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.

“Runner’s high” refers to a momentary sense of pleasure that suddenly appears during running or other exercise activities, characterized by anti-anxiety, pain relief, and other symptoms. The neurobiological mechanism of “runner’s high” is unclear. This review summarizes human and animal models for studying “runner’s high”, analyzes the neurotransmitters and neural circuits involved in runner’s high, and elucidates the evidence and shortcomings of researches related to “runner’s high”. This review also provides prospects for future research. Research has found that exercise lasting more than 30 min and with an intensity exceeding 70% of the maximum heart rate can reach a “runner’s high”. Human experiments on “runner’s high” mostly use treadmill exercise intervention, and evaluate it through questionnaire surveys, measurement of plasma AEA, miRNA and other indicators. Animal experiments often use voluntary wheel running intervention, and evaluate it through behavioral experiments such as conditional place preference, light dark box experiments (anxiety), hot plate experiments (pain sensitivity), and measurement of plasma AEA and other indicators. Dopamine, endogenous opioid peptides, endogenous cannabinoids, brain-derived neurotrophic factor, and other substances increase after exercise, which may be related to the “runner’s high”. However, attention should be paid to the functional differences of these substances in the central and peripheral regions, as well as in different brain regions. Moreover, current studies have not identified the targets of the neurotransmitters or neural factors mentioned above, and further in-depth researches are needed. The mesolimbic dopamine system, prefrontal cortex-nucleus accumbens projection, ventral hippocampus-nucleus accumbens projection, red nucleus-ventral tegmental area projection, cerebellar-ventral tegmental area projection, and brain-gut axis may be involved in the regulation of runner’s high, but there is a lack of direct evidence to prove their involvement. There are still many issues that need to be addressed in the research on the neurobiological mechanisms of “runner’s high”. (1) Most studies on “runner’s high” involve one-time exercise, and the characteristics of changes in “runner’s high” during long-term exercise still need to be explored. (2) The using of scales to evaluate subjects lead to the lacking of objective indicators. However, some potential biomarkers (such as endocannabinoids) have inconsistent characteristics of changes after one-time and long-term exercise. (3) The neurotransmitters involved in the formation of the “runner’s high” all increase in the peripheral and/or central nervous system after exercise. Attention should be paid to whether peripheral substances can enter the blood-brain barrier and the binding effects of neurotransmitters to different receptors are completely different in different brain regions. (4) Most of the current evidence show that some brain regions are activated after exercise. Is there a functional circuit mediating “runner’s high” between these brain regions? (5) Although training at a specific exercise intensity can lead to “runner’s high”, most runners have not experienced “runner’s high”. Can more scientific training methods or technological means be used to make it easier for people to experience the “runner’s high” and thus be more willing to engage in exercise? (6) The “runner’s high” and “addiction” behaviors are extremely similar, and there are evidences that exercise can reverse addictive behaviors. However, why is there still a considerable number of people in the sports population and even athletes who smoke or use addictive drugs instead of pursuing the “pleasure” brought by exercise? Solving the problems above is of great significance for enhancing the desire of exercise, improving the clinical application of neurological and psychiatric diseases through exercise, and enhancing the overall physical fitness of the population.

Traditional Chinese medicine(TCM)exerts integrative effects on complex diseases owing to the char-acteristics of multiple components with multiple targets.However,the syndrome-based system of diagnosis and treatment in TCM can easily lead to bias because of varying medication preferences among physicians,which has been a major challenge in the global acceptance and application of TCM.Therefore,a standardized TCM prescription system needs to be explored to promote its clinical application.In this study,we first developed a gradient weighted disease-target-herbal ingredient-herb network to aid TCM formulation.We tested its efficacy against intracerebral hemorrhage(ICH).First,the top 100 ICH targets in the GeneCards database were screened according to their relevance scores.Then,SymMap and Traditional Chinese Medicine Systems Pharmacology(TCMSP)databases were applied to find out the target-related ingredients and ingredient-containing herbs,respectively.The relevance of the resulting ingredients and herbs to ICH was determined by adding the relevance scores of the corresponding targets.The top five ICH therapeutic herbs were combined to form a tailored TCM prescriptions.The absorbed components in the serum were detected.In a mouse model of ICH,the new prescription exerted multifaceted effects,including improved neurological function,as well as attenuated neuronal damage,cell apoptosis,vascular leakage,and neuroinflammation.These effects matched well with the core pathological changes in ICH.The multi-targets-directed gradient-weighting strategy presents a promising avenue for tailoring precise,multipronged,unbiased,and standardized TCM prescriptions for complex diseases.This study provides a paradigm for advanced achievements-driven modern innovation in TCM concepts.

