OBJECTIVE To compare the long-term cost-effectiveness of gonadotrophin-releasing hormone analogue （GnRHa） combined with recombinant human growth hormone （rhGH） （combination therapy regimen） versus GnRHa monotherapy （monotherapy regimen） in the treatment of central precocious puberty （CPP）. METHODS From the societal perspective and based on a real-world study conducted at West China Second Hospital of Sichuan University， the cost-effectiveness analysis was performed to compare the long-term cost-effectiveness of two pharmacotherapy regimens for CPP girls， with final height as outcome indexes， using per capita disposable income of rural residents and urban residents （20 133-49 283 yuan） in 2022 as the social willing-to-pay （WTP） threshold. The robustness of the basic analysis result was verified by using one-way sensitivity analysis and probability sensitivity analysis， and the cost-effectiveness of different combinations of long-acting preparations was compared using scenario analysis. RESULTS The basic analysis result showed that the combination therapy regimen required an additional cost of 25 193.49 yuan for every one-centimeter improvement in the final height of girls with CPP compared with the monotherapy regimen， which was not cost-effective for residents in rural areas， but it was cost-effective for residents in urban areas. One-way sensitivity analysis showed that the uncertain factors with potential impacts on the results were， in order， the price of rhGH， the final height of pediatric patients in the combination therapy regimen group， the course of rhGH in the combination therapy regimen group， and the final height of pediatric patients in the monotherapy regimen group. Probabilistic sensitivity analysis indicated that the probability of the combination therapy regimen being cost-effective was higher than that of the monotherapy regimen when WTP was more than 26 010 yuan/cm. When GnRHa long-acting preparation was used for intramuscular injection every 3 months， the combination therapy regimen was not cost-effective for rural residents， but was cost-effective for urban residents； when rhGH long-acting preparation was injected subcutaneously once a week， the combination therapy regimen was not cost-effective for residents in both rural areas and urban areas. CONCLUSIONS The combination of GnRHa and rhGH is only recommended for CPP children with better affordability to improve final height. The benefits， risks， and affordability of treatment should be comprehensively considered before the decisions on pharmacotherapy， to avoid abuse of rhGH due to the blind pursuit of height growth.

BACKGROUND: Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). METHODS: A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2 * and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. RESULTS: Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata ( P <0.001) and compacta ( P <0.001), SN ( P <0.001), red nucleus (RN, P <0.001), globus pallidus ( P <0.001), putamen (PUT, P = 0.021), and thalamus ( P = 0.029) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT ( P <0.001), RN ( P = 0.003), SN ( P = 0.017), and caudate nucleus ( P = 0.017) than MSA patients, and lower iron content in RN ( P = 0.001), PUT ( P <0.001), globus pallidus ( P = 0.004), SN ( P = 0.015), and caudate nucleus ( P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.86). CONCLUSIONS: Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. REGISTRISION PROSPERO (CRD42022344413).
Humans ; Parkinson Disease/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Iron/metabolism*

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

Objective:To analyze the immune microenvironment characteristics of human dental follicle tissues from the third molars and to explore the mutual communication and the effects of innate immune cells and adaptive immune cells within the dental follicle.Methods:Sequencing data(GSA-Human:HRA008022)in the GSA database were analyzed.Bioinformatics tools were employed for gene identification and GO enrichment analysis was performed to define the biological function of innate and adaptive immune cells.CellChat analysis was used for explaining intercellular communication among immune cell populations.Results:Using t-SNE dimen-sionality reduction analysis for immune cell populations,innate immune cell populations were obtained,including innate lymphoid cells,dendritic cells,mast cells and macrophages,and adaptive immune cell populations including T cells and B cells.Pearson corre-lation analysis showed that innate immune cells,specifically innate lymphoid cells and macrophages,had a strong correlation with adap-tive immune cell populations.GO enrichment analysis revealed mutual coordination among innate immune cell populations and regulato-ry effects on adaptive immune cell populations.Further CellChat analysis indicated biological signal transmission between innate and a-daptive immune cell populations,with CLEC,MIF,ADGRE5,COLLAGEN and MIF signaling pathways is the most significant.Con-clusion:Dental follicle tissues are rich in immune cells and innate immune cell populations interact with adaptive immune cells to regulate immune responses and participate in maintaining the homeostasis of dental follicle.

