OBJECTIVE To systematically review the current application of discrete choice experiment （DCE） in the value assessment and preference measurement of orphan medicinal product （OMP）， and to provide a reference for the standardized use of this methodology in China. METHODS The systematic search was conducted across Chinese and English databases including CNKI， Wanfang Data， VIP， CBM， PubMed， Web of Science， Medline， and Embase. Original studies that employed DCE to evaluate the value or preferences related to OMP were included. The methodological quality and reporting completeness of the included studies were assessed using the ISPOR Conjoint Analysis Checklist and the DIRECT Checklist， respectively. Respondent populations， attribute setting， and the relative importance of attributes were summarized and analyzed. RESULTS Eight eligible studies were included； all studies demonstrated high-quality reporting and methodological rigor. Respondents comprised the general public， patients/caregivers， policymakers， and other stakeholders. The number of DCE attributes ranged from 4 to 13 （median＝7.5）. Through thematic synthesis， these attributes were categorized into three dimensions， namely “disease-related” “treatment-related” and “economic/financial-related” along with 14 secondary criteria. The most frequently included secondary criteria were treatment efficacy （13 occurrences）， disease severity （9 occurrences）， safety （7 occurrences）， unmet medical need （6 occurrences）， and treatment cost （5 occurrences）. Rankings of relative importance identified treatment efficacy as the most valued criterion across most studies， followed by health insurance financing. CONCLUSIONS DCE applications in the value assessment of OMP have begun to converge on a relatively consistent core attribute framework and selection preference. Future research should further promote the use of DCE to inform attribute and criterion selection in multi-criteria decision analysis frameworks for OMP.

Objective:To establish a quality control method for Aiye standard decoction.Methods:The ultra performance liquid chromatogrphy (UPLC) column Waters ACQUITY HSS T3 C18 (2.1 mm×150 mm,1.8 μm) was used to gradient elution by acetonitrile and 0.1% formic acid in water. 16 batches of Aiye standard decoction fingerprints were established by UPLC and the common peaks were determined in the fingerprints. The contents of 12 components were determined. The 16 batches of Aiye standard decoction were analyzed by similarity calculation, hierarchical cluster analysis (HCA), principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) for analysis of differential components of Artemisiae Argyi Folium from different origins.Results:A total of 13 common peaks were marked in the fingerprints of 16 batches of Aiye standard decoction, 12 of which were identified by comparison with reference substance, including chlorogenic acid, sochlorogenic acid A, neochlorogenic acid, cryptochlorogenic acid, caffeic acid,1,3-O-Dicaffeoylquinic acid, schaftoside, isochlorogenic acid B,1,5-O-Dicaffeoylquinic acid, isochlorogenic acid C, jaceosidin and eupatilin. Similarity evaluation, PCA and HCA all classified the 16 batches of Aiye standard decoction into 2 categories. Orthogonal partial least squares discriminant analysis screened 5 differential biomarkers from 13 common peaks. The content determination results showed that the phenolic compounds and flavonoids in samples from Hubei were significantly higher than that in samples from other areas.Conclusion:This method can effectively analyze the differences in the quality of Aiye standard decoction from different origins, and provide reference for the formulation of quality standards for Aiye standard decoction and related preparations.

