Objective To identify the enhancer profile marked by histone H3K27ac modification in high-grade intraepithelial neoplasia(HGIN)in order to reveal the novel regulatory mechanism of HGIN pathogensis.Methods Gastric tissue samples were collected from Department of Gastroenterology of Army Medical Center of PLA between June 2022 and June 2023,including 14 normal gastric tissues(Nor group),31 HGIN tissues(HGIN group)and 17 gastric cancer tissues(GC group).Cleavage under targets and tagmentation(CUT&Tag)technique was employed to capture enhancer regions modified by histone H3K27ac.Multi-omics analysis was performed to identify HGIN-specific active enhancers and their potentially regulated genes.Immunohistochemical profiling was performed to assess differential expression of the gene of interest across clinically stratified specimens,combined with CRISPR-dCas9-mediated ablation of active enhancers to monitor the gene of interest transcriptional dynamics and validate enhancer-mediated regulatory mechanisms.Results Epigenomic sequencing obtained the data with excellent quality,and indicated that obvious remodeling was observed in H3K27ac enhancers in HGIN and GC groups(P<0.05),though no significant difference in the genome-wide distribution of H3K27ac modification among the 3 groups.Combining transcriptome data revealed that enhancer remodeling may up-regulate the expression of the proliferation-related target gene,CD24,in the HGIN tissue;while,inhibiting enhancer activity can notably reduce CD24 expression level(P<0.05).Immunohistochemical assay displayed a positive correlation between the expression levels of CD24 and Ki-67(P<0.001).Conclusion The remodeling of H3K27ac enhancer represents a significant epigenetic feature of the transformation from normal condition to HGIN.Remodeling of H3K27ac enhancer up-regulates CD24,which may facilitate the abnormal proliferation of gastric epithelial cells.

Objective To construct a model for predicting the risk of essential hypertension accompanied by left ventricular hypertrophy using machine learning algorithms based on pulse diagram parameters;To explore its clinical application value.Methods A total of 295 patients with essential hypertension who were hospitalized in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai Hospital of Traditional Chinese Medicine and Shanghai Hospital of Integrated Traditional Chinese and Western Medicine were selected from July 2020 to May 2021 and July 2023 to July 2024.According to the echocardiographic results,the selected research subjects were divided into the essential hypertension with left ventricular hypertrophy group(referred to as the"LVH group")and the essential hypertension without left ventricular hypertrophy group(referred to as the"non-LVH group").The general data and clinical biochemical indicators were collected,and the pulse diagram parameters of the patients were detected using the SMART-I type TCM digital pulse analyzer.A clinical prediction model was constructed based on decision tree,support vector machine and extreme gradient boosting model algorithms.The predictive performance of the model was evaluated in terms of discrimination,calibration and clinical prediction ability by using the receiver operating characteristic(ROC)curve,calibration curve and decision curve analysis respectively.The influence of each predictive factor on the risk of LVH in essential hypertension was explained based on the SHAP algorithm.Results Compared with the non-LVH group,the BMI,the proportion of males,drinkers and smokers was lower in the LVH group,with statistical significance(P<0.05);the thickened ventricular wall,left ventricular internal dimension enlargement,left common carotid artery intima-media thickness and high density lipoprotein cholesterol were higher in the LVH group than in the non-LVH group(P<0.05);the left common carotid peak systolic velocity,left common carotid resistance index,serum uric acid and serum creatinine were lower in the LVH group than in the non-LVH group(P<0.05).The pulse diagram parameters T4,T,W1,W2,H3/H1 and H4/H1 were higher in the LVH group than in the non-LVH group(P<0.05).The areas of the ROC curves of the models constructed by the three types of machine learning algorithms were 0.887,0.962 and 0.873 respectively,indicating that the model had good discrimination and certain diagnostic efficacy.The calibration curve suggested that the prediction accuracy of the model was average;the clinical decision curve showed that XGBoost model has a higher net benefit.Conclusion The interpretable model constructed based on pulse diagram parameters and machine learning algorithms can be used as a reliable tool for predicting the risk of essential hypertension with LVH.

