Objective: To characterize longitudinal trajectories of testicular development in boys and breast development in girls, so as to provide reference data for understanding patterns of pubertal sexual maturation. Methods: Based on the Shanghai Pudong New Area Cohort Study on Growth, Development and Health in Children and Adolescents, a baseline survey was conducted in 2020 using a mult stage cluster random sampling method. A total of 2 184 children who completed all follow ups during the primary school period from 13 elementary schools in Pudong New Area,Shanghai,with annual follow ups during 2021-2025. Testicular volume and Tanner stage of breast development were assessed by professional physicians using standardized visual inspection and palpation. The age distribution of testicular volume and breast development was fitted by using cumulative link mixed models and Turnbull s nonparametric maximum likelihood estimation method. Results: Median ages for testicular volumes of 2, 3, 4 and 5 mL in boys were 7.07, 9.24, 10.29, and 11.57 years old, respectively. Median ages for Tanner breast stages Ⅱ, Ⅲ, Ⅳ, and Ⅴ in girls were 8.55 , 10.17, 11.18, and 13.78 years old, respectively. Based on overweight and obesity, stratified analysis showed that earlier pubertal onset among overweight/obesity children, and the key milestones for pubertal initiation were testicular volume reaching 4 mL in boys and breast Tanner II in girls for 10.29, 10.83; 8.18, 9.00 years. Conclusion Overweight and obesity are associated with earlier pubertal initiation,but there are certain gender and developmental stage specific patterns.

Objective: To explore the regulatory role of paternal involvement in parenting in the association between parental adverse childhood experiences (ACEs) and autism like behavioral problems in children aged 3-6, so as to provide a basis for intervention strategies targeting the intergenerational health effects of ACEs. Methods: A longitudinal study design was used to select 1 780 children aged 3-6 from 12 kindergartens in Wuhu City, Anhui Province in June 2021 as the subjects of the baseline survey by convenient sampling, and the follow up surveys were conducted once every six months, for a total of two follow ups. Pearson correlation analysis was used to examine the association of parental ACEs and paternal involvement in parenting with autism like behavioral problems in children. A binary Logistic regression model was used to explore the association between parental ACEs and autism like behavioral problems in children. Based on stratification, the potential role of paternal involvement in the association between parental ACEs and autism like behavioral problems in children aged 3-6 was explored. Results: Autism like behavioral problem score in children aged 3-6 was positively correlated with the total score ACEs of parents as well as scores of emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect, community violence, peer bullying, and family dysfunction( r =0.18,0.16,0.18,0.14,0.06,0.05,0.12,0.18,0.09,all P <0.05). Autism like behavioral problem score in children was negatively correlated with score of paternal involvement in parenting( r =-0.16, P <0.01). After adjusting for covariates such as gender, age, and birth weight of children, binary Logistic regression analysis showed that children whose parents had experiences of childhood emotional abuse, physical abuse, sexual abuse, community violence, peer bullying, or family dysfunction had higher risks of developing autism like behavioral problems than those in the non exposed group ( OR =3.29, 3.28, 6.71, 2.34, 4.08, 2.02, all P <0.01). In the group with low paternal involvement in parenting, all dimensions of parental ACEs(emotional abuse, physical abuse, sexual abuse, community violence, peer bullying, and family dysfunction) were significantly associated with an increased risk of autism like behavioral problems in children ( OR =1.84-8.34, all P <0.05). In contrast, in the group with high paternal involvement in parenting, no statistically significant associations were found between any dimension of parental ACEs and children s autism like behavioral problems ( OR =0.57-1.82, all P >0.05). Conclusion A high level of paternal involvement in parenting can reduce the adverse effects of parental ACEs on the occurrence of autism like behaviors in preschool children.

