Background Long-term exposure to ambient fine particulate matter (PM_2.5) is a significant risk factor for cardiometabolic disorders. However, the mechanisms of its interaction with the endogenous circadian system remain incompletely understood. Objective To investigate whether chronic PM_2.5 exposure interferes with the rhythmic expression of the cardiac circadian clock, thereby disrupting downstream antioxidant defenses and metabolic homeostasis, and ultimately driving cardiometabolic dysfunction. Methods Seventy-two male C57BL/6 mice were randomly divided into a PM_2.5 exposure group (PM group) and a filtered air control group (FA group). Whole-body exposure was conducted for 8 weeks in a meteorological environmental animal exposure system. Samples were collected at six distinct zeitgeber time (ZT) points post-exposure. The 24 h ambulatory blood pressure and serum lipid profiles were monitored. Rhythm parameters were derived via cosinor analysis to compare differences in Midline statistic of rhythm (Mesor), amplitude, and phase between the two groups. The rhythmic expression of core circadian clock genes and antioxidant genes in the myocardium was detected by quantitative polymerase chain reaction (qPCR). Myocardial reactive oxygen species (ROS) levels and downstream pathway protein expression were analyzed by immunofluorescence and Western blot (WB), respectively. The expression changes of the clock gene retinoic acid receptor-related orphan receptor α (RORα) were assessed at both the mRNA and protein levels. Finally, Spearman correlation analysis was used to explore the relationships among myocardial RORα expression, lipid profiles, and oxidative stress indicators. Results Compared to the FA group, mice in the PM group exhibited a blunted circadian rhythm in blood pressure, characterized by sustained elevation throughout the day. Chronic PM_2.5 exposure showed a significant interaction with ZT on systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) (F-interaction=9.11, 5.70, and 6.02, respectively; P<0.05), as well as on serum triglycerides (TG), total cholesterol (T-CHO), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) (F-interaction=16.32, 11.12, 15.39, and 28.09, respectively; P<0.05). Cosinor analysis further revealed that the Mesor values of T-CHO, TG, and LDL-C were significantly increased (P<0.05), while that of HDL-C was significantly decreased in the PM group (P<0.05). The oscillation amplitudes of SBP, DBP, and MAP showed a decreasing trend, whereas those of TG and LDL-C were significantly increased (P<0.05). Furthermore, SBP, T-CHO, and HDL-C all exhibited a significant phase delay (P<0.05). Mechanistically, PM_2.5 exposure significantly suppressed the expression of the positive circadian regulator RORα in the myocardium, leading to disordered rhythmic expression of core clock genes (Bmal1, Clock, Per1/2, and Cry1/2). This exposure also inhibited the rhythmic expression of antioxidant genes (GPX1, SOD2, and CAT), resulting in increased ROS generation and elevated expression of calcium/calmodulin-dependent protein kinase II (CaMKII) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) proteins. Correlation analysis further revealed that myocardial RORα expression level was negatively correlated with T-CHO, TG, and LDL-C (r=−0.55, −0.63, and −0.51, respectively; P<0.001), and positively correlated with HDL-C (r=0.37, P=0.010), and antioxidant genes GPX1, SOD2, and CAT expression (r=0.34, 0.35, and 0.56, respectively; P < 0.001). Conclusion Chronic PM_2.5 exposure induces cardiometabolic dysfunction by suppressing myocardial RORα expression. This suppression disrupts the cardiac circadian clock and the diurnal balance of oxidative stress, triggering oxidative damage and elevating expression of CaMKII/NADPH pathway proteins. Collectively, these alterations precipitate the loss of cardiac metabolic rhythms and subsequent functional impairment.

