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

OBJECTIVE To investigate the effects and mechanism of Yigan huayu formula in alleviating liver fibrosis in mice. METHODS Mice were randomly divided into blank group （normal saline）， model group （normal saline）， Yigan huayu formula low- and high-dose groups （28.98， 57.96 g/kg， calculated by crude drug）， with 8 mice in each group. Except for the blank group， the liver fibrosis model was induced by intraperitoneal injection of 15%CCl 4 -olive oil solution. From the third week， the mice received the medicine/normal saline intragastrically， once a day， for 4 consecutive weeks. After the last medication， liver indexes were calculated， the activities of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum， as well as the hydroxyproline （HYP） content in liver tissue， were measured. Liver histopathology was evaluated. Differentially expressed proteins （DEPs） in liver tissue were analyzed based on proteomics， followed by bioinfo rmatics analysis. The expressions of core DEPs were validated using Western blot （WB） and immunohistochemistry （IHC） methods. RESULTS Compared with the blank group， the model group showed significantly elevated liver indexes， serum activities of ALT and AST， and hepatic HYP content （ P ＜0.05）， along with obvious pathological damage and collagen deposition. Compared with the model group， the above indexes of mice in the Yigan huayu formula high-dose group were decreased significantly （ P ＜0.05）， with marked improvement in liver pathological damage and collagen deposition. Proteomics identified 210 DEPs between the model group and Yigan huayu formula high-dose group. DEPs were significantly enriched in extracellular matrix （ECM）-receptor interaction and lipid metabolism pathways. WB and IHC confirmed that Yigan huayu formula could significantly inhibit the abnormally elevated expressions of collagen type Ⅳ alpha1 chain （COL4A1）， secreted protein acidic and rich in cysteine （SPARC）， vitronectin （VTN） and laminin subunit alpha5 （LAMA5） in liver tissue of mice （ P ＜0.05）. CONCLUSIONS Yigan huayu formula may exert anti-hepatic fibrosis effects by inhibiting the expressions of proteins such as COL4A1， LAMA5， SPARC， and VTN， thereby blocking the ECM-receptor interaction signaling pathway， and subsequently suppressing excessive ECM deposition and basement membrane remodeling.

Objective To investigate the antimicrobial resistance of clinical isolates from elderly patients(≥65 years)in major medical institutions across China.Methods Bacterial strains were isolated from elderly patients in 52 hospitals participating in the CHINET Antimicrobial Resistance Surveillance Program during the period from 2015 to 2021.Antimicrobial susceptibility test was carried out by disk diffusion method and automated systems according to the same CHINET protocol.The data were interpreted in accordance with the breakpoints recommended by the Clinical and Laboratory Standards Institute(CLSI)in 2021.Results A total of 514 715 nonduplicate clinical isolates were collected from elderly patients in 52 hospitals from January 1,2015 to December 31,2021.The number of isolates accounted for 34.3％of the total number of clinical isolates from all patients.Overall,21.8％of the 514 715 strains were gram-positive bacteria,and 78.2％were gram-negative bacteria.Majority(90.9％)of the strains were isolated from inpatients.About 42.9％of the strains were isolated from respiratory specimens,and 22.9％were isolated from urine.More than half(60.7％)of the strains were isolated from male patients,and 39.3％isolated from females.About 51.1％of the strains were isolated from patients aged 65-＜75 years.The prevalence of methicillin-resistant strains(MRSA)was 38.8％in 32 190 strains of Staphylococcus aureus.No vancomycin-or linezolid-resistant strains were found.The resistance rate of E.faecalis to most antibiotics was significantly lower than that of Enterococcus faecium,but a few vancomycin-resistant strains(0.2％,1.5％)and linezolid-resistant strains(3.4％,0.3％)were found in E.faecalis and E.faecium.The prevalence of penicillin-susceptible S.pneumoniae(PSSP),penicillin-intermediate S.pneumoniae(PISP),and penicillin-resistant S.pneumoniae(PRSP)was 94.3％,4.0％,and 1.7％in nonmeningitis S.pneumoniae isolates.The resistance rates of Klebsiella spp.(Klebsiella pneumoniae 93.2％)to imipenem and meropenem were 20.9％and 22.3％,respectively.Other Enterobacterales species were highly sensitive to carbapenem antibiotics.Only 1.7％-7.8％of other Enterobacterales strains were resistant to carbapenems.The resistance rates of Acinetobacter spp.(Acinetobacter baumannii 90.6％)to imipenem and meropenem were 68.4％and 70.6％respectively,while 28.5％and 24.3％of P.aeruginosa strains were resistant to imipenem and meropenem,respectively.Conclusions The number of clinical isolates from elderly patients is increasing year by year,especially in the 65-＜75 age group.Respiratory tract isolates were more prevalent in male elderly patients,and urinary tract isolates were more prevalent in female elderly patients.Klebsiella isolates were increasingly resistant to multiple antimicrobial agents,especially carbapenems.Antimicrobial resistance surveillance is helpful for accurate empirical antimicrobial therapy in elderly patients.

