Objective To evaluate the radiation dose levels induced by secondary neutrons at different locations inside proton therapy treatment rooms, and analyze the distribution characteristics of neutron energy spectra by combining experimental measurements with simulations, and to provide a theoretical basis and technical support for radiation protection design and management in proton therapy. Methods Multiple representative measurement points were established in the treatment rooms of two hospital-based proton therapy centers. The DIAMON neutron spectrometer was employed to perform in-situ measurements of secondary neutron doses and energy spectra. Three-dimensional simulation models of treatment rooms were constructed using the FLUKA code to simulate the generation and transport of secondary neutrons. Results Measurements showed that the neutron dose was highest near the target region, reaching up to 4293.750 µSv/h. The doses at the maze entrance were the next highest, ranging from 422.091 to 489.268 µSv/h, while the doses in the middle section of the maze ranged from 2.860 to 6.727 µSv/h. The neutron energy spectra exhibited a triple-peak pattern. Conclusion Significant accumulation of secondary neutrons was observed near the target and in the maze regions during proton therapy, with intermediate-energy neutrons being the dominant dose contributor. The consistency between measurements and simulations validated the reliability of the model, which can provide a basis for optimizing treatment room shielding and controlling occupational exposure for staff.

OBJECTIVE: To investigate the clinical phenotype and genetic diagnosis process of fetuses with 21 hydroxylase deficiency (21-OHD) caused by compound heterozygous variant of the CYP21A2 gene . METHODS: A fetus who was diagnosed at Taizhou Hospital in Zhejiang Province on December 4, 2020 due to unclear characteristics of external genitalia on ultrasound was selected as the study subject. Chromosome copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were performed on amniotic fluid samples. Candidate variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA), and short tandem repeat (STR) analysis was used to exclude maternal blood contamination. The pathogenic mechanism of the variants was further explored. The procedure followed by this study was approved by the Medical Ethics Committee of Taizhou Hospital (Ethics No.: K20201009). RESULTS: The MRI examination of the fetal external genitalia showed thickening of labia minora and enlargement of the clitoris. The CNV-seq results of the fetus showed no significant abnormality. The WES results showed that the fetus had a homozygous c.293-13C>G variant in the CYP21A2 gene (NM-000500.9). STR testing excluded maternal blood contamination. Sanger sequencing verified the presence of heterozygous c.293-13C>G variant of the CYP21A2 gene in the fetus and its mother, while its father did not detect this mutation. Further MLPA testing results showed that the fetus and its father had heterozygous deletion (I2G-C locus) mutations in exon 1~7 of the CYP21A2 gene. Based on the "Standards and Guidelines for Interpretation of Sequence Variants" jointly developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP), both variants of the CYP21A2 gene carried by the fetus were predicted to be pathogenic. According to the imaging and genetic testing results of the external genitalia of the fetus, the fetus was prenatally diagnosed as 21-OHD caused by the CYP21A2 gene variant. Follow-up after prenatal diagnosis showed that the couple had opted to terminate the pregnancy at a local hospital at 31⁺ weeks of gestation, and the clinical phenotype of the abortion fetus was consistent with the imaging and molecular genetic diagnosis. CONCLUSION The imaging features of this fetus are suspected to be congenital adrenal hyperplasia (CAH). Combined with WES, Sanger sequencing, and MLPA testing results, the fetus was diagnosed with 21-OHD caused by compound heterozygous variants of the CYP21A2 gene, which provided a basis for prenatal diagnosis.
Humans ; Steroid 21-Hydroxylase/genetics* ; Female ; Pregnancy ; Adrenal Hyperplasia, Congenital/diagnosis* ; Heterozygote ; Prenatal Diagnosis/methods* ; Adult ; Fetus ; DNA Copy Number Variations ; Mutation ; Genetic Testing

