Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Objective To investigate the differences in clinical and radiographic features between severe influenza A H1N1 and H3N2 in children.Methods The clinical and radiographic data of children diagnosed with severe influenza A H1N1 and H3N2 were analyzed retrospectively.According to the pathogen subtypes,they were divided into H1N1 group(34 cases)and H3N2 group(23 cases).Differences in clinical data,laboratory results,treatment,hospitalization time,outcome,and radiographic features between the two groups were analyzed.The t-test was used for the comparison of normally distributed measurement data between the groups,and Mann-Whitney U test was used for the comparison of non-normally distributed measurement data between the groups.Chi-square test or Fisher's exact probability method was used for the analysis of counting data,depending on the situation.Results There were differences in the season of onset,clinical and radiographic features between the two groups.H1N1 subtype mostly occurred in win-ter,and mainly manifested as respiratory symptoms(wheezing/shortness of breath)and respiratory complications(severe pneumonia).H3N2 subtype was mainly observed in summer,and more likely to involve the central nervous system(CNS),presenting with neuro-logical symptoms(convulsions),abnormal electroencephalogram,and concurrent influenza associated encephalopathy(IAE).Conclusion There are significant differences in epidemiology,clinical and radiographic features between severe influenza A H1N1 and H3N2.H3N2 has a higher probability of concurrent IAE and should be highly vigilant in clinical practice.

ObjectiveTo investigate the effect and possible mechanism of Shenfu Injection （参附注射液） on rat cardiomyocyte injury induced by isoproterenol from the perspective of regulating the high mobility group protein B1 （HMGB1）/ Toll-like receptor 4 （TLR4）/nuclear factor κB （NF-κB） pathway through the deacetylation modification of silent information regulator 1 （SIRT1）. MethodsThe optimal concentration and intervention duration of isoproterenol hydrochloride and the optimal intervention concentration of Shenfu Injection were screened out by CCK-8 method. Logarithmically growing H9c2 rat cardiomyocytes were taken at 5×10⁴ cells/well and divided into normal group， model group， Shenfu Injection group， and SIRT1 inhibitor group， with 3 replicates in each group.Except for the normal group， the cells in the other groups were induced by isoproterenol hydrochloride to establish a chronic heart failure cell model. After modeling， the Shenfu Injection group was given Shenfu Injection at the optimal intervention concentration， and the SIRT1 inhibitor group was given 1 μmol/L of SIRT1 inhibitor EX-527， for optimal intervention duration.CCK-8 assay was used to detect the cell activity and calculate the inhibitory rate. ELISA assay was used to detect the nicotinamide adenine dinucleotide oxidation state/ nicotinamide adenine dinucleotide reduction state （NAD+/NADH） in cardiomyocytes. Immunofluorescence was used to detect the immunofluorescence localization of HMGB1 and SIRT1 in cardiomyocytes. Western blotting was used to detect the protein expression of acetylated HMGB1 in cardiomyocytes， HMGB1 in the nucleus and cytoplasm， and SIRT1， TLR4， myeloid differentiation factor 88 （MYD88） and NF-κB p65 in cardiomyocytes. RT-qPCR was used to detect the mRNA expression of SIRT1， HMGB1， TLR4， MYD88 and NF-κB p65 in cardiomyocytes. ResultsThe optimal intervention concentration of isoproterenol hydrochloride was 300 μmol/L， and the intervention duration was 48 hours； 8% was the optimal intervention concentration of Shenfu Injection. Compared to those in the normal group， the cell activity， NAD+/NADH value， nuclear HMGB1 protein expression， cardiomyocyte SIRT1 protein and mRNA expression in the model group decreased， while the cell inhibition rate， cardiomyocyte acetylated HMGB1 and cytoplasmic HMGB1 protein expression， cardiomyocyte TLR4， MYD88， NF-κB p65 protein and mRNA expression all increased （P＜0.05）； fluorescence localization showed that the content of HMGB1 in cardiomyocytes in the model group increased and was localized in both the nucleus and cytoplasm.Compared to the model group and the SIRT1 inhibitor group， the Shenfu Injection group showed significant improvements in all the above indicators （P＜0.05）； fluorescence localization showed that the SIRT1 content increased in the Shenfu injection group， while the HMGB1 content decreased， and was mainly located in the nucleus. ConclusionShenfu Injection can improve myocardial cell damage by increasing SIRT1 expression to reduce the acetylation level of HMGB1， regulating the HMGB1/TLR4/NF-κB pathway and inhibiting the nuclear translocation of HMGB1.

