ObjectiveTo explore the ethical issues and coping strategies in the diagnosis and treatment of 46, XY disorders of sex development （46, XY DSD） under a multidisciplinary team （MDT） model， and to deepen the understanding of relevant ethical issues while accumulating experience. MethodsA retrospective collection was conducted on the data of children with 46, XY disorders of sex development under a single-center MDT model from January 2017 to December 2024， and the ethical issues involved in the diagnosis and treatment process were analyzed. ResultsA total of 24 MDT discussion documents involving 20 children were collected， including 17 with female social gender and 3 with male social gender. The age ranged from 0.5 to 15.8 years， with children under 8 years accounting for 75%. The ethical issues primarily involved how to ensure adequate informed consent， whether surgery was necessary and its timing， and whether gender selection is reasonable and its timing. Among the 10 children raised as females who completed the gender role psychological scale assessment， 5 demonstrated masculine tendencies， all of whom had pathogenic genetic variants. Furthermore， only 1 patient changed the social gender to male. ConclusionThe diagnosis and treatment of 46, XY DSD is relatively complex， requiring multidisciplinary collaboration. This process involves numerous ethical issues and necessitates adhering to medical ethical principles. Ensuring adequate informed consent is crucial， especially for younger children. The surgery and its timing selection must adhere to the principles of beneficence， non-maleficence， and leaving room for the future. Gender selection constitutes a focus and challenge in diagnosis and treatment. Psychological scales and genetic etiologies are conducive to judgments regarding gender selection， yet multiple factors in the real world may interfere with the gender selection.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To explore function-structure covariant patterns in Alzheimer's disease(AD)and mild cognitive impairment(MCI),and to investigate their associations with cognitive function and activities of daily living.Methods three-way parallel group independent component analysis(three-way pGICA),was used to identify the covariant patterns of resting-state functional MRI temporal data,gray matter density maps,and fractional anisotropy(FA)maps,and the differences between different groups were compared.Furthermore,the associations of covariant patterns with the Montreal Cognitive Assessment-Basic(MoCA_B)Scale scores and Activities of Daily Living Scale scores were analyzed.Results The function-structure covariant patterns in AD and MCI were characterized by the enhanced negative functional connectivity between the left posterior salience network and the right default mode network,the decreased gray matter density in the bilateral dorsolateral prefrontal cortex,and the reduced FA values in the left superior corona radiata(correlations:P<0.001,FDR corrected).Compared with HC group,AD group showed significant abnormalities in all identified covariant patterns(P<0.01,FDR corrected),but MCI group only exhibited a significant decrease in gray matter density in the bilateral dorsolateral prefrontal cortex(P<0.05,FDR corrected).Additionally,AD group had significantly lower FA value in the left superior corona radiata than MCI group(P<0.05,FDR corrected).The loadings reflecting the degree of covariation were significantly correlated with the Activities of Daily Living Scale scores(P<0.05,FDR corrected)but not with MoCA_B Scale scores.Conclusion The function-structure covariant patterns in AD and MCI are consistent with the declines in activities of daily living.The multimodal fusion analysis(three-way pGICA)provides a novel approach to understand the brain damage mechanisms underlying the covariant evolution of MCI and AD.

