This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

ObjectiveTo evaluate the efficacy and safety of traditional Chinese exercises (TCE) in patients with diabetic peripheral neuropathy (DPN) and to recommend best practices for using TCE to improve neurological function, glycemic control, and psychological well-being.MethodsNine databases were searched from the inception to October 2024. Effect relationships were assessed using meta-analysis with Stata 17, and the methodological quality and certainty of the evidence were evaluated using standard tools.ResultsTwelve studies comprising three study designs (nine randomized controlled, one quasi-experimental controlled, and two single-arm clinical trials), were identified. Compared with usual care, TCE improved various indicators and enhanced the nerve conduction velocities of the peroneal motor (mean difference [MD] = 3.86 m/s, 95% confidence interval [CI]: 0.38 to 7.34, P = .03), sural sensory (MD = 4.15 m/s, 95% CI: 0.68 to 7.63, P = .02), median motor (MD = 3.84 m/s, 95% CI: 2.14 to 5.54, P .001), and median sensory nerves (MD = 6.14 m/s, 95% CI: 4.54 to 7.74, P .001). TCE practices also reduced glycosylated hemoglobin level (MD = −0.59%, 95% CI: −0.91 to −0.27, P .001) and fasting blood glucose (standardized mean difference [SMD] = −1.08, 95% CI: −1.79 to −0.37, P .001). The overall quality of evidence was very low.ConclusionThe results indicate that TCE therapy improves certain outcomes in patients with DPN. Although the optimal type, intensity, frequency, and duration of TCE interventions are uncertain, these preliminary findings suggest that TCE should be further studied as a potentially affordable and effective treatment for DPN.

This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Nav1.7,Nay1.8,and Nay1.9 and Kv7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Nav1.7,Nav1.8,and Nav1.9 channels with a particularly low half maximal inhibitory concentration(ICs0)for Nay1.9 by promoting sodium channel inactivation,and also effectively increased Kv7.2/73,Kv7.2,and Kv7.5 channels,excluding Kv7.1 by promoting potassium channel acti-vation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alle-viated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe thera-peutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.

Objective To use color Doppler ultrasound to measure the hemodynamic indexes,and to es-tablish the diagnostic prediction model of inflammatory fetal distress.Methods A total of 213 pregnant women admitted to the obstetrics department of the First Affiliated Hospital of Air Force Military Medical U-niversity were collected as the research subjects and divided into the control group and case group according to whether or not fetal distress occurred,including 93 cases in the control group and 120 cases in the case group.The predictive value of PI,RI,S/D values of middle cerebral artery,umbilical artery and uterine artery for pre-dicting fetal distress was analyzed The diagnostic model was constructed by logistic regression analysis.The receiver operating characteristic(ROC)curve,calibration curve and clinical decision curve were adopted to an-alyze and evaluate the diagnostic efficiency of the model for adverse perinatal outcome and the clinical benefit of the patients.Results The univariate analysis results showed that MCA-PI,MCA-RI,MCA,S/D and CPR in the case group were lower than those in the control group,while UA-RI,UA,S/D and UtA-RI were higher than those in the control group.The multivariate regression analysis further showed that MCA-PI,MCA-RI and CPR were the independent protective factors for predicting fetal distress,while UA-R1 and UA-S/D served as the independent risk factors affecting the fetal outcome.Based on five independent influencing fac-tors,the risk prediction model was constructed,and the area under the receiver operating characteristic curve was 0.880(95％CI:0.834-0.925).The sensitivity,specificity and accuracy were 0.93,0.70 and 0.83 respec-tively,and the goodness of fit was good.Conclusion The hemodynamic indexes measured by color Doppler ul-trasound have good predictive value for the diagnosis of fetal distress.The risk prediction model established by the combined indexes has a certain reference value for the intervention in advance of pregnant women with fe-tal distress occurence.