In recent years, the incidence of dry eye disease(DED)is increasing, positioning it as one of the most prevalent diseases affecting the ocular surface. Inflammatory response is the pathological basis of DED, involving various inflammatory mediators and inflammatory signaling pathways. Consequently, anti-inflammatory treatment emerges as a fundamental strategy for preventing and managing DED. This review summarizes the classic inflammatory factors involved in the development and progression of DED, including interleukins, tumor necrosis factor, matrix metalloproteinases, chemokines, and cell adhesion molecules. It also discusses the relevant inflammatory signaling pathways: the MAPKs pathway, NF-κB pathway, Wnt pathway and TLR pathway. Additionally, this review addresses the mechanisms of action and alterations in relevant biomarkers associated with current first-line recommended anti-inflammatory therapies, including corticosteroids, immunosuppressants, nonsteroidal anti-inflammatory drugs, and traditional Chinese medicine approaches to inflammation management. This comprehensive overview aims to enhance understanding of the inflammatory mechanisms underlying DED while exploring future therapeutic prospects.

In recent years, the incidence of dry eye disease(DED)is increasing, positioning it as one of the most prevalent diseases affecting the ocular surface. Inflammatory response is the pathological basis of DED, involving various inflammatory mediators and inflammatory signaling pathways. Consequently, anti-inflammatory treatment emerges as a fundamental strategy for preventing and managing DED. This review summarizes the classic inflammatory factors involved in the development and progression of DED, including interleukins, tumor necrosis factor, matrix metalloproteinases, chemokines, and cell adhesion molecules. It also discusses the relevant inflammatory signaling pathways: the MAPKs pathway, NF-κB pathway, Wnt pathway and TLR pathway. Additionally, this review addresses the mechanisms of action and alterations in relevant biomarkers associated with current first-line recommended anti-inflammatory therapies, including corticosteroids, immunosuppressants, nonsteroidal anti-inflammatory drugs, and traditional Chinese medicine approaches to inflammation management. This comprehensive overview aims to enhance understanding of the inflammatory mechanisms underlying DED while exploring future therapeutic prospects.

Objective:To investigate the influencing factors of major adverse cardiovascular events (MACE) in maintenance hemodialysis (MHD) patients, and to construct and verify the nomogram.Methods:The clinical data of 240 patients with MHD admitted to the First Affiliated Hospital of Hebei North University from July 2022 to October 2023 were retrospectively analyzed. According to whether the patients had MACE, they were divided into two groups, namely the occurrence group (with MACE, n=55) and the non-occurrence group (without MACE, n=185). After comparing the clinical data of the two groups, The independent risk factors of MHD patients with MACE were screened by binary logistic regression analysis, and the risk nomogram prediction model was constructed according to the risk factors, and the prediction efficiency of the model was analyzed by Bootstrap method. Results:There were significant differences in age, dialysis age, hyperlipidemia, hyperuricemia and hemodialysis flux between the two groups (all P<0.05). Binary logistic regression model analysis showed that dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia, and low throughput hemodialysis were independent risk factors for MHD patients with MACE (all P<0.05). The neomorph risk prediction model was constructed based on independent risk factors. The area under the curve (AUC) of the prediction model was 0.842(95% CI: 0.789-0.896), the specificity was 69.1%, the sensitivity was 89.7%, the cutoff value was 13.128, and the Yoden index was 0.588, suggesting that the accuracy of the model was good. Conclusions:Dialysis age >12 months, combined with hyperlipidemia, combined with hyperuricemia and low throughput hemodialysis are independent risk factors for MACE in MHD patients. Intervention and control of risk factors can reduce the incidence of MACE.