Objective:To compare the dose-response effects of single-fraction ultra-high dose rate (FLASH) and conventional dose rate (CONV) whole abdominal irradiation (WAI) with X-rays on acute radiation-induced intestinal injury in mice, in order to identify optimal dose parameters and potential mechanisms.Methods:A total of 186 male C57BL/6J mice were randomly assigned to a non-irradiation group ( n=6), FLASH irradiation groups ( n=90), and CONV irradiation groups ( n=90). Acute radiation-induced intestinal injury models were established using single-fraction WAI with 11, 12, 13, 14, and 15 Gy X-rays (200 Gy/s for FLASH and 4 Gy/min for CONV). Changes in body weight, stool characteristics, and disease activity index (DAI) scores were assessed at 9 d post-irradiation. At 7 d post-irradiation at 11, 12, and 13 Gy, the intestines were collected for macroscopic examination and length measurement. The small intestine was selected for HE staining and quantitative analysis of intestinal crypt number and mucosal epithelial thickness. The survival of mice was assessed at 15 d post-WAI across all dose groups. Results:After single-fraction WAI at 11, 12, and 13 Gy, the body weight was higher in the FLASH group than that in the CONV group ( t=10.17, 12.65, 10.16, P<0.05). The DAI scores for the FLASH group were 1.00±1.10, 3.17±0.75, and 2.83±1.17, respectively, which were lower than those of the CONV group (4.33±0.52, 7.00±0.00, 8.60±0.55; t=8.70, 11.71, 14.99, P<0.05). However, after WAI at 14 Gy and 15 Gy, there were no significant differences in body weight and DAI between the FLASH group and the CONV group ( P>0.05). At 7 d after single-fraction WAI at 11, 12, and 13 Gy, mice in the FLASH group exhibited less intestinal congestion, edema, and shortening compared with the CONV group. The difference between the FLASH and CONV groups were statistically significant in small intestine length at 11 and 13 Gy ( t=4.42, 3.78, P<0.05), and in colorectal length at 11 and 12 Gy ( t=3.97, 3.12, P<0.05). Small intestine HE staining revealed superior preservation of intestinal architecture in the FLASH group compared with the CONV group, characterized by longer villi, increased crypt numbers, thicker mucosal epithelium, and enhanced structural integrity. The differences in crypt number and mucosal epithelial thickness were statistically significant ( tcrypt=13.10, 23.80, 11.90; tmucosal=5.75, 2.64, 7.74; P<0.05). At 15 d post-irradiation, the survival rate in the 15 Gy FLASH group was higher than that in the CONV group (50% vs. 10%, χ2=5.39, P<0.05), with a median survival extension of 6 d ( HR=0.340, 95% CI: 0.115 4-0.999 9). No significant survival differences were observed between the FLASH group and the CONV group at 11, 12, 13, and 14 Gy ( P>0.05). Conclusions:FLASH irradiation significantly alleviated acute radiation-induced intestinal injury from medium single-fraction WAI with 11, 12, and 13 Gy X-rays compared with CONV irradiation, and showed potential to improve mouse survival after single-fraction WAI at 15 Gy. This effect is likely associated with the preservation of intestinal crypts and exhibits a dose-dependent relationship.

Objective To investigate alterations in interhemispheric functional connectivity(FC)in the cerebral cortices connected via the corpus callosum in patients with Alzheimer's disease(AD),and to explore their relationships with cognitive function and activities of daily living.Methods Resting-state functional magnetic resonance imaging data were collected from 28 patients with Alzheimer's dementia(d-AD),47 patients with mild cognitive impairment(MCI),and 37 healthy controls(HC).Using a trancallosal tract template,32 pairs of homologous cortical brain regions directly connected to 32 subregions of the corpus callosum were selected as regions of interest for interhemispheric FC analysis.Further correlation analyses were performed between FC values in patient groups and their scores on the Montreal Cognitive Assessment-Basic(MoCA-B)Scale and the Activities of Daily Living(ADL)Scale.Results Compared with HC group,both MCI and d-AD groups exhibited hyperconnectivity(significantly increased FC)in interhemispheric non-homologous brain regions.Specifically,hyperconnectivity in the MCI group was scattered across the frontal,parietal,temporal,and occipital lobes,while in the d-AD group,it was concentrated within the precentral and postcentral gyri.Notably,hyperconnectivity involving the prefrontal and occipital lobes in the MCI group showed significant declines in the d-AD group.The interhemispheric homologous FC in the d-AD group reduced more significantly than the MCI group.Additionally,in the d-AD group,2 interhemispheric FC within the prefrontal lobe(between the bilateral orbital parts of the inferior frontal gyrus,and between the left medial frontal gyrus and the right middle frontal gyrus)were correlated with MoCA-B scores,and 2 FC(between the bilateral middle occipital gyri,and between the left inferior parietal lobule and the right middle frontal gyrus)were correlated with ADL scores.Conclusion MCI and d-AD exhibit distinct patterns of interhemispheric FC alterations,and the interhemispheric FC changes in AD patients are non-progressive.The close relationships between interhemispheric homologous/non-homologous FC and MoCA-B/ADL scores in d-AD patients provide an objective basis and reference for clinical neuromodulation.