This paper aimed to explore the effects of Duzhong Decoction(DZD)-containing serum on the proliferation and osteoblast differentiation of MC3T3-E1 cells through L-type voltage-gated calcium channels(L-VGCCs). L-VGCCs inhibitors, nifedipine and verapamil, were used to block L-VGCCs in osteoblasts. MC3T3-E1 cells were divided into a control group, a low-dose DZD-containing serum(L-DZD) group, a medium-dose DZD-containing serum(M-DZD) group, a high-dose DZD-containing serum(H-DZD) group, a nifedipine group, a H-DZD + nifedipine group, verapamil group, and a H-DZD + verapamil group. The CCK-8 method was used for cell proliferation analysis, alkaline phosphatase(ALP) assay kits for intracellular ALP activity measurement, Western blot for protein expression level in cells, real-time fluorescence quantitative PCR technology for intracellular mRNA expression level determination, fluorescence spectrophotometer for free Ca~(2+) concentration determination in osteoblasts, and alizarin red staining(ARS) for mineralized nodule formation in osteoblasts. The experimental results show that compared to the control group, DZD groups can promote MC3T3-E1 cell proliferation, ALP activity, and mineralized nodule formation, increase intracellular Ca~(2+) concentrations, and upregulate the protein expression of bone morphogenetic protein 2(BMP2), collagen Ⅰ(COL1), α2 subunit protein of L-VGCCs(L-VGCCα2), and the mRNA expression of Runt-related transcription factor 2(RUNX2), and BMP2. After blocking L-VGCCs with nifedipine and verapamil, the intervention effects of DZD-containing serum were inhibited to varying degrees. Both nifedipine and verapamil could inhibit ALP activity, reduce mineralized nodule areas, and downregulate the expression of bone formation-related proteins. Moreover, the effects of DZD-containing serum on increasing MC3T3-E1 cell proliferation, osteoblast differentiation, and Ca~(2+) concentrations, upregulating the mRNA expression of osteoprotegerin(OPG) and protein expression of phosphorylated protein kinase B(p-Akt) and phosphorylated forkhead box protein O1(p-FOXO1), and upregulating phosphatase and tensin homolog(PTEN) expression were reversed by nifedipine. The results indicate that DZD-containing serum can increase the Ca~(2+) concentration in MC3T3-E1 cells to promote bone formation, which may be mediated by L-VGCCs and the PTEN/Akt/FoxO1 signaling pathway, providing a new perspective on the mechanism of DZD in treating osteoporosis.
Animals ; Osteoblasts/metabolism* ; Cell Proliferation/drug effects* ; Cell Differentiation/drug effects* ; Mice ; Drugs, Chinese Herbal/pharmacology* ; Calcium Channels, L-Type/genetics* ; Alkaline Phosphatase/genetics* ; Serum/chemistry* ; Cell Line ; Osteogenesis/drug effects* ; Bone Morphogenetic Protein 2/genetics*

The reconstruction of the temporomandibular joint presents a multifaceted clinical challenge in the realm of head and neck surgery, underscored by its relatively infrequent occurrence and the lack of comprehensive clinical guidelines. This review aims to elucidate the available approaches for TMJ reconstruction, with a particular emphasis on recent groundbreaking advancements. The current spectrum of TMJ reconstruction integrates diverse surgical techniques, such as costochondral grafting, coronoid process grafting, revascularized fibula transfer, transport distraction osteogenesis, and alloplastic TMJ replacement. Despite the available options, a singular, universally accepted 'gold standard' for reconstructive techniques or materials remains elusive in this field. Our review comprehensively summarizes the current available methods of TMJ reconstruction, focusing on both autologous and alloplastic prostheses. It delves into the differences of each surgical technique and outlines the implications of recent technological advances, such as 3D printing, which hold the promise of enhancing surgical precision and patient outcomes. This evolutionary progress aims not only to improve the immediate results of reconstruction but also to ensure the long-term health and functionality of the TMJ, thereby improving the quality of life for patients with end-stage TMJ disorders.
Humans ; Temporomandibular Joint/surgery* ; Temporomandibular Joint Disorders/surgery* ; Transplantation, Autologous ; Arthroplasty, Replacement/methods* ; Joint Prosthesis ; Plastic Surgery Procedures/methods*

Objective : To explore the role of semaphoring 6d(SEMA6D) in the malignant progression of triple-negative breast cancer(TNBC). Methods : Bioinformatics and Immunohistochemistry(IHC) were used to analyze the expression level of SEMA6D in TNBC and paracancer non-tumor tissues and its relationship with patients′ clinicopathological features. MDA-MB-231 cell line stably knocking down the expression of SEMA6D was constructed, and the effects of SEMA6D on migration and invasion of TNBC cells were investigated by Wound-healing assays and Transwell assays. cBioPortal and GEPIA2 databases were used to screen out the gene negatively associated with it, namely aurora kinase A(AURKA). Bioinformatics and IHC were used to analyze the expression level of AURKA in TNBC and paracancer non-tumor tissues and its relationship with patients' clinicopathological features. Western blot assay was used to analyze the expression of AURKA and the effect of epithelial-mesenchymal transition(EMT) makers Claudin-1, N-cadherin and Vimentin after knocking downSEMA6D. Results: Bioinformatics analysis and IHC results showed that the expression of SEMA6D in TNBC tissues was significantly lower than that in paracancer non-tumor tissues(bothP<0.05). The expression of AURKA in TNBC tissues was significantly higher than that in paracancer non-tumor tissues(bothP<0.05), SEMA6D and AURKA were significantly negatively correlated in TNBC(P<0.01). Both low expression of SEMA6D and high expression of AURKA were positively correlated with tumor size, tumor histological grade, clinical stage and lymph node metastasis in TNBC patients(allP<0.05). The knockdown ofSEMA6Dsignificantly promoted the migration and invasion ability of TNBC cells(bothP<0.01). Western blot results showed that the knockdown ofSEMA6Dupregulated AURKA expression, promoted the expression of N-cadherin and Vimentin, and inhibited the expression of Claudin-1 in tumor cells. Conclusion Down-regulation of SEMA6D expression in TNBC may be involved in the malignant progression of TNBC through up-regulation of AURKA expression and promotion of EMT.