Objective:To investigate the effect of bed board of carbon fiber for treatment combined with fixed bottom board on verification results of Portal Dosimetry(PD)dose of intensity-modulated radiation therapy(IMRT)plan of fixed field for cervical cancer.Methods:A total of 15 patients with cervical cancer who admitted to Nanjing First Hospital from January 2019 to January 2020 were retrospectively selected,and the IMRT plans of fixed field for all patients were designed.The radiation field with 180° gantry angle was selected for each case to make the corresponding PD dose verification plan,and each verification plan included two subfields:AA180_0 and AA180_1.Three types of materials were placed between the accelerator head and the electronic portal imaging device(EPID),which included material without carbon fiber,bed board with carbon fiber for treatment,and the combination of the bed board with carbon fiber for treatment and the fixed bottom board with carbon fiber,when the Clinac iX accelerator was used to conduct verification plan for each case.The γ passing rates of the subfields(AA180_0 and AA180_1)and the total field(AA180)among three kinds of conditions,which included material without carbon fiber,bed board with carbon fiber for treatment,and the combination of the bed board with carbon fiber for treatment and the fixed bottom board with carbon fiber,were compared and analyzed.Results:For the subfield AA180_0,the γ passing rates under three different material conditions were respectively(96.09±1.38)%,(90.48±2.24)%and(81.85±2.46)%.For the subfield AA180_1,the γ passing rates under the above conditions were respectively(96.05±1.06)%,(91.86±2.22)%and(86.26±2.74)%.For the total field AA180,the γ passing rates were respectively(90.78±1.40)%,(84.82±2.56)%and(78.49±3.18)%.The γ passing rates of the subfield AA180_0,subfield AA180_1,and the total field AA180 showed statistically significant differences among the three different material conditions(F=177.80,80.00,91.42,P<0.01).Compared with materials without carbon fiber,the γ passing rate of the total field AA180 of the combination of the bed board with carbon fiber for treatment and the fixed bottom board with carbon fiber significantly decreased by 12.29%.Conclusion:In the PD dose verification of IMRT for cervical cancer,the bed board with carbon fiber for treatment combined with the fixed bottom board will produce adverse effect for the verification results.The effect of the single use of bed board for treatment is relatively small.The combined use of the bed board with carbon fiber for treatment and the fixed bottom board will lead to a significant deterioration in the verification result of PD dose.

Objective:To analyze the clinical characteristics and genetic profile of patients with 46, XY Disorders of sex development (DSD) and a female phenotype in order to provide insights for the diagnosis and management of similar cases.Methods:A retrospective analysis was conducted on 36 children with 46, XY DSD and a female phenotype who were treated at the Department of Endocrinology, Genetics and Metabolism of Henan Children′s Hospital between March 1, 2016, and June 30, 2024. The evaluations included external genitalia scoring using the Prader scale and External Masculinization Score (EMS), imaging studies to assess gonadal development, and assessments of adrenal and gonadal function via adrenal hormone levels, sex hormone levels, and human chorionic gonadotropin (hCG) stimulation testing. Gender role behavior was assessed using gender role scales and sandplay therapy. Whole exome sequencing and Sanger sequencing were used to identify and validate genetic variants. A multidisciplinary team (MDT) comprehensively determined gender rearing based on molecular genetic diagnosis. This study was approved by the Medical Ethics Committee of Henan Children′s Hospital (Ethics No.: 2024-K-105).Results:The median age at initial consultation was 3 years and 1 month (range: 7 days to 16 years). Common symptoms included primary amenorrhea, clitoromegaly, and inguinal hernia. Fully feminized external genitalia were observed in 52.7% of the cases, and 80.5% had absence of the uterus. Internal gonads included absent gonads (5.6%), ovotestes (8.3%), streak gonads (5.6%), cryptorchidism (75.0%), and normally positioned testes (5.6%). At initial diagnosis, median luteinizing hormone (LH) was 1.305 IU/L, with elevated LH in 14 cases. Median follicle-stimulating hormone (FSH) was 4.87 IU/L, with elevated FSH in 17 cases. Median testosterone was 0.025 ng/mL. Median dihydrotestosterone (DHT) was 36.90 pg/mL. After hCG stimulation, median testosterone was 0.984 ng/mL and median DHT was 71.69 pg/mL. The testosterone/DHT ratio was elevated in one case (35.7). Testosterone levels remained below 1 ng/mL after hCG stimulation in 18 cases. Anti-Müllerian hormone (AMH) was decreased in 15 cases and increased in 3 cases. Inhibin B (InhB) was increased in 7 cases and decreased in 4 cases. Pathogenic variants were detected in 88.9% of the patients, involving AR (11 cases), CYP17A1 (4 cases), GATA4 (1 case), NR0B1 (1 case), NR5A1 (7 cases), SRD5A2 (1 case), WT1 (2 cases), STAR (4 cases), and LHCGR (1 case), totaling 34 variant sites. Among these, 9 variants were de novo, and 23 were inherited from parents. Sixteen variant sites were previously unreported. Gender assignment was male in 11 cases (30.6%) and female in 25 cases (69.4%). Conclusion:Common symptoms in 46, XY DSD patients with a female phenotype include primary amenorrhea, clitoromegaly, and inguinal hernia. Elevated FSH, androgen deficiency, and decreased AMH and InhB may indicate testicular dysgenesis or impaired androgen synthesis. Adrenal insufficiency should raise suspicion for defects in steroid hormone synthesis pathway enzymes.