Objective To construct a model for predicting the risk of essential hypertension accompanied by left ventricular hypertrophy using machine learning algorithms based on pulse diagram parameters;To explore its clinical application value.Methods A total of 295 patients with essential hypertension who were hospitalized in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai Hospital of Traditional Chinese Medicine and Shanghai Hospital of Integrated Traditional Chinese and Western Medicine were selected from July 2020 to May 2021 and July 2023 to July 2024.According to the echocardiographic results,the selected research subjects were divided into the essential hypertension with left ventricular hypertrophy group(referred to as the"LVH group")and the essential hypertension without left ventricular hypertrophy group(referred to as the"non-LVH group").The general data and clinical biochemical indicators were collected,and the pulse diagram parameters of the patients were detected using the SMART-I type TCM digital pulse analyzer.A clinical prediction model was constructed based on decision tree,support vector machine and extreme gradient boosting model algorithms.The predictive performance of the model was evaluated in terms of discrimination,calibration and clinical prediction ability by using the receiver operating characteristic(ROC)curve,calibration curve and decision curve analysis respectively.The influence of each predictive factor on the risk of LVH in essential hypertension was explained based on the SHAP algorithm.Results Compared with the non-LVH group,the BMI,the proportion of males,drinkers and smokers was lower in the LVH group,with statistical significance(P<0.05);the thickened ventricular wall,left ventricular internal dimension enlargement,left common carotid artery intima-media thickness and high density lipoprotein cholesterol were higher in the LVH group than in the non-LVH group(P<0.05);the left common carotid peak systolic velocity,left common carotid resistance index,serum uric acid and serum creatinine were lower in the LVH group than in the non-LVH group(P<0.05).The pulse diagram parameters T4,T,W1,W2,H3/H1 and H4/H1 were higher in the LVH group than in the non-LVH group(P<0.05).The areas of the ROC curves of the models constructed by the three types of machine learning algorithms were 0.887,0.962 and 0.873 respectively,indicating that the model had good discrimination and certain diagnostic efficacy.The calibration curve suggested that the prediction accuracy of the model was average;the clinical decision curve showed that XGBoost model has a higher net benefit.Conclusion The interpretable model constructed based on pulse diagram parameters and machine learning algorithms can be used as a reliable tool for predicting the risk of essential hypertension with LVH.

Objective:To evaluate the sound localization ability of patients with different degrees of unilateral conductive hearing loss (UCHL) in quiet and noisy environments, and to explore the changes and characteristics of sound localization.Methods:This was a cross-sectional study. 41 patients with UCHL were hospitalized in Shandong Provincial ENT Hospital from January to April 2024, including 22 males and 19 females, aged 18-55 years old, with an average age of 36.9 years. According to the pure-tone average (PTA) of 500, 1000 and 2000 Hz in the suffered ear, subjects were divided into slight-mild UCHL group (20 numbers) and moderate-moderately severe UCHL group (21 numbers). 21 patients with normal hearing (NH) were enrolled as controls. All subjects were assessed through pure-tone audiometry, horizontal sound localization test (including azimuth identification test in quiet and noisy environments), Chinese edition short form of Spatial Hearing Questionnaire (C-SHQ12) and twelve-item version of Speech, Spatial, and Qualities of Hearing Scale (SSQ12). SPSS, version 26.0, was used for statistical analysis.Results:There were significant differences in the root-mean-square errors (RMSE) of the sound localization azimuth identification test in quiet and noisy environments among the NH group, slight-mild UCHL group, and moderate-moderately severe UCHL group (Quiet: F=29.109, P<0.001; Noisy: F=24.351, P<0.001). This presented statistically marked difference in the RMSEs between the two listening environments in the slight-mild UCHL group ( t=-4.911, P<0.001). There was a statistical difference in the RMSEs between the normal and affected sides of the subjects in the slight-mild UCHL group in the quiet environment ( t=-2.055, P<0.05), but not in the noisy environment. For moderate-moderately severe UCHL subjects, there were no differences in the RMSEs between the quiet and noisy environments ( P>0.05). What’s more，no significant differences were found between normal side and affected side in both environments ( P>0.05). The RMSEs of UCHL patients in quiet and noisy environments were positively correlated with PTA of air-conduction in the suffered ears (Quiet: r=0.681, P<0.001; Noisy: r=0.346, P<0.05). RMSEs in quiet and noisy environments were negatively correlated with the average localization scores in C-SHQ12 (Quiet: r=-0.576, P<0.001, Noisy: r=-0.613, P<0.001) and in SSQ12 (Quiet: r=-0.634, P<0.001, Noisy: r=-0.663, P<0.001). Conclusions:The sound localization ability of UCHL subjects decreased compared with those with normal hearing, and the RMSE gradually increased with the worse of air conduction hearing threshold. The localization ability of UCHL subjects was further reduced in the noisy environment compared with that in the quiet environment. The slight-mild UCHL subjects had better localization performance in the normal ears while worse in the suffered ears, however, when they were in noisy environment or their hearing loss deteriorated, the localization advantage of the normal ears was no longer obvious, and both sides of the subjects presented poor localization performance.

