OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

ObjectiveThe exacerbating trend of global population aging poses profound socioeconomic and public health challenges, making the comprehensive elucidation of biological aging mechanisms and the discovery of effective anti-aging interventions an urgent priority in the life sciences. Based on our previous serum metabolomics findings that dimethylglycine, an intermediate metabolite of amino acid metabolism naturally present in the human body, was significantly enriched in the serum of longevity families, this study aimed to systematically investigate the anti-aging effects of dimethylglycine both in living organisms and in controlled laboratory environments, and to preliminarily elucidate its underlying molecular mechanisms. While existing literature indicates that dimethylglycine possesses antioxidant and immunomodulatory properties, its direct anti-aging efficacy and the specific molecular pathways through which it operates remain largely unexplored. MethodsTo comprehensively evaluate the anti-aging properties of dimethylglycine, we utilized replicative senescent human embryonic lung fibroblasts, specifically the WI-38 cell line, as an experimental model in a controlled laboratory environment. Cell viability and safety were thoroughly assessed using Cell Counting Kit-8 and lactate dehydrogenase release assays across various concentrations of dimethylglycine. The impact of dimethylglycine on cellular senescence phenotypes, oxidative stress, and proliferative capacity was evaluated via senescence-associated beta-galactosidase staining, reactive oxygen species fluorescence detection, and 5-ethynyl-2'-deoxyuridine incorporation assays. Furthermore, the molecular alterations of senescence-associated secretory phenotype factors and core senescence signaling pathways were quantified using quantitative reverse transcription polymerase chain reaction for the messenger RNA levels of interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1, and enzyme-linked immunosorbent assay for the measurement of p16 and p21 protein expression levels. For the living organism model, the wild-type nematode Caenorhabditis elegans was used to evaluate systemic physiological effects. We conducted a comprehensive lifespan analysis at 20°C, heat stress resistance survival assays at 35℃, senescence-associated beta-galactosidase staining, lipofuscin accumulation tracking, intracellular reactive oxygen species measurement, and Oil Red O staining to ascertain systemic lipid accumulation. Additionally, network pharmacology bioinformatics tools, including PharmMapper and STRING databases, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were utilized to predict target pathways, alongside highly detailed molecular docking simulations utilizing SwissDock and Protein-Ligand Interaction Profiler to examine interactions with the cytochrome P450 family 2 subfamily C member 9 protein. ResultsThe experimental outcomes robustly demonstrate the potent anti-aging capabilities of dimethylglycine. At the cellular level, toxicity analyses firmly confirmed that dimethylglycine is highly safe; continuous treatment with 50 mol/L and 70 mol/L of dimethylglycine for 5 d did not induce any cellular membrane damage or cytotoxicity, but rather actively promoted cellular proliferation. Utilizing the optimal standardized concentration of 50 mol/L, dimethylglycine treatment significantly ameliorated senescent phenotypic markers in human embryonic lung fibroblasts, which was evidenced by a drastic and highly significant reduction in the senescence-associated beta-galactosidase positive cell percentage (P<0.000 1) and intracellular reactive oxygen species levels (P<0.000 1), alongside a marked increase in the 5-ethynyl-2'-deoxyuridine-positive proliferation rate (P=0.003 5). On a molecular expression scale, dimethylglycine significantly downregulated the messenger RNA expression of multiple core senescence-associated secretory phenotype inflammatory factors, including interleukin-6, interleukin-8, p21, and matrix metalloproteinase-1. Concurrently, it effectively suppressed the protein expression of critical cell cycle arrest markers, diminishing p16 protein levels by 57.3% (P=0.000 4) and p21 protein levels by 27.2% (P=0.000 7). In the nematode Caenorhabditis elegans animal model, dimethylglycine significantly extended the mean lifespan from 20.402 d to an impressive 23.066 d (P<0.000 1) and notably enhanced overall survival rates under severe heat stress environmental conditions (P=0.017). Furthermore, systemic dimethylglycine intervention significantly mitigated age-related physiological decline by decreasing bodily lipofuscin accumulation (P<0.000 1), significantly reducing senescence-associated beta-galactosidase activity, lowering systemic reactive oxygen species fluorescence (P=0.008), and effectively alleviating overall fat accumulation (P<0.000 1). Mechanistically, extensive network pharmacology and Kyoto Encyclopedia of Genes and Genomes analyses strongly revealed that the potential targets of dimethylglycine are significantly enriched in fundamental drug metabolism and oxidative stress response pathways. Precision molecular docking simulations conclusively demonstrated that dimethylglycine forms highly stable structural interactions with the cytochrome P450 family 2 subfamily C member 9 protein, specifically highlighting the definitive formation of 5 stable hydrogen bonds involving serine 365, leucine 366, and serine 429 residues, as well as two critical salt bridge formations with arginine 97 and histidine 368 residues. It is additionally predicted to interact favorably with glutathione S-transferase family proteins. ConclusionDimethylglycine exhibits a profoundly significant and multifaceted anti-aging activity at both the cellular and entire living animal levels. By powerfully alleviating oxidative stress, heavily suppressing the core p16 and p21-dependent cellular senescence signaling pathways, and substantially mitigating the detrimental senescence-associated secretory phenotype, dimethylglycine effectively delays fundamental cellular senescence processes and drastically extends whole-organism lifespan. The biological mechanisms driving these robust protective effects are highly likely closely associated with its direct stable interactions with crucial metabolic and detoxifying enzyme systems, such as cytochrome P450 family 2 subfamily C member 9 and glutathione S-transferase family proteins, thereby systemically improving metabolic dysregulation and restoring critical redox homeostasis. This comprehensive study provides highly solid experimental evidence supporting dimethylglycine as a highly potent and safe potential anti-aging intervention agent, while simultaneously offering a clear molecular mechanistic explanation for the previously documented high abundance of dimethylglycine observed within exceptionally long-lived human populations.