Objective: To evaluate the effect of Tai Chi and Qigong on patients with lumbar disc herniation (LDH). Methods: Relevant data were retrieved from nine English and Chinese databases, including Cochrane Library, PubMed, and Wanfang Data, etc. from inception to June 2024. All published randomized controlled trials assessing the effect of Tai Chi and Qigong on visual analog scale (VAS), Japanese Orthopedic Association (JOA) score, and other health indicators in participants with LDH compared to usual medical care or other treatments were included. Grey literature, trials involving the pushing of hands (Tui Shou) or Tai Chi with weapons, and trials with co-interventions (Tai Chi/Qigong plus another treatment) were excluded. Methodological quality was analyzed using the Cochrane risk of bias tool, and evidence quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Results: Fourteen trials (954 patients) were included in this study. Tai Chi and Qigong were associated with lower VAS pain scores (standardized mean difference −0.55, 95% confidence interval [CI] −0.95 to −0.15, P = .01), higher JOA scores (mean difference [MD] 4.40, 95% CI 2.62 to 6.18, P < .001) and straight leg raise test results (MD 9.40°, 95% CI 7.64 to 11.15, P < .001) in patients with LDH. Furthermore, compared with usual care, Tai Chi and Qigong showed enhanced effects on pain and JOA scores. When compared to other exercises or massage, the effect on pain scores was similar but that on JOA scores was significant. Conclusions Tai Chi and Qigong may have favorable effects on VAS pain and JOA scores compared with usual care, and on JOA scores compared with other exercises or massage in patients with LDH. Given the overall poor quality of the evidence, the results of current study should be interpreted cautiously.

Objective:To evaluate the predictive value of angiopoietin-2 (Ang-2) for the prognosis in patients with acute respiratory distress syndrome (ARDS).Methods:A retrospective study was conducted, and ARDS patients admitted to the department of emergency medicine of Tongde Hospital of Zhejiang Province from December 2020 to September 2022 were enrolled. General information including gender, age, causes of ARDS, disease severity scores, plasma Ang-2 levels before treatment and at 24, 48, and 72 hours after treatment, and record the 60-day prognosis were collected. Differences in clinical data between groups were compared. Multivariate Logistic regression analysis was used to identify the independent risk factors affecting the 60-day prognosis of ARDS patients, and the receiver operator characteristic curve (ROC curve) was plotted to assess the predictive value of these risk factors for patient outcomes. Pearson correlation analysis was used to assess the correlation between Ang-2 and pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI).Results:A total of 132 ARDS patients were included, of which 49 patients died within 60 days and 83 patients survived. In the death group, plasma Ang-2 levels showed a gradually increasing trend, all significantly higher than before treatment (μg/L: 12.75±1.81, 12.74±1.48, 13.45±2.21 vs. 5.98±0.57, all P < 0.05), while the trend in the survival group was not significant. At 24, 48, and 72 hours after treatment, plasma Ang-2 levels in the death group were significantly higher than those in the survival group (μg/L: 12.75±1.81 vs. 7.48±1.22, 12.74±1.48 vs. 7.41±1.19, 13.45±1.41 vs. 6.88±1.41, all P < 0.05). After adjusting for confounding variables, increased plasma Ang-2 level was an independent risk factor for prognosis in ARDS patients within 60 days [odds ratio ( OR) = 0.998, 95% confidence interval (95% CI) was 0.997-0.999, P < 0.01]. ROC curve analysis demonstrated that Ang-2 levels had predictive value for prognosis in ARDS patients [area under the ROC curve (AUC) = 0.985, 95% CI was 0.971-1.000, approximate maximum Youden's index 0.867, optimal cut-off value 8.43 μg/L]. Pearson correlation analysis showed that plasma Ang-2 levels were positively correlated with PVPI and EVLWI ( r values were 0.620 and 0.712 respectively, both P < 0.01). Conclusions:Elevated level of Ang-2 is an independent risk factor for increased mortality in patients with ARDS. Higher Ang-2 levels within 72 hours after treatment may indicate poorer prognosis.

