BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

BACKGROUND: While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS: This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS: The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.
Humans ; Retrospective Studies ; Male ; Length of Stay/statistics & numerical data* ; Female ; Middle Aged ; Adult ; Psychological Distress ; Inpatients/psychology* ; Aged ; Anxiety/diagnosis* ; Depression/diagnosis*

The chemical constituents of the petroleum ether extract derived from the 90% ethanol extract of Elephantopus scaber were investigated. By silica gel column chromatography, C_(18), MCI column chromatography and semi-preparative high performance liquid chromatography, ten compounds were isolated. Their structures were identified as 3β-hydroxy-6β,7β-epoxytaraxeran-14-ene(1), 3β-hydroxyolean-12-en-28-oic acid(2), D-friedoolean-14-ene-3β,7α-diol(3), 3β-hydroxy-11α-methoxyolean-12-ene(4), 3β-hydroxyolean-11,13(18)-diene(5), 11α-hydroxy-β-amyrin(6), betulinic acid(7), 3β-hydroxy-30-norlupan-20-one(8), 6-acetonylchelerythrine(9), and 4',5'-dehydrodiodictyonema A(10) by analysis of the 1D NMR, 2D NMR, MS, and IR spectral data. Among them, compound 1 was a new triterpene and other compounds except compounds 2 and 7 were isolated from this plant for the first time.
Triterpenes/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Molecular Structure ; Asteraceae/chemistry* ; Chromatography, High Pressure Liquid ; Magnetic Resonance Spectroscopy

This consensus will introduce the characteristics of fillers used in the surgical cavities of domestic nasal surgery patients based on relevant literature and expert opinions. It will also provide recommendations for the selection of cavity fillers for different nasal diseases, with chronic sinusitis as a representative example.
Humans ; Nasal Cavity/surgery* ; Nasal Surgical Procedures ; China ; Consensus ; Sinusitis/surgery* ; Dermal Fillers

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Objective Studies on the relationship between iodine,vitamin A(VA),and vitamin D(VD)and thyroid function are limited.This study aimed to analyze iodine and thyroid-stimulating hormone(TSH)status and their possible relationships with VA,VD,and other factors in postpartum women. Methods A total of 1,311 mothers(896 lactating and 415 non-lactating)from Hebei,Zhejiang,and Guangxi provinces were included in this study.The urinary iodine concentration(UIC),TSH,VA,and VD were measured. Results The median UIC of total and lactating participants were 142.00 μg/L and 139.95 μg/L,respectively.The median TSH,VA,and VD levels in all the participants were 1.89 mIU/L,0.44 μg/mL,and 24.04 ng/mL,respectively.No differences in the UIC were found between lactating and non-lactating mothers.UIC and TSH levels were significantly different among the three provinces.The rural UIC was higher than the urban UIC.Obese mothers had a higher UIC and a higher prevalence of excessive TSH.Higher UICs and TSHs levels were observed in both the VD deficiency and insufficiency groups than in the VD-sufficient group.After adjustment,no linear correlation was observed between UIC and VA/VD.No interaction was found between vitamins A/D and UIC on TSH levels. Conclusion The mothers in the present study had no iodine deficiency.Region,area type,BMI,and VD may be related to the iodine status or TSH levels.

The Piezo protein is a non-selective mechanosensitive cation channel that exhibits sensitivity to mechanical stimuli such as pressure and shear stress. It converts mechanical signals into bioelectric activity within cells, thus triggering specific biological responses. In the digestive system, Piezo protein plays a crucial role in maintaining normal physiological activities, including digestion, absorption, metabolic regulation, and immune modulation. However, dysregulation in Piezo protein expression may lead to the occurrence of several pathological conditions, including visceral hypersensitivity, impairment of intestinal mucosal barrier function, and immune inflammation.Therefore, conducting a comprehensive review of the physiological functions and pathological roles of Piezo protein in the digestive system is of paramount importance. In this review, we systematically summarize the structural and dynamic characteristics of Piezo protein, its expression patterns, and physiological functions in the digestive system. We particularly focus on elucidating the mechanisms of action of Piezo protein in digestive system tumor diseases, inflammatory diseases, fibrotic diseases, and functional disorders. Through the integration of the latest research findings, we have observed that Piezo protein plays a crucial role in the pathogenesis of various digestive system diseases. There exist intricate interactions between Piezo protein and multiple phenotypes of digestive system tumors such as proliferation, apoptosis, and metastasis. In inflammatory diseases, Piezo protein promotes intestinal immune responses and pancreatic trypsinogen activation, contributing to the development of ulcerative colitis, Crohn’s disease, and pancreatitis. Additionally, Piezo1, through pathways involving co-action with the TRPV4 ion channel, facilitates neutrophil recruitment and suppresses HIF-1α ubiquitination, thereby mediating organ fibrosis in organs like the liver and pancreas. Moreover, Piezo protein regulation by gut microbiota or factors like age and gender can result in increased or decreased visceral sensitivity, and alterations in intestinal mucosal barrier structure and permeability, which are closely associated with functional disorders like irritable bowel sydrome (IBS) and functional consitipaction (FC). A thorough exploration of Piezo protein as a potential therapeutic target in digestive system diseases can provide a scientific basis and theoretical support for future clinical diagnosis and treatment strategies.