Objective To investigate the oral health status of second-grade primary school students in Suzhou,provide baseline data for evaluating Suzhou's"Bright Eyes and Healthy Teeth"public health project,and offer reference for formulating oral health policies for students in Suzhou.Methods A multi-stage,stratified,random sampling method was used to select 1 640 second-grade primary school students from 10 districts(county-level cities)across Suzhou.The oral health survey of primary school students in Suzhou was designedbased on WHO"Basic Methods for Oral Health Surveys"(5th edition).A survey on the students' oral health status was con-ducted.Results The caries prevalence,mean DMFT(Decayed,Missing,Filled Teeth),and caries filling rate for primary teeth among second-grade students in Suzhou were 80.73％,4.25,and 24.48％,respectively.For permanent teeth,the caries prevalence,mean DMFT(Decayed,Missing,Filled Teeth),and caries filling rate were 30.30％,0.62,and 16.96％,respectively.Specifically,the caries prevalence,mean DMFT,and filling rate for the first permanent molar were 29.88％,0.59,and 16.94％,respectively.The pit and fissure sealing rate for the first permanent molar was 13.74％.Additionally,the detection rate for gingival bleeding was 58.05％,and for dental calculus,49.15％.Conclusion The oral health status of second-grade primary school students in Suzhou is concerning.The caries prevalence rate for both primary and permanent teeth is high,while the filling rate is relatively low.Prior to the implementation of oral health programs,the pit and fissure sealing rate for the first permanent molars was low,with significant differ-ences observed between urban and rural areas,as well as among different districts(or county-level cities).

Objective To explore the characteristics and molecular mechanisms of dynamic changes in ovarian function during natural aging in mice.Methods Eighteen female ICR mice of 2,6,10 and 14 months of age(referred to as 2 M,6 M,10 M,and 14 M)were included.The estrous cycle,ovarian index,pregnancy rate and embryo number were detected.The number of follicles was observed using HE staining.Serum anti-Müllerian hormone(AMH)levels were measured using ELISA.Protein and mRNA expression of P16,P21,proliferator-activated receptor-γ coactivator-1α(PGC-1α),and mitochondrial transcription factor A(TFAM)were detected through IHC and qPCR,respectively,and the protein expression of PGC-1α and TFAM was detected by Western blot.Relationships between indicators were evaluated based on Spearman's rank correlation coefficients and logistic regression analyses.Results Compared with estimates in the 2 M group,the percentage of estrous cycle disorders(P＜0.05 in 10 M group,P＜0.01 in 14 M group),ovarian index(P＜0.05 in 10 M group,P＜0.01 in 14 M group),serum AMH level(P＜0.01 in 10 M group,P＜0.01 in 14 M group),number of embryos(P＜0.01 in the 10 M group,P＜0.01 in 14 M group),and pregnancy rate(P＜0.01 in 14 M group)were significantly lower;the number of follicles at all levels and total number of follicles were lower(all P＜0.01),and the number of atretic follicles(all P＜0.01)was higher.Furthermore,P16 and P21 mRNA(P16:P＜0.01 in 10 M and 14 M groups;P21:P＜0.05 in 10 M group,P＜0.01 in 14 M group)and protein levels(P16:P＜0.01 in each group;P21:P＜0.01 in 10 M and 14 M groups)were elevated.Spearman's correlation analyses showed that the age in months was negatively correlated with the ovarian index,serum AMH level,primordial follicle number,number of embryos,and expression of PGC-1αand TFAM and positively correlated with the expression of atretic follicle,P16 and P21(all P＜0.01).Logistic regression analysis revealed a significant negative correlation between the age in months and pregnancy rate(P＜0.01).PGC-1α mRNA was significantly decreased(all P＜0.01),and TFAM mRNA was significantly decreased in 10 M and 14 M groups(P＜0.01).PGC-1α levels were significantly decreased in the 10 M group(IHC:P＜0.05;Western blot:P＜0.01)and 14 M group(all P＜0.01);TFAM levels were significantly lower in 6 M,10 M,and 14 M groups than in the 2 M group(IHC:P＜0.01;Western blot:P＜0.01).Compared with the 2 M group,expression levels of PGC-1α and TFAM were positively correlated with the ovarian index and serum AMH level and negatively correlated with P16 and P21 expression(all P＜0.01).Conclusions Ovarian function in mice declines progressively with age in months,as reflected by reductions in follicles and fertility and the up-regulation of aging markers,which may be associated with the decreased expression of the mitochondrial biogenesis factors PGC-1α and TFAM.