OBJECTIVE: To investigate the clinical characteristics and genetic etiology of a male with a normal phenotype and SRY gene-positive 46,XX/46,XY tetrazoospermia chimerism. METHODS: A male patient with an abnormal peripheral blood chromosomal karyotype detected at the Infertility Center of Taizhou Hospital of Zhejiang Province on December 2, 2013 was selected as the study subject. Peripheral venous blood samples were collected from the proband and his family members, together with a semen sample from the proband. Chromosomal karyotype analysis, red blood cell blood group identification, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), sex-determining region Y (SRY) gene detection, and short tandem repeat (STR) microsatellite marker analysis were performed on the peripheral venous blood sample from the proband. Routine semen analysis, sperm FISH, and STR testing were also conducted. STR verification was performed on both parents. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: k20201009). RESULTS: The proband, a 37-year-old male, had normal secondary sexual characteristics and external genitalia development. The chromosomal karyotype of his peripheral blood sample was 46,XX[94]/46,XY[6]. ABO blood group typing was positive for Rh(D) type O and negative for Rh(D) type A, indicating the presence of two red blood cell populations. CMA result was arr[GRCh37](1-22)×2,(XX)×1. Autosomal and X chromosome SNP genotypes were BB-BB, AB-AB, and AA-AA, making it impossible to identify homozygous/heterozygous chimerism. FISH detection of interphase nuclei showed nuc ish XX[92]/XY[8]. Testing of the SRY gene was positive. STR analysis showed a single X peak (no Y peak) at the AMEL locus, 10/12 at the Penta D locus, and no third allele at other loci. Routine semen analysis were normal. Sperm FISH detection showed haploid nuclei nuc ish X[53]/Y[47]. Sperm STR analysis revealed an X/Y bimodal distribution at the AMEL locus and a 9/14 distribution at the Penta D locus, with no third allele observed at other loci. Above results suggested that the proband's blood and germ cell lines had originated from a heterozygous chimera formed by the fusion of two different zygotes. CONCLUSION Combined genetic techniques confirmed that the proband's peripheral blood AMEL genotype is X/X, while the sperm is X/Y. The Penta D locus showed a bi-allelic heterozygous pattern of 10/12 in the peripheral blood sample and 9/14 in the sperm sample, suggesting that the proband is a tetrazygotic chimera resulted from the fusion of 46,XX/46,XY zygotes.
Humans ; Male ; Adult ; Chimerism ; Microsatellite Repeats ; Sex-Determining Region Y Protein/genetics* ; Phenotype ; Genes, sry ; In Situ Hybridization, Fluorescence ; Karyotyping

Objective:To analyze the cost and structural impact of the new technology"transhysteroscopic mechanical rotary excision of abnormal uterine tissues"on the DRG group of"surgery for intrauterine lesions"under the DRG payment method,and to provide clinical data for supporting the development of the exclusion policy for the new technology and new items.Methods:Cases in which transhysteroscopic mechanical rotary excision of abnormal uterine tissues was used in the gynecology day unit of the Peking Union Medcial College Hospital from March 2022 to November 2023,which were paid for under the DRG group of"surgery for intrauterine pathology",were retrospectively analyzed for the impact of the new technology on the cost and structure of the cases.Results:The price of"transhysteroscopic mechanical rotary excision of abnormal uterine tissues"in the Beijing Medical Service Price Item Specification is 8 000 yuan(Class C out-of-pocket expenses),which is higher than the payment standard of 6 866 yuan for the NE19 group,and the use of this new technology significantly increased the total hospitalization medical cost,the out-of-pocket ratio of the patients and the surgical cost,which led to an increase in the burden of the patients and the loss of the hospitals.Conclusion:"Transhysteroscopic mechanical rotary excision of abnormal uterine tissue"has the advantages of improving patients'prognosis and accelerating recovery,shortening operation time,avoiding intraoperative thermal injuries,and shortening the learning curve of doctors,etc.Policy makers should take into account cost control,patients'prognosis and the development of medical technology,scientifically and prudently formulate the exclusion policy of the new technology,reasonably determine the payment standard,and make good use of the exclusion policy and the payment standard.