OBJECTIVE: To explore mechanisms of acid-sensing ion channel 1 (ASIC1) mediated lumbar nucleus pulposus cell apoptosis through extracellular-signalregulated protein kinase 5 (ERK5) signaling pathway and mitochondrial dysfunction pathway. METHODS: Totally 34 patients with degenerative lumbar disc herniation (LDH) admitted from January 2020 to December 2022 were collected as research objects, including 21 males and 13 females;aged from 29 to 52 years old with an average of (37.43±4.75) years old;22 patients with grade Ⅱ and 12 patients with grade Ⅳ, according to Pfirrmann grading criteria;15 patients with L_4,5 and 19 patients with L₅S₁. The expression of ASIC1 in nucleus pulposus of LDH patients was measured by immunohistochemical staining. Nucleus pulposus cells were cultured by primary culture method, identified by toluidine blue staining and immunohistochemical staining, and the expression of ASIC1 protein was located by immunofluorescence staining. According to the addition of siRNA-ASIC1, ASIC1 overexpression plasmid, and ERK5 inhibitors, the nucleus pulpocyte was divided into three groups, named as SIRNA-silenced group, overexpression group, and inhibitor group, with 3 patients in each group. Cells of each group were collected at 72 h after intervention, expression of ASIC1, ERK5, BCL-xL/BCL-2-associated Death promoter (Bad), B-cell lymphoma-2 associated X (Bax) and B-cell lymphoblast-2 gene (Bcl-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR);intracellular calcium ion levels were detected by calcium ion kit, mitochondrial membrane potential was detected by JC-1 kit, and apoptosis was observed by AV-PI kit. RESULTS: In LDH patients with grade Ⅳ, nucleus pulposus tissue removed during operation revealed poor elasticity, white color and poor ductility, and immunohistochemical results showed increased ASIC1 expression. There was no significant difference in mRNA relative expression of ASIC1 between siRNA silencing group (0.31±0.03) and inhibitor group (0.39±0.05) (P>0.05). The mRNA relative expression level of ERK5 in siRNA silencing group(0.32±0.05) was significantly higher than that in inhibitor group (0.15±0.04)(P<0.05), which suggested ERK5 was the downstream molecule of ASIC1. The mRNA relative expression levels of apoptosis promoting factor Bad and Bax in siRNA silencing group and inhibitor group were lower than those in overexpression group(P<0.05), the relative expression level of anti-apoptosis factor Bcl-2 mRNA was significantly increased (P<0.05). The calcium content in overexpression group was higher than that in siRNA silencing and inhibitor groups (P<0.05), the normal proportion of mitochondrial membrane potential in overexpression group was lower than that in siRNA silencing and inhibitor group (P<0.05), and the apoptosis rate in overexpression group was higher than that in siRNA silencing and inhibitor group (P<0.05). CONCLUSION After the activation of ASIC1 channel protein, calcium ions could enter the cells and act as a second messenger molecule to regulate apoptosis of nucleus pulposus cells by ERK5 signaling pathway and mitochondrial disorder pathway.
Humans ; Acid Sensing Ion Channels/physiology* ; Male ; Female ; Apoptosis ; Middle Aged ; Adult ; Signal Transduction ; Mitogen-Activated Protein Kinase 7/physiology* ; Mitochondrial Diseases/genetics* ; Nucleus Pulposus/metabolism* ; Intervertebral Disc Degeneration/metabolism* ; Mitochondria/metabolism* ; Intervertebral Disc Displacement/genetics*