Objective: To explore the impact of different blood donation scenarios on population characteristics and blood donation behaviors, and to provide a basis for precise blood donation recruitment. Methods: Eligible voluntary blood donors with complete records from four scenarios in Xi'an: medical institutions, cultural tourism SITES, commercial superstores, and blood centers. After a preliminary analysis of overall donor characteristics across the four scenarios, three core subgroups were defined based on scenarios and donor population differences: the medical subgroup (aged 30-39 years), the blood center subgroup (aged 30-39 years), and the cultural tourism and commercial superstore subgroup (aged 18-29 years). Baseline characteristics, blood donation behaviors, and blood test results were compared among the subgroups. Results: The blood donors in all four scenarios were mainly male, but the proportion of female donors in the medical scenario was the highest (26.4%, 8 878/33 634). In terms of age distribution, the cultural tourism and commercial superstore scenarios were dominated by donors aged 18-29, while the blood center and medical scenarios were dominated by those aged 30-39, with the highest proportion of donors over 40 in the medical scenario. The occupational and educational composition of blood donors in the blood center scenario spanned a wide range, exhibiting a clear bipolar distribution. Significant differences were observed in baseline characteristics, blood donation behaviors, and blood test results among the three core subgroups (P<0.001). The medical subgroup was mainly composed of enterprise/industrial workers and married individuals, with high proportions of first-time blood donors, and the highest unqualified rate of infectious indicators (2.0%, 274/13 509). The cultural tourism and commercial superstore subgroup was mainly unmarried and students, featured high proportions of large-volume donations and evening donations, and had a relatively high unqualified rate for ALT (0.4%, 130/31 443). The blood center subgroup had a complex population structure, a high proportion of repeat blood donors (45.3%, 6449/14 225), and moderate results in all test indicators. Conclusion: There is an inherent correlation between the attributes of blood donation scenarios, population characteristics, and blood donation behaviors. The differences among the three core subgroups provide a clear basis for precise scenario operation. By constructing transformation channels between different scenarios and optimizing scenario-specific strategies, the structure of blood donors can be improved, thereby supporting the sustainable development of voluntary blood donation.

Objective To explore the number of peripheral blood regulatory T cells (Treg) in patients with chronic kidney disease (CKD) and its correlation with vascular calcification. Methods This was a single-center, cross-sectional, and observational study. Non-dialysis patients with CKD treated at Zhongshan Hospital, Fudan University from March 2021 to March 2022 were enrolled. Abdominal aortic calcification (AAC) was assessed using lateral abdominal X-ray. Number of Treg and cytokine levels were measured by flow cytometry. Logistic regression analysis was performed to evaluate the related factors for AAC in CKD patients. Results A total of 83 patients were included, aged 17–86 years, with 57 males (68.7%). The distribution of CKD stages was as follows: stage G1 in 7 patients (8.4%), stage G2 in 17 patients (20.5%), stage G3 in 21 patients (25.3%), stage G4 in 19 patients (22.9%), and stage G5 in 19 patients (22.9%). No AAC was observed in patients with stages G1 and G2, while the prevalence of AAC in patients with stages G3, G4, and G5 was 23.8%, 21.1%, and 26.3%, respectively. Compared with stage G1 patients, those with stages G3–5 showed decreased number of peripheral blood Treg and elevated levels of interleukin (IL)-6 and IL-17F (P＜0.05). The area under the receiver operating characteristic curve for number of peripheral blood Treg in predicting AAC in CKD patients was 0.766 (95%CI 0.652–0.879, P＝0.002). Logistic regression analysis showed that decreased number of Treg was related factor for AAC in CKD patients (OR＝0.957, 95%CI 0.922–0.992, P＝0.018). Conclusion As CKD progresses, number of peripheral blood Treg significantly decreases, which is correlated with AAC in CKD patients.