Objective This study aimed to investigate the potential relationship between urinary metals copper (Cu), arsenic (As), strontium (Sr), barium (Ba), iron (Fe), lead (Pb) and manganese (Mn) and grip strength. Methods We used linear regression models, quantile g-computation and Bayesian kernel machine regression (BKMR) to assess the relationship between metals and grip strength.Results In the multimetal linear regression, Cu (β=-2.119), As (β=-1.318), Sr (β=-2.480), Ba (β=0.781), Fe (β= 1.130) and Mn (β=-0.404) were significantly correlated with grip strength (P < 0.05). The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was -1.007 (95％ confidence interval:-1.362, -0.652; P < 0.001) when each quartile of the mixture of the seven metals was increased. Bayesian kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength, with Cu, As and Sr being negatively associated with grip strength levels. In the total population, potential interactions were observed between As and Mn and between Cu and Mn (Pinteractions of 0.003 and 0.018, respectively).Conclusion In summary, this study suggests that combined exposure to metal mixtures is negatively associated with grip strength. Cu, Sr and As were negatively correlated with grip strength levels, and there were potential interactions between As and Mn and between Cu and Mn.

Objective:To investigate two cases of rare pathogenic genes,initiation codon mutations in HBA2 gene,combined with Southeast Asian deletion and their family members to understand the relationship of HBA2:c.2T＞C and HBA2:c.2delT mutations with clinical phenotype.Methods:The peripheral blood of family members was obtained for blood cell analysis and capillary electrophoresis hemoglobin analysis.Gap-PCR and reverse dot blotting(RDB)were used to detect common types of mutations in α-thalassaemia gene.Sanger sequencing was used to analyze HBA1 and HBA2 gene sequence.Results:Two proband genotypes were identified as--SEA/αα with HBA2:c.2T＞C and--SEA/αα with HBA2:c.2delT.HBA2:c.2T＞C/WT and HBA2:c.2delT/WT was detected in family members.They all presented with microcytic hypochromic anemia.Conclusion:When HBA2:c.2T＞C and HBA2:c.2delT are heterozygous that can lead to static α-thalassemia phenotype,and when combined with mild α-thalassemia,they can lead to the clinical manifestations of hemoglobin H disease.This study provides a basis for genetic counseling.

Objective To observe the value of self-supervised deep learning artificial intelligence(AI)noise reduction technology based on the nearest adjacent layer applicated in ultra-low dose CT(ULDCT)for urinary calculi.Methods Eighty-eight urinary calculi patients were prospectively enrolled.Low dose CT(LDCT)and ULDCT scanning were performed,and the effective dose(ED)of each scanning protocol were calculated.The patients were then randomly divided into training set(n=75)and test set(n=13),and a self-supervised deep learning AI noise reduction system based on the nearest adjacent layer constructed with ULDCT images in training set was used for reducing noise of ULDCT images in test set.In test set,the quality of ULDCT images before and after AI noise reduction were compared with LDCT images,i.e.Blind/Referenceless Image Spatial Quality Evaluator(BRISQUE)scores,image noise(SDROI)and signal-to-noise ratio(SNR).Results The tube current,the volume CT dose index and the dose length product of abdominal ULDCT scanning protocol were all lower compared with those of LDCT scanning protocol(all P＜0.05),with a decrease of ED for approximately 82.66％.For 13 patients with urinary calculi in test set,BRISQUE score showed that the quality level of ULDCT images before AI noise reduction reached 54.42％level but raised to 95.76％level of LDCT images after AI noise reduction.Both ULDCT images after AI noise reduction and LDCT images had lower SDROI and higher SNR than ULDCT images before AI noise reduction(all adjusted P＜0.05),whereas no significant difference was found between the former two(both adjusted P＞0.05).Conclusion Self-supervised learning AI noise reduction technology based on the nearest adjacent layer could effectively reduce noise and improve image quality of urinary calculi ULDCT images,being conducive for clinical application of ULDCT.