Objective:To evaluate the clinical efficacy of nasal pedicle tissue flap based on nasal blood supply in the reconstruction of nasal skull base defects.Methods:A retrospective analysis was conducted on 138 clinical cases of skull base tumors and cerebrospinal fluid rhinorrhea treated at the Department of Otolaryngology, Head and Neck Surgery at Xiangya Hospital of Central South University from March 2017 to March 2023. A total of 79 males and 59 females were enrolled, aged from 8 to 82 years, with a median age of 51 years, including 108 patients (78.3%) with skull base tumors and 30 patients (21.7%) with cerebrospinal fluid rhinorrhea (and/or meningoencephalocele). During the surgery, 88 cases (63.8%) were repaired with nasal septal mucosal flaps pedicled with the posterior nasal septal artery, 14 cases (10.1%) with mucosal flaps pedicled with the anterior ethmoidal artery on the lateral wall of the nasal cavity, 6 cases (4.3%) with mucosal flaps pedicled with the posterior lateral nasal artery on the lateral wall and nasal floor, 12 cases (8.7%) with mucosal flaps pedicled with the anterior ethmoidal artery and posterior ethmoidal artery, and 18 cases (13.0%) with nasal septal mucosal extension flaps pedicled with the sphenopalatine artery or internal maxillary artery. Patients were followed up for 12 to 72 months postoperatively. Endoscopic examination or skull base enhanced MRI was performed to assess the growth and tumor recurrence in the skull base repair area. The t-test was used for statistical analysis.Results:Among 138 patients, primary repair was successful in 133 patients (96.4%), while 5 patients (3.6%) experienced postoperative cerebrospinal fluid rhinorrhea. These 5 patients all underwent nasal septal mucosal flap repair with the posterior nasal septal artery as the pedicle. Complications included 1 case of mucosal flap necrosis, 1 case of mucosal flap central perforation, and 3 cases of mucosal flap survival peripheral leakage, of which were all successfully treated with a second repair.Conclusion:The use of nasal pedicle mucosal flap based on nasal blood supply is a reliable, safe, and effective technique for repairing skull base defects.

Objective:To assess the altered right atrial(RA) function using two-dimensional speckle-tracking imaging(2D-STI) in patients with persistent pulmonary hypertension of the newborn(PPHN), and investigate the diagnostic value of different right heart strain parameters in PPHN.Methods:Ultrasound images of 42 newborns with clinically confirmed diagnosis of PPHN in the neonatal intensive care unit of Shenzhen Children′s Hospital (median gestational age 37 + 1 weeks, median age 6 d) and 30 normal newborns (control group, median gestational age 37 + 3 weeks, median age 6.5 d) from January 2020 to January 2023 were retrospectively analyzed, all with gestational age ≥34 gestational weeks. 2D-STI was applied to evaluate RA function: RA strain(RA LS) and area change fraction(RA FAC), where RA LS included RA reservoir strain (εs), RA conduit strain (εe) and RA active contract strain (εa), while evaluating right ventricle(RV) function: RV global longitudinal strain(RV GLS), RV FAC, etc. And the degree of pulmonary artery pressure(PAP) was assessed by tricuspid regurgitation velocity(TRV). The above parameters were compared between the PPHN group and the control group, and the correlations between RA function parameters, RV function parameters and PAP in PPHN group were analyzed. The area under ROC curve (AUC) was used to compare the accuracy of each parameter in the evaluation of impaired cardiac function in PPHN patients. Results:Compared with the control group, RA function (εs, εe, εa and RA FAC) were impaired in PPHN patients (all P<0.05). εs was positively correlated with RV GLS, RA FAC ( r=0.494, 0.356, both P<0.05) and negatively correlated with minimum right atrial area (RAA min), pulmonary artery diameter (PAD), and tricuspid annular internal diameter ( rs=-0.285, r=-0.495, -0.396; both P<0.05); εe was negatively correlated with PAD ( rs=-0.256, P<0.05); εa was positively correlated with RV GLS ( r=0.499, P<0.05) and negatively correlated with PAD and tricuspid annular internal diameter ( r=-0.390, -0.380; both P<0.05); RA FAC was positively correlated with RV GLS ( r=0.365, P<0.05) and negatively correlated with PAD and tricuspid annular internal