Objective:To establish a highly-sensitive method for the rapid measurement of 137Cs in seawater with an view to its preliminary application in eight coastal provinces of China. Methods:The method employed nickel potassium polyacrylonitrile (KNiFC-PAN), an organic polymer-based ion exchanged resin material, to filter and adsorb 137Cs from seawater at a rate of 60 ml/min via a peristaltic pump. The adsorption efficiency of KNiFC-PAN was determined by measuring the cesium ion concentration before and after adsorption in seawater, with the addition of stable cesium, using inductively coupled plasma mass spectrometry (ICP-MS). Three KNiFC-PAN matrix components of 137Cs standard samples were prepared for the efficiency calibration of well type high purity germanium gamma spectrometer to obtain its detection efficiency. Results:The established measuring method can complete the filtration and adsorption of 137Cs from 20 L seawater within 6-8 h, which was twice as fast as the co-precipitation method with phosphomolybdic acid-ammonium molybdate taking more than 12 h, as stipulated in the GB/T 16145-2022 standard. The cesium recovery rate was as high as 98.02%. The relative standard deviation of the efficiency calibration result for the three prepared standard samples was 1.30%, and the detection limit for 137Cs was 0.26 Bq/m 3. The activity concentrations of 137Cs in offcoast seawater in eight coastal provinces of China were detected ranging from 0.38 to 1.24 Bq/m 3. The activity concentration of 137Cs in coastal seawater of China was at the background level, while as reported in 2019 was 0.03-1.92 Bq/m 3 in the eastern Chinese seas and 1-2 Bq/m 3 in the Pacific Ocean. Conclusions:This method has high detection sensitivity and can quickly obtain the values of activity concentration of 137Cs in seawater, thus providing a rapid and feasible method for emergency monitoring of 137Cs in China.

Objective:To investigate the current status of implementing medical insurance performance evaluation in the hospitals of China under the background of China Healthcare Security Diagnosis Related Groups (CHS-DRG) and Diagnosis-Intervention Packet (DIP) payment reform, explore the perspectives and recommendations of key department leaders (e.g., health insurance, medical affairs, pricing, and performance evaluation departments) regarding health insurance performance evaluation, analyze the influencing factors in its implementation, so as to provide references for hospitals to develop and refine health insurance performance evaluation strategies.Methods:A questionnaire was designed and distributed to hospitals across 31 provincial-level administrative regions in China from December 1 to 31, 2023. The survey targeted secondary and tertiary general or specialized hospitals. The main responsible persons from four functional departments, including medical insurance, healthcare, pricing, and performance, were invited to participate in the survey. Descriptive analysis was conducted on the questionnaire data, and the chi-square test was used for differential analysis of unordered categorical variables, while the Wilcoxon rank sum test was used for differential analysis of ordered categorical variables.Results:A total of 761 valid questionnaires were collected. Most respondents were health insurance department leaders (420, 55.19%). Among them, 741 respondents reported that their hospitals used CHS-DRG or DIP payment, with 258 indicating that their hospitals had already developed and implemented health insurance performance evaluation plans. A majority (685, 90.01%) expressed support for such initiatives. Influencing factor analysis revealed that hospital type, level, scope of health insurance management departments, and payment methods might impact the implementation of health insurance performance evaluation ( P<0.05). Conclusions:Few hospitals have currently adopted health insurance performance evaluation, underscoring the urgency to establish a scientific and reasonable evaluation plan as a robust tool for internal hospital management.

With the widespread application of proton therapy in tumor radiation treatment, the health effects of secondary neutron radiation on patients and medical personnel have become a key concern in radiation protection. Currently, there is no commonly accepted technical standard for neutron dose measurement in proton therapy, making it difficult to compare neutron doses across studies and hindering the standardized development of radiation protection strategies. This paper provides a systematic review of commonly used neutron dose measurement methods and Monte Carlo simulation approaches. This article also explores the key challenges and potential improvements in neutron dose measurement in proton therapy.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
Neoplasms/metabolism* ; Receptors, Notch/metabolism* ; Disease Resistance/physiology* ; Signal Transduction/physiology* ; Humans ; Drug Resistance, Neoplasm/physiology* ; Molecular Targeted Therapy/methods*

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.