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

ObjectiveTo clarify the expression of TRIM28 in non-M3 acute myeloid leukemia （AML） and its correlation with clinical indicators and prognosis， and to further explore the effect of TRIM28 expression levels on the proliferation and apoptosis of AML cells using small interfering RNA. MethodsThe GSE34577 dataset was analyzed using R software to compare TRIM28 expression between healthy controls and non-M3 acute myeloid leukemia （AML） patients. Clinical samples from non-M3 AML patients were collected， with TRIM28 expression levels measured using real-time quantitative PCR （qPCR）. The analysis focused on correlations between TRIM28 expression and various clinical indicators， treatment efficacy， and patient prognosis. Furthermore， small interfering RNA （siRNA） technology was employed to downregulate TRIM28 expression in human primary AML cells （HL60 cell line）. The effects on cell proliferation and apoptosis were then assessed through CCK-8 assays and flow cytometry， respectively. ResultsThe results showed that TRIM28 was up-regulated in non-M3 AML of both online database GSE34577 and clinical samples （P<0.000 1）， TRIM28 expression of new diagnosis group and relapsed refractory group was higher than iron deficiency anemia group （P<0.01）， and there was no significance between different French-American-British classification systems subtype. TRIM28 expression was higher in non-M3 AML patients with a poor genetic prognosis stratified as moderate than in the good prognosis group， and TRIM28 expression was associated with NPM1 combined with the FLT3-ITD mutation， positively correlated with age， bone marrow blast， peripheral blood blast and white blood cell， negatively correlated with hemoglobin. In addition， interference TRIM28 greatly inhibited cell proliferation and promoted cell apoptosis. ConclusionThis study reveals that TRIM28 is highly expressed in non-M3 AML and associated with prognosis， and plays a key role in the proliferation and apoptosis of AML cells， suggesting that TRIM28 may serve as a novel therapeutic target for non-M3 AML.

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.

Objective:To understand the epidemiological characteristics and spatiotemporal distribution of genital herpes in China from 2010 to 2023 and provide evidence for the prevention and control of genital herpes.Methods:The reported data of genital herpes cases in 31 provinces (autonomous regions and municipalities) in China from 2010 to 2023 were collected from the National Notifiable Infectious Disease Reporting System of China Information System for Disease Control and Prevention. Software Joinpoint 5.2.0 was used to analyze the epidemiological characteristics of genital herpes, software ArcGIS 10.5 was used for spatial autocorrelation analysis, and software SaTScan 10.2.3 was used for spatiotemporal scanning analysis.Results:The reported incidence rate of genital herpes increased from 1.58/100 000 to 2.00/100 000 in China from 2010 to 2023, with an average annual percentage change of 0.90%. The upward trend of reported incidence rate was significant ( t=2.35, P=0.037). There was a positive spatial autocorrelation in the reported incidence of genital herpes with the global Moran's I ranging from 0.36 to 0.51 (all P<0.001). Local spatial autocorrelation analysis showed that the number of hotspots increased from 144 in 2010 to 232 in 2023, mainly distributed in provinces Zhejiang, Guangdong, Guangxi, Chongqing and Hunan. The number of hotspots in of Chongqing, Sichuan, Yunnan and Guizhou increased significantly from 7 to 57. A total of 67 spatiotemporal clusters were detected by spatiotemporal scanning analysis, mainly distributed in Guangdong from 2011 to 2015, in Zhejiang and Fujian from 2015 to 2019, and in Chongqing and Guizhou from 2019 to 2023. Conclusions:From 2010 to 2023, the reported incidence of genital herpes in China showed an upward trend, and there was an obvious spatiotemporal clustering of genital herpes. The distribution of hotspots was basically consistent with the distribution of spatiotemporal clustering areas, mainly distributed in the southeastern coastal area and southwestern region, and the spatiotemporal clustering areas gradually changed from the southeast coastal area to the southwest region.