diameter ( r=-0.439, -0.328; both P<0.05). RA LS and RA FAC had no correlations with TRV-estimated PAP ( P>0.05). ROC analysis showed that the sensitivity and specificity of εs<40.50% for diagnosing PPHN was 0.905 and 0.800, respectively, with an AUC of 0.929; the sensitivity and specificity of RV GLS<18.55% for diagnosing PPHN were 0.905 and 0.900, respectively, with an AUC of 0.963; εs combined with RV GLS was the best indicator for early detection of right heart functional impairment in PPHN, with sensitivity and specificity of 0.905 and 1.000, respectively, and AUC was 0.985. Conclusions:RA function and RV function are both impaired in PPHN patients. εs combined with RV GLS is the best indicator for early assessment of right heart function impairment and diagnosis of PPHN.

To summarize the clinical manifestations of a case with 46, XY sex development disorder caused by myelin regulatory factor(MYRF) gene mutation and review the literature to deepen the specialists′ understanding of the clinical disease spectrum resulting from MYRF gene variations. The child had a female phenotype with mild masculinity, chromosome 46, XY, sex-determining region of Y gene(SRY gene) positive, laboratory tests were consistent with primary hypogonadism, ultrasound did not detect the gonads, but the residual reproductive tract was visible, and echocardiography suggested coarctation of the aorta, MYRF gene c. 2518C>T(p.R840*) heterozygous variant. The father did not carry this variant. The mother was untraceable, and genetic testing had not been completed. It was analyzed as pathogenic variation according to American College of Medical Genetics and Genomics(ACMG) guidelines. Sixteen cases of disorders of sex development caused by MYRF gene variation reported from 2018 to 2021 were reviewed, MYRF gene variants, 46, XY, and 46, XX individuals can be pathogenic, can affect the gonad and reproductive tract at the same time, and can also affect multiple systems. In this case, the patient presents with 46, XY sex development disorder due to MYRF gene mutation, accompanied by rare cardiovascular complications. When encountering 46, XY primary hypogonadism without well-developed Müllerian duct structures, this condition should be considered. Following confirmation, a comprehensive assessment of multi-organ function is necessary.

ObjectiveTo study the modeling characteristics of primary dysmenorrhea models in animals and to provide references for the standardization of the primary dysmenorrhea animal models. MethodThe research articles on animal models of primary dysmenorrhea were retrieved to establish a database. The types of experimental animals， modeling methods， modeling cycle， drug dosage， drug injection methods， high-frequency detection indicators， positive drug types， etc.， were summarized and analyzed. ResultA total of 171 research articles that met the criteria were included. The animals for primary dysmenorrhea model induction were mainly SD rats， Wistar rats， and Kunming mice. Most of them were prepared by combining estradiol and oxytocin with the modeling cycle of 9 d≤t≤12 d. In terms of drug dosage for rats， estradiol benzoate was 0.5 mg·d^-1 on the 1st and 10th days and 0.2 mg·d^-1 on the 2^nd to 9^th days， while oxytocin at 2 U·d^-1 was the most common. In terms of drug dosage for mice， diethylstilbestrol at 2 mg·kg^-1·d^-1 and oxytocin at 20 U·kg^-1·d^-1 were the most common. In terms of injection methods， oxytocin was mainly administered by intraperitoneal injection and estradiol （estradiol benzoate and diethylstilbestrol） by subcutaneous injection. The detection indicators were mainly behavioral indicators of the writhing assay or the related biochemical indicators in the uterus or serum by enzyme-linked immunosorbent assay. The positive western medicines were dominated by ibuprofen and Chinese medicines by Tongjingbao. ConclusionAlthough primary dysmenorrhea animal models have become a hot topic， the existing reviews are not comprehensive， and the modeling standards and traditional Chinese medicine （TCM） syndrome evaluation are inadequate. By summarizing and analyzing the big data of the animal models， this study proposed some specific views to provide guidance and references for establishing the standard and ideal animal models of primary dysmenorrhea， so as to carry out research on this disease.