ObjectiveTo systematically review the intervention effect of cognitively engaging physical activity (CEPA) on executive function of children and adolescents. MethodsLiteratures in Chinese and English were retrieved from databases of Web of Science, PubMed, Medline, EBSCO and CNKI, from the establishment to November 30th, 2023. According to the inclusion and exclusion criteria, the literatures that met the requirements were screened, and their quality was evaluated and systematically reviewed. ResultsA total of 15 literatures were included, published between 2014 and 2023, from eight countries, involving 1 806 subjects aged four to 16 years. The average score of PEDro scale was 6.6. The intensity of the CEPA intervention ranged from 64% to 93% HR_max, the duration of a single session ranged from ten to 60 minutes, and the frequency of the intervention was two to five sessions a week, for four to 24 weeks. Specific forms of CEPA included football, basketball and floorball combined with cognitive tasks; running, jumping, squatting, sitting, spinning and balancing combined with cognitive tasks; and exergaming combined with cognitive tasks. Eleven researches showed positive effects of CEPA intervention on at least one component of executive function. However, six of the seven researches involving working memory failed to verify the positive effects. Twelve researches compared the intervention effects of CEPA and rutine exercise or regular physical education classes, and nine researches found that CEPA was more effective on executive function. ConclusionThe CEPA is effective on the executive function of children and adolescents, specifically on cognitive flexibility; it shows inconsistent effects on inhibitory control, and its effect on working memory has not been verified. The intervention types of CEPA are divided into ball games combined with cognitive tasks, basic motor skills training combined with cognitive tasks, and exergaming combined with cognitive tasks.

Objective:To investigate whether murine peroxidase reductase-5(mPRDX5)has anti-tumor activity in mice,so as to further confirm the anti-tumor activity and mechanism of recombinant peroxidase reductase-5.Methods:High purity mPRDX5 was obtained by heterologous expression and purification in vitro.Pancreatic cancer Pan02 cells were inoculated subcutaneously on the left axillary back of mice to establish a tumor bearing mouse model.Mice were randomly divided into PBS(solvent control)group,GEM(gemcitabine)50.0 mg/kg group and mPRDX5 10.0 mg/kg group,with 10 mice in each group,and the tumor related indexes were detected in mice.Results:Compared with PBS group,weight of tumor-bearing mice in GEM group was decreased obviously,while weight of mPRDX5 group was increased to a certain extent.Tumor growth was good in PBS group,according to tumor volume,com-pared with PBS group,tumor growth inhibition rates in D7 were 87.07%in GEM group and 52.82%in mPRDX5 10.0 mg/kg group,re-spectively;according to tumor weight,compared with PBS group,GEM group and mPRDX5 10.0 mg/kg group had tumor growth inhibi-tion rates of 95.39%and 48.33%in D7,respectively.Polarization state of macrophages in tumor tissues of mice in PBS group and mPRDX5 group was analyzed,and it was found that compared with PBS group,M1 macrophages expressing CD86 in tumor tissues of mice in mPRDX5 group were significantly increased,while M2 macrophages expressing CD206 were significantly decreased.Conclu-sion:mPRDX5 has significant anti-pancreatic cancer activity in mice,and the activity is exerted by promoting M1-type polarization of macrophages in the tumor microenvironment.

Objective:To study the morphology of hemophagocytosis (HPC) in bone marrow smears of patients with infection-associated hemophagocytic lymphohistiocytosis (IAHLH), and further analyse if there were differences in the clinical and laboratory features, the cytokines level and prognosisMethods:24 patients newly diagnosed with IAHLH from 2016-Dec-1 to 2021-Dec-31 in Beijing Friendship Hospital were included as study group, and 20 patients with infectious disease as non-HLH control group. In IAHLH group, mean age was 34±13 years, including 17(71%) males and7(29%) females. In Non-HLH group, mean agewas 43±16 years, including 14 (70%) males and6 (30%) females. Depending on re-checking phagocytic cell type on the initial bone marrow smear, the HPCs were divided into HPC-1, phagocytizing non-nucleated cells (mature erythrocyte or platelets), and HPC-2, phagocytizing nucleated cells. The differences in clinical presentations covered in HLH-2004 criteria, cytokines value(IL-6, IL-10, IL-18, IFN-γ) recommended in HLH-2022-China guideline, and the mortality within 1 year of diagnosis, were compared between IAHLH and non-HLH groups, between patients with or without HPC, and between patients with HPC-2 or only with HPC-1. For categorical variables, two groups were compared with the use of either the chi-square test or Fisher′s exact test. For non-normal distribution continuous variables, the difference between two groups variation was performed by using Mann-Whitney U test, and for normal distribution continuous variables, the difference was by the Independent Samples t-test.Results:The positive rates of fever, hepatomegaly and splenomegalyand the motrtality in IAHLH were 100% (24/24), 63% (15/24), 92% (22/24) and 46% (11/24), respectivelyin non-HLH were 55%(11/20),0(0/20),25% (5/20),0(0/20),and the differences between two groups were all statistically significant( P<0.01), but thedifferences between groups with and without HPC and between IAHLH patients with HPC-2 or only with HPC-1 were no statistically significanlly, ( P>0.05).In IAHLH group, IFN-γ in patients with HPC-2 was 400(246, 532)ng/L, significantly higher than 146(38, 180)ng/L in patients only with HPC-1 [ P=0.02, 95% CI was 233(75.8 to 397)], andthe other test parameters and cytokines level showed no obvious differences ( P>0.05).