Objective:To evaluate the effects of different exercises on executive function, moter skills and core symptoms in children with attention deficit hyperactivity disorder (ADHD) using network Meta-analysis, and to provide evidence-based basis for the treatment of children with ADHD.Methods:The randomized controlled trails(RCTs)of exercises on children with ADHD were searched in Web of Science, PubMed, Cochrane Library, Embase, PsycINFO, CNKI, Wanfang Data, VIP and CBM databases.The retrieval time limit was from the establishment of each database to May 2023.The Cochrane quality review manual was used to evaluate the quality of the included literatures.Stata 17.0 software was used to perform network Meta-analysis.Results:Finally, twenty-four studies were enrolled including five types of exercise intervention, such as aerobic exercise, multicomponent exercise, exergaming, high intensity interval training (HIIT) and traditional low-to-moderate intensity exercise therapy (TRAD).The results of network Meta-analysis showed that: in terms of improving executive function(working memory, inhibitory control, and cognitive flexibility), motor skills and core symptoms of children with ADHD, the optimal exercise intervention was aerobic exercises (surface under the cumulative ranking were 78.9%, 73.0%, 88.7%, 77.9% and 69.9% respectively).Conclusion:Exercises can improve executive function, improve motor skills, and alleviate ADHD core symptoms.Aerobic exercise has a better effect on improving executive function, motor skills and core symptoms of ADHD children.

OBJECTIVE: To carry out carrier screening for Spinal muscular atrophy (SMA) in reproductive-aged individuals from Dongguan region and determine the carrier frequency of SMN1 gene mutations. METHODS: Reproductive-aged individuals who underwent SMN1 genetic screening at the Dongguan Maternal and Child Health Care Hospital from March 2020 to August 2022 were selected as the study subjects. Deletions of exon 7 and 8 (E7/E8) of the SMN1 gene were detected by real-time fluorescence quantitative PCR (qPCR), and prenatal diagnosis was provided for carrier couples by multiple ligation-dependent probe amplification (MLPA). RESULTS: Among the 35 145 subjects, 635 were found to be carriers of SMN1 E7 deletion (586 with heterozygous E7/E8 deletion, 2 with heterozygous E7 deletion and homozygous E8 deletion, and 47 with sole heterozygous E7 deletion). The carrier frequency was 1.81% (635/35 145), with 1.59% (29/1 821) in males and 1.82% (606/33 324) in females. There was no significant difference between the two genders (χ² = 0.497, P = 0.481). A 29-year-old woman was found to harbor homozygous deletion of SMN1 E7/E8, and was verified to have a SMN1∶SMN2 ratio of [0∶4], none of her three family members with a [0∶4] genotype had clinical symptoms. Eleven carrier couples had accepted prenatal diagnosis, and one fetus was found to have a [0∶4] genotype, and the pregnancy was terminated. CONCLUSION This study has determined the SMA carrier frequency in Dongguan region for the first time and provided prenatal diagnosis for carrier couples. The data can provide a reference for genetic counseling and prenatal diagnosis, which has important clinical implications for the prevention and control of birth defects associated with SMA.
Humans ; Child ; Pregnancy ; Male ; Female ; Adult ; Homozygote ; Sequence Deletion ; Prenatal Diagnosis ; Genetic Testing ; Muscular Atrophy, Spinal/genetics* ; Survival of Motor Neuron 1 Protein/genetics* ; Genetic Carrier Screening