Objective:To report embryonic testicular regression syndrome(ETRS) caused by DHX37 heterozygous variant for the first time in China and summarize the clinical manifestations of ETRS as to improve the understanding of doctors for this disease.Methods:The clinical data and whole exome sequencing results of five cases of ETRS from Shenzhen Children′s Hospital were collected. The reported cases of DHX37 heterozygous variant were reviewed.Results:Five patients with ETRS visited the doctors at the age of 2 months to 5 years and 5 months. Three patients raised as males came to hospital due to virilition and 2 female patients visited a doctor due to clitoral hypertrophy. No uterus was detected by ultrasound in all patients. The gonadal pathologies from 4 cases displayed no testicular tissue or gonadal dysgenesis, complicated with gonadoblastoma in one case. The genetic testing revealed that the heterozygous variant(c.923G>A, p. R308Q) in DHX37 was found in 2 cases, without variant in other 3 cases. According to the review, ETRS and 46, XY gonadal dysgenesis due to DHX37 herozygous variant was firstly reported in 2019. A total of 40 cases, including 21 cases of ETRS, presented with the virilition or female phenotype, with the disappearance of testicular tissue as the main pathologies. There is no report in China.Conclusion:The article summarized the clinical manifestations and whole exome sequencing results of 5 patients with ETRS, among which two cases were caused by DHX37 variants and one was complicated with gonadoblastoma.

Objective:To quantify the left ventricular myocardial work in patients with repaired tetralogy of Fallot (TOF), and to evaluate the changes in left ventricular systolic function after TOF repair by pressure-strain loops (PSL).Methods:Seventy-six cases of children after TOF complete surgery in Shenzhen Children′s Hospital from September 2015 to September 2021 were analyzed retrospectively. There were 41 cases in the ≤4-year group and 35 cases in the >4-year group. Seventy-six healthy children with matched body surface area in the same period were selected as the control group. All subjects underwent complete echocardiography and quantitative analysis of left ventricular myocardial work, including global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). Compared with the normal control group, the changes of left ventricular myocardial work after TOF repair were analyzed. For patients with complete echocardiographic data before and after surgery, the correlation between postoperative left ventricular myocardial work and preoperative degree of right ventricular outflow tract (RVOT) obstruction was analyzed.Results:①In the ≤4-year group, compared with control subjects, GLS, GWI, GCW, GWE decreased, and GWW increased in patients with repaired TOF. All the differences were statistically significant [(-20.00±1.52)% vs (-21.59±1.73)%, (1 349.37±133.63)mmHg% vs (1 553.51±246.09)mmHg%, (1 589.39±167.85)mmHg% vs (1 749.12±249.45)mmHg%, 94.0%(94.0%, 95.0%) vs 96.0%(95.0%, 97.0%), (78.80±20.53)mmHg% vs (62.27±21.44)mmHg%; all P<0.05]. ②In >4-year group, compared with the control group, GLS, GWI, GWE decreased, and GWW increased in patients with repaired TOF. All the differences were statistically significant [(-19.89±1.66)% vs (-21.31±1.60)%, (1 486.09±172.42)mmHg% vs (1 713.14±227.05)mmHg%, 96.0%(94.0%, 96.0%) vs 97.0%(96.0%, 97.0%), 75.00(65.00, 95.00)mmHg% vs 55.00(42.00, 71.00)mmHg%; all P<0.05]. ③GWW was negatively correlated with preoperative RVOT diameter and RVOT-Z score( r=-0.422, -0.433; both P<0.05). GWE was positively associated with preoperative RVOT diameter and RVOT-Z score( r=0.441, 0.540; both P<0.05). ④GLS, GWI, GCW, GWW, GWE had good repeatability within and between observers.All the differences were not statistically significant (all P>0.05). Conclusions:Left ventricular systolic function in patients with repaired TOF is lower than that in healthy children of the same age by echocardiography PSL, although traditional indicators are still within the normal range. Patients with more severe RVOT obstruction before surgery have worse left ventricular systolic function after operation. Quantification of left ventricular myocardial work by echocardiography PSL is helpful for long-term follow-up of children after TOF repair.