OBJECTIVES: To investigate the clinical efficacy and safety of salbutamol in the treatment of children with later-onset spinal muscular atrophy (SMA). METHODS: This study is a prospective single-arm phase Ⅲ clinical study. Pediatric patients with SMA type Ⅱ and Ⅲ who visited Department of Neurology, Children's Hospital, Zhejiang University School of Medicine from December 2020 to June 2022 were enrolled. All patients were evaluated with motor function scales, pulmonary function test and drug safety before study. Patients were treated with salbutamol tablets orally, with an initial dose of 1 mg (tid). If tolerable, the dose was increased to 1.5 mg (tid) in the second week, then increased to 2 mg (tid) from the third week and maintained for 6 months. Patients were followed up at 1, 3 and 6 months of treatment. RESULTS: Twenty-six patients were enrolled, including 10 boys and 16 girls. There were 16 cases of SMA type Ⅱ and 10 cases of type Ⅲ with age at treatment initiation of 5.67 (3.13, 7.02) years and disease duration of 2.54 (1.31, 4.71) years. The Hammersmith Functional Motor Scale-Expanded (HFMSE) scores were increased from 14.0 (6.5, 43.0) before treatment to 26.0 (15.0, 46.5) after treatment (Z=－4.144, P<0.01) in 25 cases. The Revised Upper Limb Module Scale scores were increased from 33.0 (25.5, 36.0) before treatment to 35.0 (31.0, 36.5) after treatment (Z=－2.214, P<0.05) in 9 cases. In 7 ambulant children with SMA type Ⅲ, the six minutes walking distance was increased by 30 (15, 52) m after a 6-month treatment (Z=－2.366, P<0.05). Compared with the baseline pulmonary functions the patients showed a significant increase in forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), and peak expiratory flow (PEF) in 15 cases after treatment (all P<0.05). According to patients and caregivers subjective reporting, there were various degrees of improvement in coughing, sputum production ability and exercise endurance. No serious adverse events were observed during the study. CONCLUSIONS Short-term oral administration of salbutamol may improve motor and pulmonary functions in later-onset SMA children with good safety.
Male ; Female ; Humans ; Child ; Albuterol/therapeutic use* ; Prospective Studies ; Muscular Atrophy, Spinal/drug therapy* ; Spinal Muscular Atrophies of Childhood/drug therapy* ; Treatment Outcome

Objective:To explore the clinical efficacy of disease-modifying drug nusinersen on children with spinal muscular atrophy.Methods:The baseline and longitudinal clinical data of 15 children who were treated with nusinersen in the Children′s Hospital, Zhejiang University School of Medicine from October 2019 to October 2021 were retrospectively collected. The general data (gender, age, genotype, and clinical classification, etc.), motor function, nutritional status, scoliosis and respiratory function were analyzed. Wilcoxon rank-sum test was used for comparing multi-system conditions before and after treatment.Results:The age of 15 cases (7 males, 8 females) was 6.8 (2.8, 8.3) years, with 2 cases of type 1, 6 cases of type 2, and 7 cases of type 3 respectively, and the course of disease was 55.0 (21.0, 69.0) months. After 9.0 (9.0, 24.0) months of treatment, the motor function scale evaluations of the Hammersmith neurological examination section 2 (13.0 (7.0, 23.0) vs. 18.0 (10.0, 25.0) scores, Z=-2.67, P=0.018) of 15 children, the Hammersmith functional motor scale expanded (38.0 (18.5, 45.5) vs. 42.0 (23.0, 51.0) scores, Z=-2.38, P=0.018), and the revised upper limb module (27.0 (19.5, 32.0) vs. 33.0 (22.5, 35.5) scores, Z=-2.52, P=0.012) of children with type 2 and 3 had significantly improved. Thirteen patients achieved clinically significant motor function improvement, and 2 of them had kept stable scale scores. Subjective reports also indicated that the muscle strength and daily exercise ability of these children improved after treatment, and no serious adverse reactions were reported. Supplemented by the multi-disciplinary team management, the levels of some indicators such as Cobbs angle of scoliosis and forced vital capacity all had significantly improved (all P<0.05). Conclusions:Nusinersen can improve the motor function of patients with 5q spinal muscular atrophy, which is also proved safe to be used in children. The drug treatment supplemented by the multi-disciplinary team management is helpful to improve the multi-system function of the children with spinal muscular atrophy.