Objective: To determine the potential genetic causal relationship between sleep related phenotypes and female pubertal onset using the two sample Mendelian randomization approach. Methods: Genetic instrumental variables for sleep and age at menarche were sourced from FinnGen, IEU Open GWAS and GWAS Catalog three publicly available Genome Wide Association Study databases. Causal effects were estimated using the inverse variance weighted method, supplemented by sensitivity analyses and tests for heterogeneity, pleiotropy, and direction. Results: Genetically predicted sleep duration was positively associated with age at menarche ( β =0.61, 95% CI =0.30-0.91, P <0.01). Conversely, overall sleep problems ( β =-0.13, 95% CI =-0.20 to -0.07 ), two specific types of sleep disorders (sleep apnea: β =-0.10, 95% CI =-0.16 to -0.03; insomnia: β =-0.40, 95% CI = -0.69 to -0.11) were causally associated with earlier age at menarche (all P <0.01). Sensitivity analyses confirmed the robustness of these findings with consistent effect directions and no evidence of significant directional pleiotropy. Conclusions The study reveales a genetic causal relationship between sleep and pubertal onset. Adequate sleep duration appears to have a protective effect. These findings suggest that sleep may have a critical regulatory role in the initiation of pubertal development.

Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are linked to numerous chronic conditions, including cardiovascular disease, atherosclerosis, chronic kidney disease, and type II diabetes. Previous research identified the natural flavonoid diosmin, derived from Chrysanthemum morifolium, as a regulator of glucose metabolism. However, its effects on lipid metabolism and underlying mechanisms remained unexplored. The AMP-activated protein kinase (AMPK) pathway serves a critical function in glucose and lipid metabolism. The relationship between diosmin and the AMPK pathway has not been previously documented. This investigation examined diosmin's capacity to reduce lipid content through AMPK pathway activation in hepatoblastoma cell line G2 (HepG2) and 3T3-L1 cells. The study revealed that diosmin inhibits lipogenesis, indicating its potential as an anti-obesity agent in obese mice. Moreover, diosmin demonstrated effective MASLD alleviation in vivo. These findings suggest that diosmin may represent a promising therapeutic candidate for treating obesity and MASLD.
Diosmin/administration & dosage* ; Animals ; AMP-Activated Protein Kinases/genetics* ; Humans ; Non-alcoholic Fatty Liver Disease/enzymology* ; Mice ; Obesity/enzymology* ; Hep G2 Cells ; Male ; 3T3-L1 Cells ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Lipid Metabolism/drug effects* ; Chrysanthemum/chemistry* ; Lipogenesis/drug effects*

Objective:To evaluate the long-term effectiveness of lingual mucosal graft ureteroplasty (LMGU) for managing long-segment (≥5 cm) ureteral strictures in a multi-institutional cohort of patients.Methods:A multi-center retrospective case series study was conducted on clinical data from 42 patients undergoing LMGU for long-segment ureteral strictures (≥5 cm) across five institutions between February 2017 and June 2024. The cohort comprised 31 males and 11 females, with an age of (43.4±12.0) years (range: 15 to 64 years) and a body mass index of (24.6±2.6) kg/m2 (range: 16.0 to 30.0 kg/m2). Strictures involved the left ureter in 24 cases and right ureter in 18 cases, demonstrating a stricture length of (6.4±1.5) cm (range: 5.0 to 11.5 cm). Surgical interventions included either onlay ureteroplasty or augmented anastomotic ureteroplasty, selected according to intraoperative findings. Intraoperative parameters, postoperative complications, and follow-up outcomes were analyzed.Results:Laparoscopic surgery was performed in 22 cases and robot-assisted surgery in 20 cases. Among the 42 patients, 22 underwent onlay ureteroplasty while 20 received augmented anastomotic ureteroplasty. The graft length was (5.9±1.8) cm (range: 3.0 to 12.0 cm), operative time (191.5±55.6) minutes (range: 105.0 to 350.0 minutes), and intraoperative estimated blood loss (86.7±73.6) ml (range: 10.0 to 400.0 ml). All procedures were successfully completed without conversion to open surgery. The postoperative hospital stay was (7.6±2.0) days (range: 4.0 to 15.0 days), with double-J stent removal at 6 to 8 weeks postoperatively. During a follow-up of (49.1±25.0) months (range: 12.0 to 99.0 months), no stricture recurrence was observed in any patient.Conclusion:LMGU is a safe, feasible, and effective long-term technique for managing long-segment (≥5 cm) ureteral strictures.