OBJECTIVE: To investigate the variability of bone metabolism levels among different populations and its association with knee osteoarthritis (KOA) pain. METHODS: A total of 50 people (control group) who participated in physical examination from January 2023 to June 2023 were selected, including 26 males and 24 females, wtih a mean aged of (52.14±9.04) years old ranging 41 to 65 years old. The other 50 patients with knee osteoarthritis(case group) who attended the outpatient clinic of the Orthopedics and Traumatology Department in the same time period, including 19 males and 31 females, with a mean age of (53.60±7.76) years old ranging 40 to 65 years. The two groups of Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC) and bone metabolism markers, such as 25-hydroxy-cholecalciferol[25(OH)D], β-isomerized typeⅠcollagen C-telopeptide breakdown products (β-CTX), total typeⅠprocollagen N-terminal propeptide (t-PINP), osteocalcin (OC), parathormone (PTH) levels were compared. Pearson correlation analysis was used to compare the correlation between two groups of bone metabolism related markers and WOMAC. RESULTS: The WOMAC score of the case group (39.90±2.34) was higher than that of the control group (3.60±0.57), with significant difference (P<0.05). There was no significant difference between the two groups of 25 (OH)D, β-CTX and PTH (P>0.05). The t-PINP and OC of the case group were (62.90±52.40) and (19.88±10.15) ng·ml-1, respectively, and those of the control group were (38.86±10.82) and (14.90±3.62) ng·ml^-1, respectively;the t-PINP and OC of the case group were higher than those of the control group, with significant difference (P<0.05). Pearson correlation analysis showed that t-PINP was positively correlated with WOMAC pain score in the case group (r²=0.045, P<0.01). CONCLUSION Bone metabolism levels in the serum of patients with knee osteoarthritis are different from those of healthy people, and the difference between OC and t-PINP is the most obvious, and the concentration of t-PINP levels is positively correlated with pain symptoms in patients with KOA. However, the specific mechanism of correlation between the bone metabolism levels of patients with KOA and their pain symptoms needs to be further elucidated by basic experimental research as well as by enlarging the samples.
Humans ; Female ; Male ; Middle Aged ; Osteoarthritis, Knee/metabolism* ; Aged ; Adult ; Bone and Bones/metabolism* ; Pain/etiology* ; Biomarkers/metabolism*

PURPOSE: The rate of complications among patients undergoing surgery has increased due to infection with SARS-CoV-2 and other variants of concern. However, Omicron has shown decreased pathogenicity, raising questions about the risk of postoperative complications among patients who are infected with this variant. This study aimed to investigate complications and related factors among patients with recent Omicron infection prior to undergoing orthopedic surgery. METHODS: A historical control study was conducted. Data were collected from all patients who underwent surgery during 2 distinct periods: (1) between Dec 12, 2022 and Jan 31, 2023 (COVID-19 positive group), (2) between Dec 12, 2021 and Jan 31, 2022 (COVID-19 negative control group). The patients were at least 18 years old. Patients who received conservative treatment after admission or had high-risk diseases or special circumstances (use of anticoagulants before surgery) were excluded from the study. The study outcomes were the total complication rate and related factors. Binary logistic regression analysis was used to identify related factors, and odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the impact of COVID-19 infection on complications. RESULTS: In the analysis, a total of 847 patients who underwent surgery were included, with 275 of these patients testing positive for COVID-19 and 572 testing negative. The COVID-19-positive group had a significantly higher rate of total complications (11.27%) than the control group (4.90%, p < 0.001). After adjusting for relevant factors, the OR was 3.08 (95% CI: 1.45-6.53). Patients who were diagnosed with COVID-19 at 3-4 weeks (OR = 0.20 (95% CI: 0.06-0.59), p = 0.005), 5-6 weeks (OR = 0.16 (95% CI: 0.04-0.59), p = 0.010), or ≥7 weeks (OR = 0.26 (95% CI: 0.06-1.02), p = 0.069) prior to surgery had a lower risk of complications than those who were diagnosed at 0-2 weeks prior to surgery. Seven factors (age, indications for surgery, time of operation, time of COVID-19 diagnosis prior to surgery, C-reactive protein levels, alanine transaminase levels, and aspartate aminotransferase levels) were found to be associated with complications; thus, these factors were used to create a nomogram. CONCLUSION Omicron continues to be a significant factor in the incidence of postoperative complications among patients undergoing orthopedic surgery. By identifying the factors associated with these complications, we can determine the optimal surgical timing, provide more accurate prognostic information, and offer appropriate consultation for orthopedic surgery patients who have been infected with Omicron.
Humans ; COVID-19/complications* ; Male ; Female ; Middle Aged ; Postoperative Complications/epidemiology* ; SARS-CoV-2 ; Orthopedic Procedures/adverse effects* ; Aged ; Nomograms ; Adult ; Retrospective Studies ; Risk Factors