Objective: To analyze the distribution and related factors of spherical equivalent(SE) anisometropia in school aged children in ethnic minority areas of Yunnan Province, so as to provide a scientific basis for the intervention and control of SE anisometropia. Methods: In October 2021,a total of 1 852 school aged children in three counties/cities(Lijiang City,Dali City,Xishuangbanna) in Yunnan Province were examined by multi stage cluster random sampling method for computer optometry visual acuity examination for non ciliary paralysis and questionnaire survey.Demographic characteristics, ocular biological parameters and SE data were obtained for SE anisometropia. Group comparisons were conducted using Mann-Whitney U test or Kruskal-Wallis H test, and Logistic regression was used to explore the related factors of anisometropia in SE. Results: The prevalence of SE anisometropia among school age children was 23.0%, and the prevalence was higher in girls (24.2%) than that in boys (21.6%). Compared with non anisometropic children, school aged children with SE anisometropia had longer axial length (AL) [24.03 (23.41, 24.76), 23.93 (23.26, 24.61) mm] and corneal curvature radius (CR) [43.42 (42.43, 44.42), 43.14 (42.23, 44.04)mm], SE[-1.75(-2.75,-1.00),-0.94(-2.63,-0.25)D], smaller spherical scope [-1.38(-2.38,-0.75),-0.75(-2.38,0)D], deeper anterior chamber depth(ACD)[3.77(3.62, 3.93), 3.72(3.55, 3.89)mm], and grater differences in AL[0.58(0.32,0.82), 0.13( 0.06 ,0.22)mm], ACD[0.05(0.02,0.08), 0.03(0.01,0.06)mm] and AL/CR[0.01(0.01,0.02), 0.01(0.00,0.01)]( Z =-22.47 to -2.41, all P <0.05). The results of Logistic regression showed that mild myopia( OR =2.74), moderate myopia( OR =3.52), and high myopia( OR =8.92) had a relatively high risk of anisometropia SE in school aged children(all P <0.05). Conclusion The prevalence of SE anisometropia in school aged children in ethnic minority areas of Yunnan Province is relatively high, and the prevalence and degree of anisometropia were closely related to myopia degree and related refractive parameters.

Objective To explore function-structure covariant patterns in Alzheimer's disease(AD)and mild cognitive impairment(MCI),and to investigate their associations with cognitive function and activities of daily living.Methods three-way parallel group independent component analysis(three-way pGICA),was used to identify the covariant patterns of resting-state functional MRI temporal data,gray matter density maps,and fractional anisotropy(FA)maps,and the differences between different groups were compared.Furthermore,the associations of covariant patterns with the Montreal Cognitive Assessment-Basic(MoCA_B)Scale scores and Activities of Daily Living Scale scores were analyzed.Results The function-structure covariant patterns in AD and MCI were characterized by the enhanced negative functional connectivity between the left posterior salience network and the right default mode network,the decreased gray matter density in the bilateral dorsolateral prefrontal cortex,and the reduced FA values in the left superior corona radiata(correlations:P<0.001,FDR corrected).Compared with HC group,AD group showed significant abnormalities in all identified covariant patterns(P<0.01,FDR corrected),but MCI group only exhibited a significant decrease in gray matter density in the bilateral dorsolateral prefrontal cortex(P<0.05,FDR corrected).Additionally,AD group had significantly lower FA value in the left superior corona radiata than MCI group(P<0.05,FDR corrected).The loadings reflecting the degree of covariation were significantly correlated with the Activities of Daily Living Scale scores(P<0.05,FDR corrected)but not with MoCA_B Scale scores.Conclusion The function-structure covariant patterns in AD and MCI are consistent with the declines in activities of daily living.The multimodal fusion analysis(three-way pGICA)provides a novel approach to understand the brain damage mechanisms underlying the covariant evolution of MCI and AD.

Objective To conduct a comprehensive review on application status and future development prospects of proton therapy for pediatric medulloblastoma.Methods A total of 218 literatures were retrieved from PubMed and CNKI database using the search terms"pediatric medulloblastoma,proton therapy,radiotherapy"(English)and"儿童髓母细胞瘤,质子治疗,放射治疗"(Chinese),with a publication timeframe from January 1,2004,to June 1,2025.Inclusion criteria were as follow:(1)proton therapy for pediatric medulloblastoma;(2)radiotherapy for pediatric medulloblastoma;(3)proton therapy for pediatric brain tumors;(4)development and applications of proton therapy.Exclusion criteria were as follow:(1)outdated literatures;(2)redundant or highly similar studies.After screening,89 literatures met the inclusion criteria.Results Compared with conventional treatments such as surgery,photon therapy,and chemotherapy,proton therapy for pediatric medulloblastoma significantly reduced acute toxicity and long-term side effects including cognitive dysfunction,endocrine disorders,and hearing loss.Additionally,proton therapy exhibited favorable cost-effectiveness.In the future,the therapeutic outcomes would be further enhanced through the optimization of proton therapy techniques,treatment planning,and equipment.Conclusion With ongoing technological advancements and growing clinical experience,proton therapy is expected to become one of the standard treatment modalities for pediatric medulloblastoma.