Objective:To investigate and evaluate the clinical efficacy and safety of a modified anterior approach for transpupillary silicone oil removal combined with phacoemulsification and intraocular lens (IOL) implantation.Methods:A retrospective case-control study. A total of 148 patients (148 eyes) who underwent silicone oil removal combined with cataract surgery at the Department of Ophthalmology, Guangdong Provincial People's Hospital between January 2020 and November 2024 were included in the study. All affected eyes underwent preoperative examinations including best-corrected visual acuity (BCVA), intraocular pressure, corneal topography, and optical coherence tomography (OCT). Based on the method of silicone oil removal, the eyes were divided into two groups: group A (modified anterior approach transpupillary silicone oil removal combined with phacoemulsification and IOL implantation, 99 eyes) and group B (standard pars plana vitrectomy for silicone oil removal combined with phacoemulsification and IOL implantation, 49 eyes). The surgical duration, changes in BCVA and intraocular pressure at 1 day, 7 days, and 1 month postoperatively, as well as the incidence of complications such as corneal edema and its resolution, conjunctival congestion, iris prolapse, posterior capsule rupture, nucleus drop, IOL position, residual silicone oil in the vitreous cavity or anterior chamber, vitreous hemorrhage, recurrent retinal detachment (RD), and choroidal detachment or hemorrhage, were compared between the two groups. The independent sample t-test was used for the comparison of measurement data between the two groups, and the χ2 test was used for the comparison of count data. Results:The operation time of group A and group B was (17.01±1.28) min and (31.62±2.32) min, respectively. The operation time of group A was significantly shorter than that of group B, and the difference was statistically significant ( t=?41.002, P<0.001). The comparison of BCVA ( t =?0.561, ?0.833, ?1.386) and IOP ( t=?0.055, 1.375, ?0.507) between the two groups of affected eyes before surgery and at 1 day and 7 days after surgery showed no statistically significant differences ( P>0.05). There was no silicone oil residual in group A, while 3 eyes in group B were observed with silicone oil residual (6.1%, 3/49). Neovascular glaucoma was observed in one eye. Compared to group A, group B exhibited a statistically significant increase in the incidence of postoperative conjunctival congestion, silicone oil retention, and posterior capsular opacification ( χ2=10.600, 6.187, 92.617; P<0.05). In contrast, no statistically significant differences were observed between the groups in the incidence of corneal edema or recurrent retinal detachment (RD) ( χ2=0.272, 1.557; P>0.05). No intraoperative complications, such as iris prolapse, posterior capsular rupture, nucleus drop, zonular dehiscence, choroidal detachment, or hemorrhage, occurred in any of the operated eyes. Furthermore, no postoperative complications, including corneal endothelial decompensation, IOL displacement, or endophthalmitis, were observed during the follow-up period. Conclusion:Compared to the conventional pars plana approach for silicone oil removal combined with cataract surgery, the modified anterior perfusion transpupillary approach demonstrated significantly shorter surgical duration and a reduced incidence of postoperative complications.