Angiopoietin-like proteins(ANGPTLs)are a family of proteins that are structurally similar to angio-poietin.So far,eight ANGPTLs have been discovered,namely ANGPTL1 to ANGPTL8.They are not only angiogenic fac-tors,but also play a pivotal role in various pathophysiological processes such as glucose and lipid metabolism,redox regu-lation,chronic inflammation and cancer,and having a close connection with the occurrence and development of metabolic diseases.This review focuses on the mechanism of action of ANGPTLs in metabolic associated fatty liver disease,in order to make a contribution to the prevention and treatment of MAFLD and concurrent diseases.

This study was aimed at providing basic data for the control and prevention of Yersinia enterocolitica(Ye)infections.Ye isolates from stool samples collected from patients with diarrhea in a Beijing district between January 2019 and June 2024 were studied.Basic patient information and stool samples were collected,and quantitative polymerase chain reaction(qPCR)was applied to enriched cultures.Further analyses included virulence gene detection,whole-genome sequencing,and drug resistance detection.The detection rate of Ye was 0.76%(11/1 439),according to culture methods,thus yielding 12 Ye strains from distinct patients:11 isolated during the study period and 1 from 2017.The 12 Ye positive patients were 6-41 years of age,and their clinical presentations predominantly featured watery stools(66.67%,8/12)and loose stools(33.33%,4/12).The frequencies of nausea,vomiting,and fever were 41.67%(5/12),41.67%(5/12),and 8.33%(1/12),respectively.The drug resistance rates of Ye to TET,AMP,and NAL were 50.00%(6/12),33.33%(4/12),and 25.00%(3/12),respectively.One Ye strain exhibited multidrug resistance to ETP,MEM,TET,CIP,NAL,and AMP.According to qPCR detection of five common virulence genes,two Ye strains were identified as ystA+/ystB-type(ystA+/ystB-/ail+/yadA+/virF+),whereas ten strains were identified as ystA-/ystB+type(ystA-/ystB+/ail-/yadA-/virF-).VFDB database analysis based on genome sequences indicated that 12 Ye strains carried an average of 11 key virulence genes associated with adhesion,invasion,protease activity,and flagellar movement,and predicted 106 virulence genes and 12 virulence gene profiles.Only the two ystA+/ystB-Ye strains contained elements related to the TTSS and ABC transporter function.Detection of ystA-/ystB+Ye in stool isolation and culture of diarrhea cases might potentially have been missed in some cases,thus highlighting the importance of fluorescence PCR screening of fecal growth solutions to enhance isolation efficiency.Moreover,our findings revealed the genetic diversity of Ye isolated from diarrhea cases,thereby indicating the presence of multiple types of virulence genes within this pathogen.

