This study investigates the neuroprotective potential of extracellular vesicles (EVs) delivering quercetin-3-O-β-d-glucuronic acid (QG-EVs) in cerebral ischemia-reperfusion injury (CIRI). Targeted brain delivery of QG-EVs was confirmed, with neuron cells identified as pivotal in modulating CIRI through single-cell RNA sequencing (scRNA-seq). Activating transcription factor 4 (Atf4) was highlighted as a critical regulatory factor, and in vitro studies revealed that silencing Atf4 diminished the neuroprotective effects of QG-EVs, increasing oxidative stress levels and neuronal apoptosis. In a CIRI mouse model, the knockdown of Atf4 attenuated the protective outcomes provided by QG-EVs, further affirming the role of Atf4 in mediating neuroprotection. Behavioral assessments and protein analysis showed that QG-EVs significantly reduced neuronal damage and pro-apoptotic markers, while improving neurological function via Atf4 upregulation. The outcomes hint at the potential of QG-EVs as a beneficial therapeutic modality to mitigate neuronal damage in CIRI by enhancing Atf4 expression, highlighting its potential for improving ischemic stroke outcomes.

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected with Hypertrophic cardiomyopathy (HCM) due to a truncating variant of ALPK3 gene. METHODS: A 44-year-old male admitted to Taizhou Hospital of Zhejiang Province on December 29, 2018 was selected as the study subject. Whole-exome sequencing (WES) was carried out, and candidate variant was interpreted by following the guidelines from the American College of Medical Genetics and Genomics (ACMG). For ALPK3 was considered an autosomal recessive gene, the WES results was considered insufficient to explain his phenotype. In April 2023, the proband's WES data were re-analyzed using updated annotation pipelines, and peripheral blood samples were collected from his first-degree relatives (mother and brother) for Sanger sequencing validation. Conservation analysis and protein structural modeling were performed to assess the impact of the variant. Clinical evaluation and genetic counseling were provided to the proband's family members. Relevant literature on ALPK3tv-induced HCM patients were searched in Wanfang Data Knowledge Service Platform, CNKI, and PubMed database using "ALPK3" and "hypertrophic cardiomyopathy" as keywords. Clinical characteristics of HCM patients with heterozygous ALPK3tv variants were summarized and compared with the clinical characteristics of HCM patients with positive sarcomere-associated gene variants (SARC+). This study was approved by the Medical Ethics Committee of Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University (Ethics No.: K20230314). RESULTS: The proband was a 44-year-old male who was transferred to our institution on December 29, 2018 due to "chest tightness and pain for 6 months, exacerbated for 2 days". Emergency coronary angiography was performed, which led to a preliminary diagnosis of "acute coronary syndrome", and the patient was admitted to the Cardiology Department for treatment. Based on electrocardiogram and echocardiogram findings, the diagnosis was revised as HCM. The patient's condition has stabilized post-coronary angiography, and he was discharged with improved condition. On January 2019, WES was conducted to determine the etiology of the proband's HCM. WES results identified a novel heterozygous c.2156dupC (p.Pro720ThrfsTer53) truncating variant in the ALPK3 gene. At that time, the inheritance pattern could not explain the phenotype. In 2022, a literature indicated that heterozygous ALPK3tv could lead to autosomal dominant HCM. Consequently, in April 2023, the proband's whole-exome data were re-annotated, revealing changes in the transcript and protein versions, with the updated site annotated as ALPK3 (NM_020778.5): c.1550dupC (p.Pro518ThrfsTer53). Sanger sequencing confirmed that the proband's mother and brother also carried this variant. The mother exhibited obstructive HCM, while the brother showed no related phenotype. Bioinformatics analysis demonstrated conservation of this site across multiple species, and the variant has resulted in the loss of a protein domain. Based on ACMG guidelines, the variant was classified as likely pathogenic. Literature review and Bayesian calculation further elevated the pathogenicity rating, indicating that this variant was the cause of HCM in the patient. Literature study revealed distinctions between HCM caused by this variant type and SARC+ HCM. The age of onset among heterozygous ALPK3tv patients was delayed by approximately 10 years compared to SARC+ patients. Both forms of HCM exhibited a male predominance, which was particularly marked in individuals with ALPK3tv. Electrocardiographic left ventricular hypertrophy was more prevalent in heterozygous ALPK3tv patients than in SARC+ patients. The incidence of apical or concentric hypertrophy patterns was higher in heterozygous ALPK3tv patients compared to asymmetric septal hypertrophy, which predominated in SARC+ patients. ALPK3tv patients exhibited lower penetrance and later onset compared to SARC+ patients. A positive correlation between left ventricular wall thickness and age was noted in female patients only. CONCLUSION In this pedigree, the proband has presented with HCM, characterized by echocardiographic evidence of apical left ventricular hypertrophy without significant outflow tract obstruction or extracardiac phenotypes. Although his mother and brother had carried the same heterozygous ALPK3 (NM_020778.5) c.1550dupC (p.Pro518ThrfsTer53), the mother exhibited severe obstructive HCM, while the brother was asymptomatic, suggesting incomplete or age-dependent penetrance within the family. This study has enriched the evidence for the pathogenicity of ALPK3tv among Chinese HCM pedigrees and underscored the importance of periodic literature reviews and genetic re-analysis for unresolved genetic testing results.
Humans ; Male ; Pedigree ; Adult ; Cardiomyopathy, Hypertrophic/genetics* ; Heterozygote ; Asian People/genetics* ; Exome Sequencing ; Mutation ; China ; Female ; East Asian People