OBJECTIVE To understand the current status of standard precautions knowledge,behaviors of the pri-mary health care workers and analyze the influencing factors so as to provide bases for improving the standard pre-caution behaviors of the primary health care workers.METHODS A total of 1320 primary health care workers from a district of Luoyang were recruited as the research subjects.In Dec.2024,a cross-sectional survey was conducted by using self-designed questionnaires on standard precautions knowledge,behavior scales,and Health Belief Mod-el(HBM)scales.The survey data were treated with statistical description,reliability and validity tests and struc-tural equation model(SEM)fitting.RESULTS A total of 1205 valid questionnaires were recovered,with an effec-tive recovery rate 91.29％(1205/1320).Among the primary health care workers,45.64％mastered standard pre-cautions knowledge,and 62.99％could implement standard precautions behaviors.There was significant differ-ence in the score of standard precautions knowledge among the health care workers of different genders and age(P＜0.05);the significant differences in standard precautions behavior scores were observed among the health care workers of different genders,professional titles,work regions,and unit natures(P＜0.05).After the Knowledge-Attitude-Behavior(KAB)theory was integrated with the Health Belief Model,the knowledge,per-ceived severity,perceived benefits,perceived barriers,cues to action and self-efficacy had direct impacts on stand-ard precautions behaviors during the implementation process of standard precautions,with direct effect values 0.054,0.112,0.276,-0.062,0.223 and 0.213,respectively.CONCLUSIONS The awareness rate of standard pre-cautions and the implementation level of related behaviors are relatively low among the primary health care work-ers.The standard precautions behaviors can be remarkable improved by designing reasonable training programs to improve medical staff's knowledge,perceived severity,perceived benefits,cues to action and self-efficacy,while by reducing perceived barriers.

Objective:To investigate the clinical features and prognosis associated risk factors of non-eosinophilic esophagitis eosinophilic gastrointestinal diseases (non-EoE EGID) in children.Methods:A retrospective cohort study was conducted. Clinical data, including symptoms, laboratory test results, endoscopic findings, treatment and prognosis of 48 children diagnosed with non-EoE EGID at Children′s Hospital, Zhejiang University School of Medicine from May 2015 to March 2023 were collected. Patients were grouped according to the eosinophils (EOS) diagnostic threshold of new guideline for non-EoE EGID. Independent sample t tests, Wilcoxon rank-sum test, chi-squared test or Fisher exact test were used for intergroup comparisons. Kaplan-Meier method was used to plot the survival curve of disease recurrence in children with non-EoE EGID. Log-Rank test and the proportional hazards model were respectively used for univariate analysis and multivariate analysis. Results:Of the 48 children with non-EoE EGID, there were 38 males and 10 females. Twenty-six patients (54%) with onset age >6-10 years accounted for the highest proportion. The most common symptom was abdominal pain, occurring in 34 patients (71%). Laboratory test results showed that 32 patients (67%) had increased EOS count in peripheral blood. A total of 35 imaging examination showed thickened intestinal wall in 17 patients (49%) and bowel dilatation in 3 patients (9%). Twenty-five patients (52%) received glucocorticoid treatment. The serum albumin level in the high diagnostic threshold group was lower than that in the low diagnostic threshold group ( Z=2.17, P=0.030), no statistically significant difference was found in other clinical characteristics (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates for non-EoE EGID children were (81±6)%, (81±6)%, and (44±13)% respectively. Multivariate analysis showed that bowel dilatation ( HR=5.87, 95% CI 1.06-32.48) was an independent predictor of disease recurrence. Conclusions:A higher proportion of non-EoE EGID patients are male. The most common symptom is abdominal pain, and the peripheral blood EOS counts are often elevated. Among children with non-EoE EGID, those with higher pathological EOS counts have lower serum albumin levels. Bowel dilatation is a risk factor for disease recurrence in non-EoE EGID children.