Objective To explore effects and action mechanism of Fu Fang Ku Shen Zhu She Ye on adverse reactions of 5-fluorouracil(5-FU)chemotherapy in rats with liver cancer.Methods The rat model of liver cancer was constructed by diethylnitrosamine(DEN).Model rats were divided into the liver cancer group,the chemotherapy group and the chemotherapy+Fu Fang-L/M/H groups.At 24 h after modeling,the chemotherapy group and the chemotherapy+Fu Fang groups were given intraperitoneally injection of 5-FU(100 mg/kg,once/week),and the chemotherapy+Fu Fang-L/M/H groups were given intraperitoneally injection of Fu Fang Ku Shen Zhu She Ye[0.7,1.4 and 2.8 mL/kg,once/d]for 8 weeks.The cardiac function,myocardial injury markers and pathological changes of myocardial tissue were compared between different groups.Serum levels of brain natriuretic peptide(BNP),cardiac troponin I(cTnI)and creatine kinase MB(CK-MB)were detected by enzyme-linked immunosorbent assay.The expression levels of glucose-regulating protein 78(GRP78),activating transcription factor 6(ATF6)and endoplasmic reticulum stress-related protein(CHOP)in myocardial tissue were detected by Western blot assay.Changes of immune function indexes were compared between different groups.Results Compared with the liver cancer group,left ventricular ejection fraction(LVEF)and left ventricular anterior wall thickness in systole(LVAWs)were decreased in the chemotherapy group(P＜0.05),left ventricular end diameter in systole(LVEDs),levels of BNP,cTnI and CK-MB were increased(P＜0.05),levels of tumor necrosis factor α(TNF-α),interleukin(IL)-1β and IL-6 in myocardial tissue,expression levels of GRP78,ATF6 and CHOP were increased(P＜0.05).Levels of CD3+,CD4+,CD4+/CD8+,IgG,IgM and IgA were decreased in the chemotherapy group(P＜0.05).The myocardial tissue was disordered,vacuolated and infiltrated by inflammatory cells.Compared with the chemotherapy group,the above indexes and pathological changes of myocardial tissue were significantly improved in the chemotherapy+Fu Fang-L/M/H groups,and the improvement was more significant in the chemotherapy+Fu Fang-H group.Conclusion Fu Fang Ku Shen Zhu She Ye injection can alleviate cardiotoxic injury induced by 5-FU in rats with liver cancer,which may be related to alleviating endoplasmic reticulum stress.It can also alleviate immunosuppression.

Advancements in artificial intelligence(AI)and emerging technologies are rapidly expanding the exploration of chemical space,facilitating innovative drug discovery.However,the transformation of novel compounds into safe and effective drugs remains a lengthy,high-risk,and costly process.Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development.Despite this need,no comprehensive tool currently supports systematic evaluation and efficient screening.Here,we present druglikeFilter,a deep learning-based framework designed to assess drug-likeness across four critical dimensions:1)physicochemical rule evaluated by systematic determination,2)toxicity alert investigated from multiple perspectives,3)binding affinity measured by dual-path analysis,and 4)compound synthesizability assessed by retro-route prediction.By enabling automated,multidimensional filtering of compound libraries,druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates,which can be freely accessed at https://idrblab.org/drugfilter/.