Objective:To investigate and evaluate the correct cognition and influencing factors of mpox expertise among relevant Chinese clinicians and to provide a reference for prevention and control.Methods:A cross-sectional survey was conducted among clinicians in relevant departments using a structured questionnaire compiled by ourselves through a non-random network recruitment method. The content includes demography, clinical specialties, and characteristics of medical institutions, and 37 questions to evaluate the professional cognition of mpox etiology, clinical characteristics, transmission, prevention, and control. Using the modified Bloom's cutoff point to determine the correct answer is greater than or equal to 26 entitled correct cognition. A logistic regression model was used to analyze the factors influencing the correct cognition rate.Results:A total of 4 332 clinicians in 23 provinces (autonomous regions, municipality) in China were investigated by online questionnaires and 4 276 effective questionnaires were collected, with an effective rate of 98.71%. The mean age of the respondents was (39.46±9.54) years old, 61.18% were female. The overall correct cognition rate of mpox expertise was 62.04% (95% CI: 60.59%-63.50%), the correct cognition rates of mpox etiology, clinical characteristics, transmission, prevention and control were 48.25% (95% CI: 46.68%-49.82%), 78.66% (95% CI: 77.38%-79.95%), 68.56% (95% CI: 67.10%-70.02%), respectively. Multivariate logistic regression analysis showed that the relevant factors affecting the overall correct cognition of mpox expertise among Chinese clinicians included gender (female: OR=1.54, 95% CI: 1.31-1.80), region (eastern region: OR=1.46, 95% CI: 1.18-1.79; midwestern region: OR=1.24, 95% CI: 1.04-1.49), professional title (deputy senior: OR=1.43, 95% CI:1.16-1.76; senior: OR=1.72, 95% CI:1.30-2.28), the clinical field (the clinical fields of dermatology and venereal diseases: OR=1.78, 95% CI: 1.42-2.23). Conclusions:The overall correct cognition rate of mpox expertise among relevant Chinese clinicians was low. It was essential to conduct mpox knowledge training for clinicians in males, northeast regions, junior professional title and the clinical fields other than dermatology and venereal diseases to improve their correct cognition rates and epidemic prevention and control ability.

Objective:To analyze the relationship between the optimal surgical margin value and clinical prognosis of transoral robotic surgery（TORS） in treating human papillomavirus（HPV） -positive oropharyngeal squamous cell carcinoma. Methods:A single-center, prospective, observational cohort study was conducted, enrolling patients with early and moderated stage（≤T3 stage） oropharyngeal carcinoma undergoing TORS between July 2020 and April 2024. The proposed optimal surgical margin cutoff value for TORS was set as 2 mm. The primary objectives were to evaluate the optimal clear margin for TORS and its association with overall survival（OS） and progression-free survival（PFS）. Logistic regression was used to analyze correlations between surgical margins and clinical variables, while Cox regression models assessed the impact of surgical margins on OS and PFS. Results:A total of 90 patients（60 males, 66.7%） were included, all had squamous cell carcinoma, with a mean age of 58.0±9.0 years（range: 39-84 years） old. The 1, 2 and 3-year OS rates were 92.3%, 89.9% and 85.0%, respectively, while the 1, 2 and 3-year PFS rates were all 90.1%. For surgical margins ≤2 mm, the 1, 2 and 3-year OS rates were 80.8%, 69.3% and 69.3%, respectively, and PFS rates were 77.9% across three time points. For surgical margins>2 mm, the 1, 2 and 3-year OS rates were 96.5%, 96.5% and 90.6%, respectively, with PFS rates of 94.6%. Logistic regression showed no correlation between surgical margins and tumor type, T/N stage, smoking, alcohol use, or gender（P>0.05）. Cox analysis identified surgical margins>2 mm as a significant factor improving PFS（HR=0.14, 95%CI 0.02-0.90, P=0.038）. Conclusion:This systematic analysis suggests setting a 2 mm and longer as clear surgical margin for TORS. Margins>2 mm are associated with superior postoperative PFS rate and prolonged PFS time in HPV-positive oropharyngeal carcinoma patients.
Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Carcinoma, Squamous Cell/virology* ; Human Papillomavirus Viruses/isolation & purification* ; Margins of Excision ; Oropharyngeal Neoplasms/virology* ; Papillomavirus Infections/virology* ; Prognosis ; Prospective Studies ; Robotic Surgical Procedures/methods*

Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

Adenomyosis is a common gynecological disease characterized by the invasion of endometrial glands and stroma into the myometrium of uterus, the pathological mechanism of which remains unclear yet. Disturbed lipid metabolism extensively affects abnormal cell proliferation and invasion in various diseases. However, the lipidome signature of human myometrium, which could be crucial in the development of adenomyosis, remains unknown. In this study, we generated the first lipidome profiling of human myometrium using a high-coverage and quantitative lipidomics approach based on ultra-performance liquid chromatography (UPLC) coupled with triple quadrupole (QqQ)-mass spectrometry (MS). A total of 317 lipid species were successfully quantified in the myometrial tissues from women with (n = 38) or without (n = 65) adenomyosis who underwent hysterectomy at Peking Union Medical College Hospital (Bejing, China). Up to 83 lipid species showed significant alternations in content between the two groups. These lipid aberrations involved multiple metabolic pathways, and emphasized inflammation, cell migration, and immune dysregulation upon adenomyosis. Moreover, receiver operating characteristic (ROC) curve analysis found that the combination of five lipid species could accurately distinguished the myometrial samples from women with and without adenomyosis with an area under the curve (AUC) of 0.906. Desorption electrospray ionization MS imaging (MSI) further underscored the heterogeneous distributions of these lipid markers in the adenomyosis lesion and adjacent myometrial tissue. Collectively, these results extremely improved our understanding on the molecular basis of adenomyosis, and could shed light on developing potential biomarkers and new therapeutic directions for adenomyosis.

Objective:To evaluate the association between postoperative delirium (POD) and preoperative frailty in elderly patients undergoing knee or hip arthroplasty.Methods:This nested case-control study utilized medical records from elderly patients who underwent knee or hip arthroplasty under combined spinal-epidural anesthesia at Qingdao Municipal Hospital between September 2021 and May 2023. Participants were divided into 2 groups based on clinically diagnosed POD: POD group ( n=53) and non-POD group ( n=256). Univariate analysis was conducted on suspected influencing factors, and logistic regression analysis was utilized to identify the risk factors for POD. Receiver operating characteristic and clinical decision curves were plotted to evaluate the predictive performance of these risk factors for POD. Mediation analysis was performed, and a clinically applicable nomogram was constructed to achieve visual prediction of outcomes. Results:There were statistically significant differences in age, preoperative frailty, body mass index, American Society of Anesthesiologists Physical Status classification, Memorial Delirium Assessment Scale scores, and concentrations of Aβ 42, Aβ 40, phosphorylated tau protein (p-tau protein) and tau protein, Aβ 42/tau ratio and Aβ 42/p-tau ratio in cerebrospinal fluid (CSF) between non-POD group and POD group ( P<0.05). Preoperative frailty was a risk factor for POD ( P<0.05). Mediation analysis revealed that the association between preoperative frailty and POD was mediated by CSF tau protein concentrations. The area under the receiver operating characteristic curve of preoperative frailty and CSF biomarker concentrations in predicting POD was 0.974 ( P<0.05). The clinical decision curve demonstrated that the model combining the preoperative frailty and CSF biomarker concentrations predicted a higher net benefit ( P<0.05). The clinical decision curve showed that the model combining preoperative frailty and CSF biomarker concentrations predicted a higher net benefit. Conclusions:Preoperative frailty is a risk factor for POD in elderly patients undergoing knee or hip arthroplasty, and its combination with CSF biomarker concentrations can effectively predict the occurrence of POD. CSF tau concentration mediates the association between preoperative frailty and development of POD.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.