OBJECTIVES: To investigate the application value of thromboelastography (TEG) in assessing coagulation function in children with severe hemophilia A (HA) after emicizumab (EMI) therapy. METHODS: A retrospective analysis was performed on the activated partial thromboplastin time (APTT) and TEG testing results of 17 children with severe HA before and after EMI treatment at Shenzhen Children's Hospital from January 2023 to July 2024. Correlation analysis was conducted between coagulation factor VIII (FVIII) equivalent activity and reaction time (R value) measured by TEG. RESULTS: After EMI treatment, the mean bleeding rate for children with severe HA was 1.6 events per year, with 15 children (88%) without spontaneous bleeding or joint bleeding. The children with severe HA showed a significant reduction in APTT after EMI treatment (P<0.05), with a significantly shorter APTT than the normal control group (P<0.05). There was no correlation between APTT and FVIII equivalent activity after treatment (P>0.05). After EMI treatment, TEG parameters, including R value, kinetic time, alpha angle (α), maximum amplitude, clot strength, and coagulation index, shifted from a hypocoagulable state before treatment to a nearly normal state after treatment (P<0.05). The R value demonstrated a strong negative correlation with FVIII equivalent activity (r=-0.758, P<0.05). CONCLUSIONS The bleeding condition of children with severe HA can be effectively controlled after EMI treatment. Routine APTT testing cannot reflect true coagulation function, whereas TEG testing is clinically valuable in assessing the coagulation function of children with severe HA undergoing EMI treatment.
Humans ; Thrombelastography ; Hemophilia A/physiopathology* ; Male ; Child ; Antibodies, Bispecific/therapeutic use* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; Blood Coagulation/drug effects* ; Child, Preschool ; Retrospective Studies ; Female ; Partial Thromboplastin Time ; Adolescent ; Infant

OBJECTIVE: To investigate the clinical features and risk factors associated with cutaneous chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: A retrospective analysis was conducted on the clinical data of children who underwent allo-HSCT in the Wuhan Children's Hospital from August 1, 2016, to December 31, 2023, and were regularly followed up for 1 year or more. The differences in clinical features between children with and without cutaneous cGVHD were compared, and the risk factors affecting the occurrence of cutaneous cGVHD were analyzed. RESULTS: During the study period, 296 children received allo-HSCT. Until December 31, 2024, follow-up showed that 20 children (6.8%) developed cutaneous cGVHD, which manifested as cutaneous lichenification, hyperpigmentation, keratosis pilaris, sclerotic changes, and hair or nail involvement. According to their skin lesion area and degree of grading, 5 cases were mild, 10 cases were moderate, and 5 cases were severe. Multivariate logistic regression analysis revealed that female donors and previous acute GVHD were risk factors for the development of cutaneous cGVHD after allo-HSCT. All 20 children were treated with glucocorticoid ± calcineurin inhibitors (tacrolimus/cyclosporine) as first-line therapeutic agents. Only 1 child improved after first-line treatment. The remaining 19 children treated with a second-line regimen of combination interventions based on individualized status, including 10 children who could not tolerate hormonotherapy or first-line treatment, and showed no significant improvement after 3 months, as well as 9 children with multi-organ cGVHD. After comprehensive second-line treatment, 17 children showed improvement in cutaneous symptoms. There were 3 deaths, including 1 due to primary disease recurrence and 2 due to pulmonary infections. CONCLUSION The skin is the first manifestation and most common organ involved in cGVHD in children. Cutaneous cGVHD severely affects the daily activities of transplanted children and requires prolonged immunosuppressive therapy, but has a favorable prognosis. First-line treatments for adults are not applicable to children who usually require a combination treatment with multiple drugs.
Humans ; Graft vs Host Disease/etiology* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Retrospective Studies ; Risk Factors ; Female ; Child ; Skin Diseases/etiology* ; Chronic Disease ; Transplantation, Homologous ; Male ; Child, Preschool ; Adolescent