Facing the requirements of promoting the healthy China initiative and improving people's health, the "bone health program" was proposed in 2024. In-depth development of a traditional Chinese medicine(TCM) prevention and control system is of strategic significance to the implementation of the "bone health program". Focusing on osteoporosis(OP), a representative disease affecting people's bone health, this paper concludes that accelerating the research on the prevention and control of OP by TCM is conducive to enhancing the knowledge and awareness of OP among the public, and it is beneficial to revealing the evolutionary pattern of OP and improving the understanding and management of this disease. Additionally, it can provide an overall framework for and strengthen the systematicity and completeness of the research on the prevention and treatment of OP by TCM. Meanwhile, it can help to explore new research paradigms and optimize the existing research model, so as to promote innovative breakthroughs in the prevention and treatment of bone health-related diseases by TCM. Under the overall layout of the "bone health program", importance should be attached to the early prevention and the innovation of very early diagnosis and intervention of OP. Emphasis should be put on the discovery of the target network of disease and treatment mechanism for revealing the core pathogenesis of OP and the therapeutic mechanism of TCM. In addition to local lesions of the bone and its clinical outcomes, attention should be paid to the development of multiple metabolic complications. The fusion of advanced interdisciplinary technologies should be promoted for OP and its complications, and thus a research and development system based on clinical application scenarios and driven by big data can be built. The measures above will facilitate the progress in the prevention and treatment of OP and other bone diseases by TCM and provide new momentum for enriching and deepening the research connotation of the "bone health program".
Osteoporosis/therapy* ; Humans ; Medicine, Chinese Traditional/methods* ; Drugs, Chinese Herbal/therapeutic use* ; China ; Bone and Bones/drug effects*

In the development of traditional Chinese medicine(TCM), the concept of "preventive treatment of disease" has a long history and plays a crucial role in bridging the past and the future. With the continuous growth of public health needs and the ongoing transformation of the registration management of TCM, its position in the research and development of new drugs has become increasingly significant. As one of the important sources of new drug innovation, the new TCM for "preventive treatment of diseases" represents a new thinking proposed based on the current routine registration and research and development. The research and development of TCM for "preventive treatment of diseases" mainly cover four stages: prevention(before the onset of disease), early intervention(when the disease is about to occur), interruption and reversal(when the disease has already occurred), and prevention of recurrence after recovery(after the disease). This study aims to comprehensively analyze the positioning, key points, and difficulties in the research and development of TCM for "preventive treatment of diseases" and explore effective paths to promote the innovative development of TCM through relevant cases. The research and development of new TCM for "preventive treatment of disease" require researchers to seize the opportunities for innovation before the start of the research and development, accurately grasp the key issues at different stages, and pay attention to the full lifecycle evaluation of the drugs. Meanwhile, in the design of the research plan, the optimal effectiveness evaluation indicators should be explored; key and difficult areas such as chronic diseases and rare diseases should be taken seriously, and the limitations of new drug development only based on the diagnosed diseases should be broken, so as to cater to more patients. In addition, through relevant representative cases in China and abroad, the unique advantages of TCM for "preventive treatment of diseases" should be fully leveraged. By learning from the past, all aspects of key points in the evaluation of new drug research and development should be strengthened. Finally, this study proposed that TCM for "preventive treatment of diseases" can employ novel methods and advanced technologies such as new biomarkers and innovative clinical design protocols, as well as new perspectives on disease research and health management. This can provide new paths for the innovation of TCM and public health management.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional/methods* ; Pharmacy Research

INTRODUCTION: Obstructive sleep apnoea (OSA) is common in Singapore, with moderate to severe OSA affecting around 30% of residents. These consensus statements aim to provide scientifically grounded recommendations for the management of OSA, standar-dise the management of OSA in Singapore and promote multidisciplinary collaboration. METHOD: An expert panel, which was convened in 2024, identified several areas of OSA management that require guidance. The expert panel reviewed the current literature and developed consensus statements, which were later independently voted on using a 3-point Likert scale (agree, neutral or disagree). Consensus (total ratings of agree and neutral) was set a priori at ≥80% agreement. Any statement not reaching consensus was excluded. RESULTS: The final consensus included 49 statements that provide guidance on the screening, diagnosis and management of adults with OSA. Additionally, 23 statements on the screening, diagnosis and management of paediatric OSA achieved consensus. These 72 consensus statements considered not only the latest clinical evidence but also the benefits and harms, resource implications, feasibility, acceptability and equity impact of the recommendations. CONCLUSION The statements presented in this paper aim to guide clinicians based on the most updated evidence and collective expert opinion from sleep specialists in Singapore. These recommendations should augment clinical judgement rather than replace it. Management decisions should be individualised, taking into account the patient's clinical characteristics, as well as patient and caregiver concerns and preferences.
Humans ; Sleep Apnea, Obstructive/diagnosis* ; Singapore ; Consensus ; Adult

ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.