Osteosarcoma is the most common primary malignant bone tumor,typically treated with a combination of surgery and chemotherapy in clinical practice.However,the increasing prevalence of chemotherapy resistance poses a significant challenge.Chemotherapy resistance can lead to a sharp decline in patients'survival rates.Traditional Chinese medicine,known for its low cost,wide-ranging efficacy,and diverse varieties,has attracted significant attention from researchers.Their attempts to investigate the sensitizing effect of extracted ingredients on osteosarcoma chemoresistance both in vitro and in vivo have yielded promising results.This review has summarized the studies of single traditional Chinese medicine ingredients on reversing osteosarcoma chemoresistance by the mechanisms of chemoresistance,and found that the current research of the clinical mechanism of traditional Chinese medicine ingredients in reversing osteosarcoma chemoresistance is still lacking,indicating significant potential for future development.Utilizing the theory of herbal medicine properties as the theoretical basis for ingredient development may provide novel strategies for the development of new therapeutic approaches.

Objective:To explore the clinical effects and value for application of the tibial flap of the second toe with the vascular pedicle including a plantar vein on the reconstruction of fingertip soft tissue defects.Methods:From October 2020 to August 2022, retrospective analysis of 12 patients (12 digits) were treated at the Department of Hand Surgery, Suzhou Ruihua Orthopaedic Hospital for small soft tissue defects of fingertip. The patients were 9 males and 3 females and aged 29-54 years, at 38 years in average. The fingertip defects were measured at approximately 1.2 cm × 0.8 cm to 1.2 cm × 1.2 cm. In the surgery, a tibial flap of second toe was designed to reconstruct the defect in fingertip. The flap were designed on the tibial of second toe without an extended incision in dorsal foot. The pedicle of the flap carried with the lateral proper digital artery, a nerve and the plantar vein of the second toe. At the recipient site, the artery, nerve and vein carried by the pedicle of the flap were end-to-end anastomosed with the digital artery, digital nerve and subcutaneous vein of the finger. The flaps were measured at 1.5 cm×1.0 cm - 1.5 cm×1.5 cm in size. All donor sites were reconstructed with skin grafts from the ipsilateral calf. Scheduled postoperative follow-ups were conducted at the outpatient clinic. The Michigan Hand Function Questionnaire (MHQ) evaluation criteria was employed to assess the recovery of hand function, and Total Active Movement (TAM) was used to evaluate the recovery of range of motion of the interphalangeal joints of the affected fingers.Results:All 12 flaps in the fingertips survived. Postoperative follow-ups lasted from 6 months to 2 years, with an average of 11 months. One flap was slightly bloated and a flap aesthetic surgery was followed at 3 months after the primary reconstructive surgery, and the rest of flaps were all in good appearance. TPD was found at 12 -14 mm for all flaps at 9 months after surgery. All donor sites in the feet and calfs had primary healing, without a contracture or rupture of skin graft or an obvious dysfunction at the donor sites. According to the evaluation criteria of the MHQ, 8 patients were very satisfied with the overall appearance of the hand, and 4 were satisfied. Finger movement was evaluated according to TAM criteria, all 12 fingers were rated excellent.Conclusion:Reconstruction of a fingertip defect with a tibial flap of the second toe with the vascular pedicle including a plantar vein of the second toe has a good clinical efficacy. It has advantages in flap harvest, avoids an extended incision on dorsal foot, and makes a minimal damage to the donor site.

Objective To explore the risk factors of nonalcoholic fatty liver disease(NAFLD)in obese children,and evaluate the diagnostic value of each index for NAFLD and establish a Nomogram prediction model.Methods A total of 207 obese children admitted at Department of Pediatrics the Second Hospital of Jiaxing from January 2022 to January 2025 were selected.These children were divided into two groups based on NAFLD diagnosis:non-NAFLD group(n=99)and NAFLD group(n=108).Differences in gender,age,body mass index(BMI),and related metabolic indicators were compared between two groups.Logistic regression was employed to analyze potential risk factors for NAFLD development,while receiver operating characteristic(ROC)curve and Nomograms were used to evaluate the predictive value of different factors for NAFLD.Results ROC curve analysis demonstrated diagnostic value for NAFLD in triglyceride-glucose index(TyG),triglyceride-to-cholesterol ratio,TyG-waist circumference,and TyG-BMI.Among these,the area under the curve(AUC)of TyG showed the highest value of 0.713,with an optimal cutoff of 8.189,sensitivity of 50.5％and specificity of 83.3％.Univariate Logistic regression analysis revealed multiple insulin resistance indicators associated with NAFLD development.Multivariate analysis identified homeostatic model assessment of insulin resistance(HOMA-IR)and TyG as independent risk factors,with TyG showing the best predictive value(OR=3.038 95％CI:1.089-8.475,P＜0.05).The constructed Nomogram prediction model demonstrated strong comprehensive discriminant capability(AUC=0.742).Conclusion The Nomogram model based on HOMA-IR,TyG and its derived indexes has certain clinical application value in the screening of NAFLD in children.