Objective:To discuss the expression and clinical significance of inositol polyphosphate-4-phosphatase type Ⅱ(INPP4B)gene in hepatocellular carcinoma(HCC)based on The Cancer Genome Atlas(TCGA)database and experimental verification with clinical samples.Methods:Based on data from 424 clinical samples in the TCGA database(including 374 HCC tissues and 50 paracarcinoma tissues),Kaplan-Meier method and Cox regression analysis were used to evaluate the relationship between INPP4B gene and the clinical characteristics and survival prognosis of the HCC patients.The correlations between INPP4B gene and the number of 24 types of immune cells,matrix,immune cell infiltration and tumor purity in tumor tissue,and the expression level of the high-frequency mutant gene tumor protein 53(TP53)in HCC were analyzed.The clinicopathological data and paraffin-embedded tissue sections of 60 HCC patients treated with surgical resection from December 2022 to December 2023 were collected.According to clinical diagnosis,they were divided into poorly differentiated group(HCC-L group),moderately differentiated group(HCC-M group)and well-differentiated group(HCC-H group),with 20 cases in each group;20 patients during the same period who underwent biopsy and were pathologically diagnosed as non-tumor were selected as normal group,and their clinicopathologic data and liver tissue paraffin sections were collected.HE staining was used to observe the pathomorphology of HCC tissue and normal liver tissue of the subjects in various groups;immunohistochemistry method was used to detect the expressions of Ki-67 and INPP4B proteins in the HCC tissue and normal liver tissue of the subjects in various groups.Results:The TCGA database analysis results showed that compared with normal tissue,the expression level of INPP4B mRNA in HCC tissue was significantly increased(P<0.01).Compared with INPP4B low expression group,the overall survival(OS)of the patients in INPP4B high expression group was significantly prolonged(P<0.05).The univariate Cox regression analysis results showed that tumor stage,pathological stage,tumor status and residual tumor had impacts on OS of the HCC patients(P<0.05).The univariate regression analysis results showed that the INPP4B prognostic risk model score ratio was HR=0.781,95％confidence interval(CI):0.552-1.105,P=0.168.The AUC value for the impact of INPP4B on OS of the HCC patients was 0.558,indicating that the INPP4B gene prognostic risk model had certain predictive value in survival prognosis.The INPP4B mRNA expression level was not correlated with TNM stage,stage,patient gender,age,race or body mass index(BMI)(P>0.05).In tumor tissue with high and low INPP4B expression,22 types of immune cells showed statistically significant differences(P<0.05);the INPP4B mRNA expression level was positively correlated with the number of 23 types of immune cells except T helper(Th)17 cells(r>0),among which all Th cells except natural killer(NK)CD56+cells were statistically significant(P<0.01);INPP4B was significantly correlated with matrix(r=0.475),immune cell infiltration(r=0.641)and tumor purity(r=0.599)in tumor tissue(P<0.01).INPP4B was correlated with TP53(r=0.287,P<0.01).The HE staining results showed that clear and complete lobular structure,neatly arranged cells and slight inflammatory cell infiltration were observed in liver tissue of the subjects in normal group;completely destroyed lobular structure,significant hepatocellular steatosis,massive inflammatory cell infiltration,and lesions such as ballooning degeneration and small cell hyperplasia in some cells were observed in HCC tissue of the patients in HCC-L,HCC-M and HCC-H groups,and the lower the HCC differentiation degree,the more severe the tissue destruction;The immunohistochemistry results showed that compared with normal group,the expression levels of Ki-67 protein in HCC tissue of the patients in HCC-L,HCC-M and HCC-H groups were significantly increased(P<0.01),and the lower the differentiation degree of the HCC patients,the higher the Ki-67 positive rate.Brownish-yellow granules evenly distributed in the cells and INPP4B protein was highly expressed in liver tissue of the subjects in normal group;compared with normal group,the expression levels of INPP4B protein in HCC tissue of the patients in HCC-L,HCC-M and HCC-H groups were significantly decreased(P<0.01),and the lower the differentiation degree of the HCC tissue,the lower the INPP4B positive rate.Conclusion:INPP4B is a protective factor for the prognosis of HCC patients;as a new tumor suppressor gene,INPP4B may become a potential target for new drug screening in HCC treatment.

Advancements in artificial intelligence (AI) and emerging technologies are rapidly expanding the exploration of chemical space, facilitating innovative drug discovery. However, the transformation of novel compounds into safe and effective drugs remains a lengthy, high-risk, and costly process. Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development. Despite this need, no comprehensive tool currently supports systematic evaluation and efficient screening. Here, we present druglikeFilter, a deep learning-based framework designed to assess drug-likeness across four critical dimensions: 1) physicochemical rule evaluated by systematic determination, 2) toxicity alert investigated from multiple perspectives, 3) binding affinity measured by dual-path analysis, and 4) compound synthesizability assessed by retro-route prediction. By enabling automated, multidimensional filtering of compound libraries, druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates, which can be freely accessed at https://idrblab.org/drugfilter/.