OBJECTIVE: To analyze the clinical characteristics and genetic profile of patients with 46,XY Disorders of sex development (DSD) and a female phenotype in order to provide insights for the diagnosis and management of similar cases. METHODS: A retrospective analysis was conducted on 36 children with 46,XY DSD and a female phenotype who were treated at the Department of Endocrinology, Genetics and Metabolism of Henan Children's Hospital between March 1, 2016, and June 30, 2024. The evaluations included external genitalia scoring using the Prader scale and External Masculinization Score (EMS), imaging studies to assess gonadal development, and assessments of adrenal and gonadal function via adrenal hormone levels, sex hormone levels, and human chorionic gonadotropin (hCG) stimulation testing. Gender role behavior was assessed using gender role scales and sandplay therapy. Whole exome sequencing and Sanger sequencing were used to identify and validate genetic variants. A multidisciplinary team (MDT) comprehensively determined gender rearing based on molecular genetic diagnosis. This study was approved by the Medical Ethics Committee of Henan Children's Hospital (Ethics No.: 2024-K-105). RESULTS: The median age at initial consultation was 3 years and 1 month (range: 7 days to 16 years). Common symptoms included primary amenorrhea, clitoromegaly, and inguinal hernia. Fully feminized external genitalia were observed in 52.7% of the cases, and 80.5% had absence of the uterus. Internal gonads included absent gonads (5.6%), ovotestes (8.3%), streak gonads (5.6%), cryptorchidism (75.0%), and normally positioned testes (5.6%). At initial diagnosis, median luteinizing hormone (LH) was 1.305 IU/L, with elevated LH in 14 cases. Median follicle-stimulating hormone (FSH) was 4.87 IU/L, with elevated FSH in 17 cases. Median testosterone was 0.025 ng/mL. Median dihydrotestosterone (DHT) was 36.90 pg/mL. After hCG stimulation, median testosterone was 0.984 ng/mL and median DHT was 71.69 pg/mL. The testosterone/DHT ratio was elevated in one case (35.7). Testosterone levels remained below 1 ng/mL after hCG stimulation in 18 cases. Anti-Müllerian hormone (AMH) was decreased in 15 cases and increased in 3 cases. Inhibin B (InhB) was increased in 7 cases and decreased in 4 cases. Pathogenic variants were detected in 88.9% of the patients, involving AR (11 cases), CYP17A1 (4 cases), GATA4 (1 case), NR0B1 (1 case), NR5A1 (7 cases), SRD5A2 (1 case), WT1 (2 cases), STAR (4 cases), and LHCGR (1 case), totaling 34 variant sites. Among these, 9 variants were de novo, and 23 were inherited from parents. Sixteen variant sites were previously unreported. Gender assignment was male in 11 cases (30.6%) and female in 25 cases (69.4%). CONCLUSION Common symptoms in 46,XY DSD patients with a female phenotype include primary amenorrhea, clitoromegaly, and inguinal hernia. Elevated FSH, androgen deficiency, and decreased AMH and InhB may indicate testicular dysgenesis or impaired androgen synthesis. Adrenal insufficiency should raise suspicion for defects in steroid hormone synthesis pathway enzymes.