Objective:To construct a predictive model for mortality in patients with multiple trauma combined with thoracic injuries and evaluate its predictive value.Methods:A retrospective cohort study was conducted to analyze the clinical data of 184 patients with multiple trauma combined with thoracic injuries admitted to the International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine from April 2019 to December 2023, including 129 males and 55 females, aged 19-85 years [(46.1±13.7)years]. According to the prognostic outcomes at 3-month follow-up after discharge, the patients were divided into survival group ( n=145) and death group ( n=39). Data were recorded in both groups at admission, including gender, age, and cause of injury, laboratory tests such as systolic blood pressure, oxygen saturation (SaO 2), hemoglobin (Hb), neutrophil-to-lymphocyte ratio (NLR), and lactate, combined injuries such as the number of combined injuries, number of rib fracture, bilateral rib fracture, first-rib fracture, sternum fracture, thoracic vertebral fracture, bilateral pulmonary contusion, bilateral pneumothorax, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, skull fracture, skull base fracture, cervical vertebral fracture, brain herniation, cerebral contusion, lumbar vertebral fracture, pelvic and abdominal cavity hematoma, liver injury, kidney injury, spleen injury, clavicle fracture, scapular fracture, femoral fracture, and pelvic fracture, and injury scores such as shock index (SI), modified shock index (MSI), injury severity score (ISS), revised trauma score (RTS), Glasgow coma score (GCS), and thoracic trauma severity (TTS) score. Univariate binary logistic regression analysis was used to screen for risk factors of death in patients with multiple trauma combined with thoracic injuries. LASSO regression and multivariate logistic regression analysis were employed to identify predictive variables and independent risk factors for mortality in those patients and to construct a regression equation. A nomogram prediction model based on the regression equation was developed using R language. Receiver operating characteristic (ROC) curves were plotted to evaluate the discrimination of the model. The ROC curves were internally validated using the Bootstrap method with 1 000 resamples. The calibration of the model was assessed using the Hosmer-Lemeshow (H-L) goodness-of-fit test. The clinical application value of the model was evaluated using decision curve analysis (DCA) and clinical impact curve (CIC) analysis. Results:There were statistically significant differences between the survival group and the death group in systolic blood pressure, SaO 2, NLR, lactate, number of combined injuries, subarachnoid hemorrhage, subdural hematoma, skull fracture, skull base fracture, brain herniation, liver injury, SI, MSI, ISS, RTS, GCS, and TTS ( P<0.05 or 0.01). The results of the univariate binary logistic regression analysis showed that the above-mentioned related variables except for systolic blood pressure were all significantly associated with death in patients with multiple trauma combined with thoracic injuries ( P<0.05 or 0.01). Five predictive variables, TTS, GCS, brain herniation, ISS, and lactate were obtained in LASSO regression analysis. The results of the multivariate logistic regression analysis showed that GCS ( OR=0.70, 95% CI 0.58, 0.83), brain herniation ( OR=46.18, 95% CI 4.27, 499.26), TTS ( OR=1.71, 95% CI 1.30, 2.24), and lactate ( OR=1.35, 95% CI 1.01, 1.80) were independent risk factors for death in patients with multiple trauma combined with thoracic injuries ( P<0.05 or 0.01). Based on the aforementioned independent risk factors, a regression formula was constructed as follows: P=e x/(1+e x), with the x=-0.36×"GCS"+3.83×"brain herniation"+0.53×"TTS"+0.30×"lactate levels"-11.03. The area under the ROC curve (AUC) of the predictive model for mortality in patients with multiple trauma combined with thoracic injuries based on the equation was 0.97 (95% CI 0.93, 1.00). The AUC was internally validated using the Bootstrap method with 1 000 samples, resulting in an AUC of 0.97 (95% CI 0.91, 1.00). The results of the H-L goodness-of-fit test showed that the bias-corrected calibration curve of the model was in good consistence with the actual curve and both of them were close to the ideal curve. In the evaluation of the clinical application value of the predictive model, the DCA results showed that the predictive model could achieve good clinical net benefit. The CIC results showed that when the threshold probability was greater than 0.7, the model-identified high-risk patients for death highly matched the patients who actually died. Conclusion:The predictive model for mortality in patients with multiple trauma combined with thoracic injuries based on GCS, brain herniation, TTS, and lactate has good predictive performance and clinical application value.