Objective:To analyze the changing trend of incidence and prevalence of pneumoconiosis globally, and provide scientific basis for the formulation of health policy.Methods:In June 2022, through the Global Health Data exchange (GHDx) query tool (http: //ghdx.healthdata.org/gbd-results-tool) , the pneumoconiosis incidence and prevalence data was downloaded and organized. Estimated annual percentage change (EAPC) and age-standardized rate (ASR) were used to estimate the trends of pneumoconiosis from 1990 to 2019. EAPC was estimated by linear regression model based on ASR.Results:The overall ASR of the incidence and prevalence of pneumoconiosis decreased from 1990 to 2019, and their EAPCs were-0.85% (95% CI: -1.11%--0.60%) and -0.78% (95% CI: -1.08%--0.49%) . Over the past 30 years, the incidence and prevalence of pneumoconiosis in all SDI areas showed decreasing trends, especially in high SDI areas, their EAPCs were -1.46% (95% CI: -1.76%--1.15%) and -1.99% (95% CI: -2.44%--1.53%) . 110 countries/areas showed increasing trends in age standardized incidence rate (ASIR) , with Iran and Georgia showing the most pronounced upward trend, their EAPCs were 5.32% (95% CI: 4.43%-6.22%) and 4.39% (95% CI: 3.81%-4.97%) . 125 countries/areas showed anincreasing trends in prevalence ASR, with Iran had the fastest rise in prevalence (EAPC=6.40%, 95% CI: 5.33%-7.49%) . Conclusion:Although decreasing trends in the burden of pneumoconiosis are observed globally from 1990 to 2019, but the burden of pneumoconiosis in low-and middle-income countries or regions are still heavy. We need more effective strategies to prevent and reduce the burden of pneumoconiosis.

Objective:To analyze the disease burden of Noise-Induced Hearing Loss (NIHL) in China from 1990 to 2019, forecast the disease burden of NIHL from 2020 to 2030, and provide data support for the prevention and control of NIHL.Methods:In July 2022, the disease burden data of NIHL in different age groups and genders in China during 1990-2019 were selected from the GBD database. The Jointpoint regression model was established to analyze the trend of the disease burden of NIHL in China. An age-period-cohort model was constructed to analyze the changing trend of NIHL in terms of age, period, and cohort, and a Bayesian age-period-cohort model was developed to predict the disease burden of NIHL in China from 2020 to 2030.Results:From 1990 to 2019, the disability adjusted life year (DALY) of China's NIHL increased from 1361600 to 2327700 years. The coarse rate of DALY increased from 115.03/100000 to 163.65/100000 (AAPC=1.23, P<0.001), and the normalization rate of DALY decreased from 127.67/100000 to 119.83/100000 (AAPC=-0.21, P<0.001). It is predicted that from 2020 to 2030, the DALYs of China's NIHL will increase from 2412900 in 2020 to 2655000 in 2030, and the DALY normalization rate will decrease from 241.29/100000 in 2020 to 125.71/100000 in 2030. Conclusion:The burden of noise-induced hearing loss (NIHL) in China is significant and should not be overlooked. To reduce this burden, we need to focus on strengthening source management, process control, personal protection, and comprehensive prevention and treatment through various methods.