Humans ; Female ; Disorder of Sex Development, 46,XY/diagnosis* ; Child ; Male ; Phenotype ; Child, Preschool ; Retrospective Studies ; Adolescent ; Infant

Objective:To evaluate the value of D-dimer(D-D) levels in the diagnosis of thromboembolism in children with severe Mycoplasma pneumoniae pneumonia (SMPP).Methods:A case control study was conducted on 51 SMPP patients admitted to Qingdao Women and Children′s Hospital Affiliated to Qingdao University and Jining First People′s Hospital from January 1, 2021 to August 1, 2024.They were divided into a thrombus group (19 cases) and a non-thrombus group (32 cases) according to whether they had thromboembolism.The characteristics of the cases were analyzed.Logistic regression was used to analyze the relationship between increased D-D levels and the risk of thrombosis.The value of D-D levels in predicting thromboembolism in SMPP patients was evaluated by the receiver operating characteristic curve.Results:Of the 19 patients with thrombosis, 11 had with pulmonary thrombosis, 6 had cerebrovascular thrombosis, 3 had heart thrombosis, 1 had spleen artery thrombosis, and 3 had multiple site thrombosis.Compared with the non-thrombus group, the thrombus group had higher D-D levels[(18.5±4.9) mg/L vs.(3.1±0.8) mg/L, t=3.118, P=0.006], higher C-reactive protein levels[25.5(15.5, 92.7) mg/L vs.7.9(3.9, 21.4) mg/L, Z=3.292, P=0.001], higher lactate dehydrogenase levels[484(351, 743) U/L vs.347(285, 396) U/L, Z=2.770, P=0.006] and a higher proportion of pleural effusion[63.1%(12/19) vs.25.0%(8/32), χ2=7.282, P=0.009].Increased D-D levels were an independent risk factor for thromboembolism in SMPP patients ( P=0.005, OR=1.254, 95% CI: 1.069-1.472).When the D-D level was used for predicting thromboembolism in SMPP patients, its cut-off value was 4.46 mg/L, its Youden index was 0.707, its area under the curve was 0.893(95% CI: 0.807-0.979), its sensitivity was 89.5%, its specificity was 81.2%, and its negative predictive value was 92.9%. Conclusions:D-D levels have high value in predicting thromboembolism in SMPP patients, and it can help timely identify patients at high risk.

Objective Network pharmacology and molecular docking technology were used to analyze the potential mechanism of Sinisan(SNS)in the treatment of adolescent depression,and the relevant results were verified by experiments.Methods Through the TCMSP and ETCM databases,the effective chemical components and targets of SNS(Chaihu,Zhishi,Baishao and Gancao)were screened,and the main targets of adolescent depression were screened in the GeneCards and OMIM databases,and the common targets of drugs and disease were obtained by Venn diagram.Cytoscape 3.9.1 software was used to draw the Chinese herb-active ingredient-target action network of SNS.The STRING platform was used to construct a portein-protein interaction network(PPI)of drug-disease-common targets,and the core targets were obtained after screening.The Metascape platform was used to perform enrichment analysis of core targets.Molecular docking was carried out through the software AutoDockTools 1.5.7 to evaluate the binding ability of effective active ingredients to potential core targets.Western blotting(WB)experiments were used to verify the potential targets of SNS against adolescent depression.Results The core effective active ingredients of SNS in the treatment of adolescent depression include quercetin,kaempferol,isorhamnetin,paeoniflorin,etc.,and the potential core targets including AKT1,IL-6,PPARG,PTGS2,F7,etc.,were identified through PPI network topology analysis.The molecular docking results showed that the active substance had strong binding activity to its main target.WB experiments verified that AKT1,IL-1B and IL-6 were potential targets related to anti-adolescent depression.The main biological processes of PPI network four inverse dispersion in the treatment of adolescent depression include hormone response,and the main signaling pathways regulated such as AGE-RAGE and PI3K-AKT signaling pathway.Conclusion This study preliminarily confirmed the effective active ingredients and target information of SNS treatment in adolescent depression,and revealed the potential mechanism of SNS in the treatment of adolescent depression.