Objective:To explore the value of paediatric age-adjusted shock index（SIPA）in early identification of septic shock in children，and to evaluate the relationship between SIPA and disease severity and prognosis.Methods:The infected children admitted to the department of critical care medicine of the Children's Hospital Affiliated to Capital Institute of Pediatrics from May 2023 to July 2024 were collected. Dynamic assessment was performed 0 to 6 hours after admission. Patients diagnosed with sepsis without septic shock were classified as the sepsis group and those diagnosed with sepsis with septic shock were classified as the septic shock group. According to whether the blood pressure of the children decreased，they were divided into two groups：compensated septic shock group and decompensated septic shock group. The difference of SIPA among the three groups was analyzed，and the predictive value of SIPA on case fatality rate，lactate level，pediatric critical illness score，ventilator utilization rate and length of hospital stay were analyzed.Results:Among 203 children with sepsis，112 were males and 91 were females. There were 146 cases in the sepsis group，37 cases in the compensated septic shock group and 20 cases in the decompensated septic shock group. There was no significant difference between the three groups in gender（ P>0.05），but there was a statistically significant difference in age（ χ 2=32.905， P<0.001）. There was no significant difference in age between the sepsis group and the compensated septic shock group（ P>0.05）. The age of sepsis group and decompensated septic shock group，compensated septic shock group and decompensated septic shock group were statistically significant（ χ 2=29.431， P<0.001； χ 2=19.764， P=0.001）. The proportion of increased SIPA was statistically different among the three groups，with both the compensated septic shock group and the decompensated septic shock group being higher than the sepsis group（ χ2=20.383， P<0.001； χ2=33.600， P<0.001）. The decompensated septic shock group was higher than the compensated septic shock group（ χ2=6.555， P=0.01）. SIPA was correlated with case fatality rate，lactate level，pediatric critical illness score，ventilator use rate and length of stay of the children，with statistically significant differences（ P<0.05）. Conclusion:The increase of SIPA can be used for the early identification of septic shock in children，and it has a certain early warning value for the prognosis assessment of sepsis and septic shock.

Male factors contribute to infertility at roughly the same rate as female factors,and sperm DNA methylation in ad-vanced-aged males directly affects semen parameters and significantly reduces fertility and increases the miscarriage rate of spouses.Many adverse outcomes of reproductive health are associated with advanced reproductive age of men,and few studies are reported on the influence of paternal age on the health of the offspring.The role of advanced age in human sperm DNA methylation variation and mechanism of its subsequent influence on the offspring health remain unclear.Attention should be paid to the influence of reproductive age on pregnancy outcomes in this population.This reviews focuses on the impacts of advanced male age on sperm DNA methylation and consequently on reproductive outcomes and the offspring,with elucidation of its underlying mechanisms,aiming to provide some more useful evidence for solving related clinical problems.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Excessive ionizing radiation can disrupt the molecular structures of organisms,leading to health issues such as acute radiation syndrome and cancer,posing serious threats to human health.The development of radioprotective drugs holds significant importance for mitigating ionizing radiation damage and safeguarding public health,yet its research process faces multidimensional ethical challenges.This paper systematically explores the ethical issues involved in the full lifecycle of radioprotective drug development,focusing on the ethical particularities of animal experimentation,ethical dilemmas in human trials,data privacy and security risks,as well as challenges in managing conflicts of interest.Targeted solutions are proposed,including strengthening ethical review mechanisms,promoting interdisciplinary collaboration,constructing data security management systems,and establishing conflict-of-interest mediation mechanisms.These comprehensive measures aim to build a scientifically rigorous ethical framework for radioprotective drug research,fostering sustainable development in this field.

Creutzfeldt-Jakob disease(CJD)is a rapidly progressive and fatal neurodegenerative disorder caused by prions,with certain infectivity and iatrogenic transmission risks.With the rapid progress and application of new dia-gnostic biomarkers and detection methods,as well as the construction and improvement of surveillance and reporting systems,the detection of CJD in patients domestically and internationally has shown an increasing trend year by year.Due to its long incubation period and heterogeneity of early symptoms,early identification and diagnosis of the disease is difficult,increasing the risk of transmission within medical institutions.Currently,there is a lack of con-sensus on the infection prevention and control of CJD.In order to timely identify and diagnose CJD as well as effec-tively block its transmission in medical institutions,this consensus summarizes 15 clinical concerns and formulates 24 specific recommendations based on the latest domestic and international research findings and clinical evidence,as well as combines with clinical practice,aiming to standardize healthcare-associated infection prevention and control measures for CJD and reduce its transmission risk in medical institutions.