OBJECTIVE To evaluate the cost-effectiveness of cefiderocol versus best available therapy （BAT） or standard-of- care （SOC） for the treatment of confirmed or suspected carbapenem-resistant Gram-negative bacterial （CRGNB） serious infections from the perspective of the Chinese healthcare system， and to explore its reasonable pricing. METHODS A decision tree model was constructed based on data from two phase Ⅲ clinical trials （CREDIBLE-CR and GAME CHANGER） to simulate the cost- effectiveness of cefiderocol in two scenarios： salvage therapy for confirmed CRGNB infection （scenario 1） and empirical therapy for suspected CRGNB infection （scenario 2）. The primary outcome measure was the incremental cost-effectiveness ratio （ICER）. The willingness-to-pay （WTP） was set at 1 to 3 times China’s per capita GDP in 2024. To verify the robustness of the results， one- way and probabilistic sensitivity analyses were conducted， and based on these， a reasonable price range for cefiderocol in the Chinese market was explored. RESULTS The results for scenario 1 showed that the clinical cure rate in the cefiderocol group was higher than that in the BAT group （47.50% vs. 34.21%）， but its ICER was 415 065.03 yuan per cured case， exceeding three times China’s GDP per capita. Scenario 2 revealed that the ICER for cefiderocol relative to SOC was as high as 1 362 446.16 yuan per cured case， far exceeding the WTP. Sensitivity analysis indicated that the treatment duration and price of cefiderocol were key factors affecting its cost-effectiveness. In the two scenarios described above， the unit price of cefiderocol must fall below 683.47 and 242.00 yuan/g， respectively， to be considered cost-effective. CONCLUSIONS Based on the current market price， cefiderocol lacks sufficient cost-effectiveness for treating confirmed or suspected CRGNB serious infections within China’s healthcare system. To improve its accessibility， price negotiations or a tiered medical insurance payment strategy are required.

Objective A Social Care Needs Assessment Tool for Terminal Patients at Home is constructed and tested for its reliability and validity.Methods In view of the Social Ecosystem Theoiy,based on the semi-structured interviews,participatory observation and literature analysis of the social care needs of terminal patients at home,a questionnaire item pool was formed.Through 3 rounds of Delphi expert consultations,the initial version of the tool was formed.From April to December 2023,a convenient sampling method was used to select 504 terminal patients from 22 hospitals in 5 provinces as the research subjects.The reliability and validity of the tool were tested.Result The constructed tool in this study contained 3 dimensions:micro,meso,macro,with a total of 34 items.Cronbach's α of the tool was 0.966 and split-half reliability was 0.877;I-CVI at the item level was 0.875～1.000 and S-CVI/Ave was 0.989;the exploratory factor analysis results showed that the factors load of each dimension were greater than 0.4;the results of confirmatory factor analysis showed that the tool had good fitting degree.Conclusion The reliability and validity of the nursing-based social care needs assessment tool for terminal patients at home constructed in this study are good,and it can provide a valid tool for healthcare professionals to assess the home-based social care needs of terminal patients.

Objective To evaluate the clinical utility of the f-wave to QRS complex amplitude ratio(f/R ratio)in intracardiac electrogram(IC-ECG)-guided positioning of peripherally inserted central catheter(PICC)tips in patients with atrial fibrillation(AF),providing evidence to enhance clinical practice.Methods This study employed a conve-nience sampling method to enroll eligible AF patients admitted to a tertiary hospital in Suzhou from July 2023 to July 2024.During PICC placement,IC-ECG was utilized to monitor f-wave and QRS complex amplitude variations.Following successful catheterization,the f/R ratio was measured,and chest X-ray was performed to confirm the catheter tip position.The accuracy of PICC tip positioning across different f/R ratio ranges was analyzed,and the incidence of arrhythmias was recorded.A receiver operating characteristic curve was constructed to assess the diag-nostic performance of the f/R ratio in PICC tip localization.Results A total of 68 AF patients were included,with f/R ratios ranging from 20.63％to 91.24％.PICC tip positioning accuracy varied significantly across different f/R ratio ranges(P=0.006).The area under the ROC curve(AUC)for f/R ratio in PICC tip positioning was 0.784(P=0.009),with a maximum Youden index of 0.567,an optimal diagnostic threshold of 40.00％,a sensitivity of 81.7％,a speci-ficity of 75.0％,a positive predictive value of 96.1％,and a negative predictive value of 35.3％.No arrhythmias other than AF occurred during the procedure.Conclusion The f/R ratio provides reliable and safe guidance for PICC tip positioning in AF patients.An f/R ratio ≥40％is associated with higher accuracy in identifying the optimal catheter tip position.

