abnor-mal changes in glomeruli,renal tubule and renal interstitium.Renal interstitial fibrosis and inflammatory cell infiltration were seen after 24 h in the experimental group,but there was no obvious change in the renal tu-bules.After 48 h,moderate focal-like atrophy of renal tubules,epithelial cell granule degeneration and vacuolar changes were obviously seen.Conclusion The oxidative stress mechanism plays a role in CIN.The contrast a-gent acute renal injury mainly acts on the renal tubules and renal interstitium,and there is no obvious damage to the glomeruli.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Objective:To investigate the efficacy of Shuotong ureteroscope combined with flexible ureteroscope in the treatment of 2-3 cm lower calyceal calculi, and analyze the influencing factors.Methods:A total of 102 patients with lower calyceal calculi were treated in the Second People′s Hospital of Yulin from February 2019 to December 2022, and they were divided into the observation group and the control group, with 51 cases in each group. The patients of the observation group were treated with Shuotong ureteroscope combined with flexible ureteroscope, while the patients of the control group were treated with flexible ureteroscope. According to whether the stones were completely removed after operation, all patients were divided into non-stone removal group ( n=13) and stone removal group ( n=89). The operation time, hospitalization time, lithotripsy time, intraoperative blood loss, complication rate and stone clearance rate were compared between the observation group and the control group. Generalized Estimation Equation was used to analyze and evaluate the effects of treatment time, treatment scheme and their interaction on visual analogue scale (VAS), white blood cell (WBC), blood urea nitrogen (BUN), blood creatinine (Cr), hemoglobin (HGB) and procalcitonin (PCT). Univariate and multivariate Logistic regression were used to analyze the risk factors of stone removal rate. Nomogram model was constructed based on risk factors and evaluate the model. Results:Compared with the control group, operation time [(118.72±9.61) min vs (136.65±11.27) min], hospitalization stay [(6.43±1.12) d vs (10.29±2.23) d] and the lithotripsy time [ (51.23±10.38) min vs (56.62±11.43) min] of the observation group were shorter, and the amount of intraoperative blood loss [(128.52±10.20) mL vs (157.53±15.31) mL] were significantly less than those of the control group ( P< 0.05). The results of Generalized Estimation Equation analysis showed that treatment time, treatment regimen and their interaction had significant effects on WBC, HGB, BUN, Cr, PCT and VAS ( P< 0.05). Compared with the control group, the incidence of complications (5.88% vs 19.61%) of the observation group was lower and the stone clearance rate ( 94.12% vs 80.39%) was significantly higher than those in the control group ( P< 0.05). The mode of operation, infundibulopelvic angle(IPA), caliceal pelvic height (CPH) and the maximum diameter of stones were all influencing factors of stone removal rate in patients with 2-3 cm lower calyceal calculi. The nomogram model constructed in this study has good differentiation, calibration and clinical practicability, and can better identify high-risk patients with incomplete removal of 2-3 cm lower calyceal calculi. Conclusions:Shuotong ureteroscope combined with flexible ureteroscope is a safe, effective method for the treatment of 2-3 cm lower calyceal calculi. It has the advantages of simple operation, less intraoperative bleeding, less postoperative complications and high stone clearance rate. IPA, CPH, the maximum diameter of calculi and the mode of operation were all independent factors affecting the stone clearance rate of 2-3 cm lower calyceal calculi. The nomogram model constructed in this study can well identify the high-risk patients with incomplete clearance of 2-3 cm lower calyceal calculi.

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma. Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment. Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway. Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.