Objective To investigate the impact of anti-reflux modified duodenal exclusion surgery on glucose metabolism in rats with type 2 diabetes mellitus (T2DM), and to elucidate the role of the duodenum in maintaining glucose homeostasis. MethodsForty male Sprague-Dawley rats aged 5 weeks were fed a high-fat diet and induced with T2DM using low-dose streptozotocin. Thirty-six rats that met the T2DM model criteria were randomly divided into three groups: the simple duodenal exclusion surgery group (DE group), the anti-reflux modified duodenal exclusion group (MDE group), and the sham operation group (SO group), with 12 rats in each group. Gastroenterography was performed 4 weeks after surgery, and the body weight, fasting blood glucose levels, and serum glucagon-like peptide-1 (GLP-1) concentrations were measured before surgery and at 1, 2, 4, and 8 weeks post-surgery. Eight weeks post-surgery, the rats were euthanized, and a 1 cm segment of the biliopancreatic loop was collected from each group for pathological sectioning and HE staining to observe the intestinal mucosal villus length under an optical microscope. Results Gastroenterography showed that there was significant reflux of the contrast agent into the duodenal lumen in the DE group, while no reflux was observed in the MDE group. At one week post-surgery, the body weights of rats in all three groups significantly decreased compared to before surgery (P<0.05), and then the body weights of all groups increased over time, with no significant differences between the groups (P>0.05). Compared with the SO group, the fasting blood glucose levels in the MDE and DE groups significantly decreased at all time points post-surgery (P<0.05), while GLP-1 concentrations significantly increased (P<0.05). The fasting blood glucose levels in the MDE group were lower than those in the DE group at all time points post-surgery (P<0.05), but there were no significant differences in serum GLP-1 concentrations between the MDE and DE groups (P>0.05). Regarding intestinal mucosal morphology, the villus lengths of the biliopancreatic loops in the MDE group were significantly shorter than those in the DE and SO groups (P<0.05). Conclusion Anti-reflux modified duodenal exclusion surgery effectively improves glucose metabolism in T2DM rats by preventing the reflux of chyme into the diverted duodenum, thereby enhancing its hypoglycemic effect.

Objective To establish the theories and methods for the compatibility of Chinese patent medicines in pre-scription review.Methods Based on the prescription combination theory and the classics literatures of traditional Chinese med-icine,the methods of prescription suitability review for the compatibility of Chinese patent medicines were discussed.Results Based on the examples of the compatibility of Chinese patent medicines,five basic principles of combined Chinese patent medi-cines and the key points for reviewing the combined Chinese patent medicines dosage form were discussed in detail.Conclusion The methods for the compatibility of Chinese patent medicines prescription review have been established,which can provide a theoretical reference for the review of combined Chinese patent medicines prescriptions.

Objective To observe the value of drug-eluting bead TACE(D-TACE)combined with apatinib and camrelizumab for treating massive hepatocellular carcinoma(HCC).Methods Data of 35 patients with massive HCC who underwent D-TACE sequential apatinib and camrelizumab were retrospectively analyzed.The overall survival(OS)and progression free survival(PFS)were recorded,and the objective response rate(ORR),disease control rate(DCR)and treatment-related adverse event(TRAE)were evaluated.Results Combination treatment were all successfully performed in all 35 cases.At the last follow-up,the median PFS was 8.09 months,and the median OS was 20.00 months.One,3,6,and 12 months after treatments,ORR was 65.71%(23/35),71.43%(25/35),65.71%(23/35)and 60.71%(17/28),respectively,DCR was 94.29%(33/35),88.57%(31/35),80.00%(28/35)and 67.86%(19/28),respectively.TRAE of combination treatment mainly ranged from grade 1 to 2,and all relieved after symptomatic treatments.Conclusion D-TACE combined with apatinib and camrelizumab was effective and safe for treating massive HCC,with controllable adverse reactions.