Objective To translate the Urinary Incontinence Awareness and Attitude Scale(URINAS)and test its reliability and validity.Methods The Chinese version of the URINAS was developed by Brislin's translation model for translation,back translation,cultural adaptation,and pilot investigation.A convenience sampling method was used to select 384 urinary incontinence patients who visited a tertiary hospital in Nanchang,Jiangxi Province from June 2024 to October 2024 for investigation,in order to evaluate the reliability and validity of the scale.Results The Chinese version of the URINAS consisted of 5 dimensions with 26 entries.The Cronbach's alpha coefficient of this scale was 0.843;the folded half reliability was 0.917;the retest reliability was 0.852.The content validity of the scale at the level of the entries ranged from 0.846 to 1.000,and that at the level of the scale was 0.979.A total of 5 metrics were extracted by exploratory factor analysis,and the cumulative variance contribution rate of 74.286％.The results of the validation factor analysis showed a chi-square/degree of freedom of 2.268,a root mean square error of approximation of 0.064,a standardized fit index of 0.916,a Tucker-Lewis index of 0.923,a comparative fit index of 0.906,and a goodness-of-fit index of 0.922.Conclusion The URINAS has good reliability and validity,and can better reflect the level of patients' cognition and attitude towards urinary incontinence,thus providing theoretical basis for the development of corresponding intervention programs for such patients.

Objective:To explore the effectiveness of digital health management in the management of community patients with essential hypertension comorbid with somatization symptom disorder.Methods:This was an intervention-controlled study. Patients with essential hypertension comorbid with somatization symptom disorder who visited the outpatient clinic of Jiangwan Town Community Health Service Center in Hongkou District, Shanghai from January to December 2022 were enrolled. Based on the time of initial diagnosis, patients were divided into a digital health management group (initial diagnosis from January to June 2022) and a control group (initial diagnosis from July to December 2022). Baseline clinical data were collected. The control group received conventional interventions, while the digital health management group utilized the Health Cloud APP 5.3.11 platform for online digital health management without altering the original medication regimen. The intervention lasted for 24 weeks. Before and after the intervention, the Somatization Symptom Scale (SSS), 9-item Patient Health Questionnaire (PHQ-9), and 7-item Generalized Anxiety Disorder Scale (GAD-7) were used to assess somatization symptoms, depression, and anxiety, respectively. The reduction rate in SSS scores was calculated, and blood pressure and heart rate were measured. The evaluation criteria for somatization symptom intervention effectiveness were as follows: at the endpoint of the intervention, SSS ≤29 or a reduction rate of SSS ≥ 75% was considered "cured"; a reduction rate of 50% to <75% was considered "markedly effective"; a reduction rate of 25% to <50% was considered "effective"; and a reduction rate of <25% was considered "ineffective".The overall effectiveness rate=(number of cured patients + number of markedly effective patients + number of effective patients)/total number of patients × 100%.Results:A total of 62 patients in the digital health management group and 65 patients in the control group were included in the final analysis. The mean age of the digital health management group was (50.5±3.5) years, with 30 males (48.4%), while the mean age of the control group was (50.2±3.2) years, with 31 males (47.7%). There were no statistically significant differences in the age or gender distribution between the two groups (both P>0.05). Before the intervention, there were no significant differences between the two groups in SSS sub-item scores, total SSS scores, PHQ-9 scores, GAD-7 scores, blood pressure, or heart rate (all P>0.05). After 24 weeks of intervention, all scores decreased in both groups, and did blood pressure and heart rate (all P<0.05). The differences in SSS sub-item scores, total SSS scores, PHQ-9 scores, GAD-7 scores, blood pressure, and heart rate before and after the intervention were greater in the digital health management group than in the control group (all P<0.05). The proportion of patients with effective intervention for somatization symptom was higher in the digital health management group than in the control group (57 cases (91.9%) vs. 38 cases (58.5%), P<0.001). Conclusion:Digital health management can improve somatization symptom disorder, blood pressure, and heart rate in patients with hypertension.

Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.