Objective:To explore the impact of the two-way referral model on compliance and prognosis in patients with heart failure.Methods:This bidirectional cohort study enrolled chronic heart failure (CHF) patients treated at Qilu Hospital of Shandong University or designated primary hospitals between March 2018 and March 2022. Patients were categorized into two groups based on referral status: two-way referral group (participating in the referral model with≥1 follow-up visit at primary hospitals) and the core hospital group (receiving treatment and follow-up exclusively at Qilu Hospital). Baseline clinical characteristics were collected and compared between groups. Patients underwent followed-up, with primary endpoints including follow-up rate, drug (β-blockers, angiotension converting enzyme inhibitor (ACEI)/angiotensin Ⅱ receptor blockers (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists) utilization rate and target dose achievement rate. Secondary endpoints encompassed changes from baseline in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), and N-terminal pro-brain natriuretic peptide (NT-proBNP), plus cardiovascular mortality and heart failure rehospitalization. Generalized linear mixed models analyzed longitudinal trends in LVEF, LVEDd, and NT-proBNP levels. Kaplan-Meier curves and Cox regression evaluated LVEF recovery rates, supplemented by subgroup analyses. Multivariate logistic regression was used to identify factors influencing target dose achievement rate for β-blockers and ACEI/ARB/ARNI therapies in CHF patients.Results:A total of 357 patients were enrolled, aged 53 (41, 63) years, including 256 males (71.7%). 157 patients were in the two-way referral group and 200 patients in the core hospital-treated group. Compared with the core hospital-treated group, the two-way referral group had lower baseline LVEF (28 (22, 34)% vs. 31 (23, 36)%, P=0.021) and systolic blood pressure (116 (104, 125) mmHg vs. 121 (109, 134) mmHg (1 mmHg=0.133 kPa), P=0.010). The 12-month follow-up rate of the two-way referral group was higher than the core hospital-treated group (73.8% vs. 56.0%, P=0.004). No significant between-group differences were observed in drug utilization rate of β-blockers, ACEI/ARB/ARNI, or sodium-glucose cotransporter 2 inhibitors during follow-up (all P>0.05), while mineralocorticoid receptor antagonists use showed a declining trend in both groups. Although the core hospital-treated group had higher target dose achievement rates for β-blockers (65.4% vs. 49.3%, P=0.042) and ACEI/ARB/ARNI (79.8% vs. 65.8%, P=0.046) than the two-way referral group, multivariate logistic regression indicated that the two-way referral model was not a negative predictor for these outcomes (all P>0.05). Both groups showed improved NT-proBNP, LVEDd, and LVEF from baseline (all P<0.001) with no significant difference in trends between groups (all P>0.05). There was no significant difference in the composite incidence (7.6% vs. 6.5%, P=0.674) and cumulative incidence (log-rank P=0.684) of cardiovascular death and heart failure rehospitalization at 12 months between two groups. Conclusion:The two-way referral model demonstrates advantages in improving medication adherence, drug utilization rates, and targetdoseachievement rates among CHF patients. This model not only promotes cardiac functional recovery but also reduces risks of cardiovascular mortality and heart failure rehospitalization, achieving comparable therapeutic and management outcomes to those observed in core hospital-treated patients.