Objective:The aim of this study is to analyze the clinical characteristics and genetic variants of a late-onset auditory neuropathy pedigree caused by maternally inherited- mitochondrial mutation.Methods:A male proband who presented with bilateral sensorineural hearing loss at Henan Children′s Hospital in September 2023 was chosen, along with his family members (4 generations, 20 individuals) as the study subjects. Data from this pedigree were collected, organized, and analyzed for clinical genetic characteristics. Medical histories were obtained from family members, pedigree charts were drawn, audiological, imaging, and physical examinations were conducted. Pathogenic genes and mutations were screened using high-throughput sequencing. Sanger sequencing was employed for variant confirmation and segregation validation in the family.Results:In this family, a total of 12 members (10 members collected) had sensorineural hearing loss, characterized by late-onset hearing impairment with an onset age ranging from 9 to 30 years. The patients exhibited poor speech recognition rates, and audiometric examinations are consistent with auditory neuropathy. There was no history of ototoxic drug use. High-throughput sequencing identified the variant NC_012920.1:m.7471dup in the mitochondrial MT-TS1 gene as the pathogenic variant. Sanger sequencing results confirmed that the pathogenic gene mutation site perfectly co-segregated with the auditory neuropathy phenotype in this family. According to the classification criteria and guidelines for genetic variations by the American College of Medical Genetics and Genomics, the variant was classified as a pathogenic mutation. Conclusion:The mitochondrial MT-TS1 gene mutation m.7471dup is considered to be the pathogenic cause in this late-onset auditory neuropathy pedigree.

OBJECTIVE: To explore the neuroprotective effects of Xuefu Zhuyu Decoction (XFZYD) based on in vivo and metabolomics experiments. METHODS: Traumatic brain injury (TBI) was induced via a controlled cortical impact (CCI) method. Thirty rats were randomly divided into 3 groups (10 for each): sham, CCI and XFZYD groups (9 g/kg). The administration was performed by intragastric administration for 3 days. Neurological functions tests, histology staining, coagulation and haemorheology assays, and Western blot were examined. Untargeted metabolomics was employed to identify metabolites. The key metabolite was validated by enzyme-linked immunosorbent assay and immunofluorescence. RESULTS: XFZYD significantly alleviated neurological dysfunction in CCI model rats (P<0.01) but had no impact on coagulation function. As evidenced by Evans blue and IgG staining, XFZYD effectively prevented blood-brain barrier (BBB) disruption (P<0.05, P<0.01). Moreover, XFZYD not only increased the expression of collagen IV, occludin and zona occludens 1 but also decreased matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2), which protected BBB integrity (all P<0.05). Nine potential metabolites were identified, and all of them were reversed by XFZYD. Adenosine was the most significantly altered metabolite related to BBB repair. XFZYD significantly reduced the level of equilibrative nucleoside transporter 2 (ENT2) and increased adenosine (P<0.01), which may improve BBB integrity. CONCLUSIONS XFZYD ameliorates BBB disruption after TBI by decreasing the levels of MMP-9 and COX-2. Through further exploration via metabolomics, we found that XFZYD may exert a protective effect on BBB by regulating adenosine metabolism via ENT2.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Blood-Brain Barrier/metabolism* ; Brain Injuries, Traumatic/metabolism* ; Adenosine/metabolism* ; Male ; Rats, Sprague-Dawley ; Rats

Traditional Chinese medicine (TCM) exerts integrative effects on complex diseases owing to the characteristics of multiple components with multiple targets. However, the syndrome-based system of diagnosis and treatment in TCM can easily lead to bias because of varying medication preferences among physicians, which has been a major challenge in the global acceptance and application of TCM. Therefore, a standardized TCM prescription system needs to be explored to promote its clinical application. In this study, we first developed a gradient weighted disease-target-herbal ingredient-herb network to aid TCM formulation. We tested its efficacy against intracerebral hemorrhage (ICH). First, the top 100 ICH targets in the GeneCards database were screened according to their relevance scores. Then, SymMap and Traditional Chinese Medicine Systems Pharmacology (TCMSP) databases were applied to find out the target-related ingredients and ingredient-containing herbs, respectively. The relevance of the resulting ingredients and herbs to ICH was determined by adding the relevance scores of the corresponding targets. The top five ICH therapeutic herbs were combined to form a tailored TCM prescriptions. The absorbed components in the serum were detected. In a mouse model of ICH, the new prescription exerted multifaceted effects, including improved neurological function, as well as attenuated neuronal damage, cell apoptosis, vascular leakage, and neuroinflammation. These effects matched well with the core pathological changes in ICH. The multi-targets-directed gradient-weighting strategy presents a promising avenue for tailoring precise, multipronged, unbiased, and standardized TCM prescriptions for complex diseases. This study provides a paradigm for advanced achievements-driven modern innovation in TCM concepts.