Objective:To evaluate the efficacy of first-line tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors (ICI) in metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC).Methods:The data of 87 metastatic FH-deficient RCC patients from West China Hospital ( n=44), Renji Hospital ( n=27) and Sun Yat-sen University Cancer Center (n=16) from Mar 2019 to Aug 2022 were retrospectively analyzed. The median age was 37(30, 47) years, the male to female ratio was 1.9∶1. The median size of tumor was 7.5(5.0, 10.0) cm. Sixty-one patients (70.1%) had germline FH mutations, and 26 patients (29.9%) had somatic FH mutations. Forty-nine patients (56.3%) metastasis disease at initial diagnosis, and 38 patients (43.7%) had metachronous metastasis. The most common site of metastasis was lymph node (41/87, 47.1%), followed by bone (33/87, 37.9%), liver (22/87, 25.3%), and lung (14/87, 16.1%). Fifteen patients (17.2%) had weak expression of FH protein and 59 patients (67.8%) had positive PD-L1 expression. The most common treatments were sintilimab plus axitinib (52/87, 59.8%), followed by pembrolizumab plus cabozantinib (7/87, 8.0%), tirelizumab plus axitinib (6/87, 6.9%), pembrolizumab plus axitinib (5/87, 5.7%), and toripalimab plus axitinib (4/87, 4.6%). Thirteen patients (13/87, 14.9%) received other ICI plus TKI combination treatments. Statistical analysis was conducted using R 4.2.3 software. Kaplan Meier survival curve was used to evaluate survival data, and log-rank test was used to compare differences between treatment groups. Results:The overall objective response rate (ORR) and disease control rate (DCR) of first-line TKI + ICI were 39.1% and 89.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 16.5 months and 71.0 months, respectively. For first-line sintilimab plus axitinib, the ORR and DCR were 44.2% and 92.3%, respectively. The median PFS was 17.3 months and the median OS was not reached for this combination treatment. The efficacy of first-line tirelizumab plus axitinib was inferior to other treatment strategies (median PFS: 4.0 vs. 16.6 months, P<0.001; median OS: 22.0 vs. 71.0 months, P=0.043). Subgroup analyses further showed that the efficacy of ICI+ TKI combination therapy was consistent in patients with different clinicopathologic and genomic features. However, patients with liver metastasis had shorter OS than those without liver metastasis (median OS: 26.3 vs. 71.0 months, P=0.021). Conclusion:First-line TKI + ICI is effective for metastatic FH-deficient RCC and can significantly prolong the survival of the patients.

Objective:Central nervous system leukemia(CNSL)is one of the main causes of recurrence and death in patients with acute leukemia.This study aims to dynamically monitor minimal residual disease(MRD)in cerebrospinal fluid and bone marrow of patients with different types of acute leukemia by flow cytometry(FCM),and to compare the timeliness and consistency of MRD detection between the 2 methods to further explore the application value of monitoring MRD in cerebrospinal fluid. Methods:A total of 199 patients with acute leukemia admitted to the Guangdong Provincial people's Hospital between October 2018 and January 2022 were retrospectively analyzed,and multiparametric FCM method was adopted to summarize and analyze MRD in cerebrospinal fluid of patients with different types of leukemia and MRD in cerebrospinal fluid and bone marrow specimens of the same patients,and its role in assessing the prognostic value of patients was discussed. Results:Among the 199 acute leukemia cases,a total of 31 cases(15.58%)were positive MRD in the cerebrospinal fluid,of which 18 cases(58%)were detected earlier than the corresponding bone marrow specimens.Among the 19 patients with acute T lymphoblastic leukemia,134 patients with acute B lymphoblastic leukemia,and 46 patients with acute myeloid leukemia counted,there were 4,18,and 9 patients with positive MRD in the cerebrospinal fluid.The Kappa value of the concordance test between the results of cerebrospinal fluid MRD and bone marrow MRD in different types of acute leukemia was only 0.156,demonstrating a low concordance between them. Conclusion:Dynamic monitoring of cerebrospinal fluid MRD by FCM can be used as a monitoring index for central nervous system leukemia,and monitoring cerebrospinal fluid can detect MRD earlier compared with bone marrow,which complements each other as a sensitive index for evaluating prognosis with significant guidance in clinic.