Objective:To analyze the difference between Z score and previous criteria in the diagnosis characteristics of coronary artery aneurysm (CAA) in Kawasaki disease, and to investigate the clinical distribution of Kawasaki disease CAA in the Z score group.Methods:This study retrospectively analyzed the clinical and echocardiographic data of 2 419 children with Kawasaki disease in Shenzhen Children′s Hospital from January 2009 to December 2019. The traditional criteria and Z score criteria were used to diagnose CAA, and the differences of diagnostic efficiency between the 2 diagnostic methods were analyzed. The clinical distribution characteristics of CAA in children with Kawasaki disease were analyzed by grouping their sex, clinical classification (complete Kawasaki disease, incomplete Kawasaki disease) the sensitivity to intravenous immunoglobulin (IVIG) (IVIG-sensitive Kawasaki disease,IVIG-unresponsive Kawasaki disease). And the course of the disease (≤6 weeks, >6-8 weeks, >8 weeks to 6 months) etc. The χ2 test or Kruskal-Wallis test was used for comparison between the groups, and the Kappa test was used for consistency evaluation.Results:Among the 2 419 children with Kawasaki disease, 1 558 were males and 861 were females. The age of onset was 1.8 (1.0, 3.2) years. The rate of CAA by Z score criteria was higher than that by traditional method (21.9% (529/2 419) vs. 13.9% (336/2 419), χ 2=1 074.94, P<0.001). Compared to the traditional method, the Z score criteria found higher rate of CAA in male patients, patients with incomplete Kawasaki disease, and IVIG-unresponsive patients (25.2% (392/1 558) vs. 16.0% (249/1 558), (32.7% (166/507) vs. 19.5% (99/507), 30.5% (95/312) vs. 24.0% (75/312), χ 2=694.05, 216.19, 184.37, all P<0.001). The Z score criteria was consistent with the traditional method in diagnosing CAA (κ=0.642, P<0.001). Moreover, in the Z score criteria, the rate of CAA in males (25.2%, 392/1 558) was higher than that in females (15.9%, 137/861), higher in incomplete Kawasaki cases (32.7%, 166/507) than that in complete Kawasaki case (19.0%, 363/1 912), and higher in IVIG-unresponsive cases (30.4%, 95/312) than that in IVIG-sensitive cases (20.6%, 434/2 107), with statistically significant differences (χ 2=27.76, 44.38, 15.43, all P<0.001). Coronary Z score of course ≤ 6 weeks was greater than that of course between>6-8 weeks and >8 weeks to 6 months (1.3 (0.7, 2.3) vs. 0.7 (0.3, 1.4), 0.7 (0.3, 1.3), Z=20.65, 13.70, both P<0.001). Conclusions:The rate of CAA in Kawasaki disease by Z score criteria is higher than that by traditional method. In the Z score group, most CAA occur within 6 weeks of the course of the disease, and the rate of CAA in male, incomplete Kawasaki disease, and IVIG-unresponsive is higher.