Tumor cells use glycolysis to provide material and energy under hypoxic conditions to meet the energy requirements for rapid growth and proliferation， namely the Warburg effect. Even under aerobic conditions， tumor cells mainly rely on glycolysis to provide energy. Therefore， glucose transporter protein 1（GLUT1）， which is involved in the process of glucose metabolism， plays an important role in tumorigenesis， development and drug resistance， and is considered to be one of the important targets in the treatment of malignant tumors. In recent years， research on tumor glucose metabolism has gradually become a hot spot. It has been shown that various factors are involved in the regulation of tumor energy metabolism， among which the role of GLUT1 is the most critical. In this paper， the authors reviewed the latest research progress of GLUT1-targeted traditional Chinese medicine（TCM） active ingredient nano-delivery system in tumor therapy， aiming to reveal the feasibility and effectiveness of this system in the delivery of chemotherapeutic drugs. The GLUT1-targeted TCM active ingredient nano-delivery system can overcome the bottleneck of the traditional targeting strategy as well as the high-permeability long retention（EPR） effect. In summary， the authors believe that the GLUT1-targeted TCM active ingredient nano-delivery system provides a new strategy for targeted treatment of tumors and has a broad application prospect in tumor prevention and treatment.

Clinical trials are an important method for evaluating the safety and efficacy of in vitro diagnostic reagents, and are a key basis for product registration review and approval. In order to strengthen the management of clinical trials of in vitro diagnostic reagents, the National Medical Products Administration and relevant departments have formulated a series of regulations at the regulatory level, and require applicants and clinical trial institutions to establish a quality management system for clinical trials of in vitro diagnostic reagents. Medical laboratory is the main department and implementer of in vitro diagnostic reagent clinical trials in medical institutions. In recent years, with the rapid development of the in vitro diagnostic industry, the clinical trial projects of in vitro diagnostic reagents conducted by medical laboratory have been increasing day by day. However, there are currently few discussions on the clinical trial of in vitro diagnostic reagents from the perspective of researchers. Therefore, this article summarizes the characteristics of clinical trials of in vitro diagnostic reagents, analyzes the problems and difficulties in conducting clinical trials of in vitro diagnostic reagents in current medical laboratories, and introduces the laboratory′s experience in management; to provide reference for medical testing laboratories that have not yet conducted or have already conducted clinical trials of in vitro diagnostic reagents, in order to improve the quality and efficiency of clinical trials.

Clinical trials are an important method for evaluating the safety and efficacy of in vitro diagnostic reagents, and are a key basis for product registration review and approval. In order to strengthen the management of clinical trials of in vitro diagnostic reagents, the National Medical Products Administration and relevant departments have formulated a series of regulations at the regulatory level, and require applicants and clinical trial institutions to establish a quality management system for clinical trials of in vitro diagnostic reagents. Medical laboratory is the main department and implementer of in vitro diagnostic reagent clinical trials in medical institutions. In recent years, with the rapid development of the in vitro diagnostic industry, the clinical trial projects of in vitro diagnostic reagents conducted by medical laboratory have been increasing day by day. However, there are currently few discussions on the clinical trial of in vitro diagnostic reagents from the perspective of researchers. Therefore, this article summarizes the characteristics of clinical trials of in vitro diagnostic reagents, analyzes the problems and difficulties in conducting clinical trials of in vitro diagnostic reagents in current medical laboratories, and introduces the laboratory′s experience in management; to provide reference for medical testing laboratories that have not yet conducted or have already conducted clinical trials of in vitro diagnostic reagents, in order to improve the quality and efficiency of clinical trials.