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*

Cervical spinal cord injury without fracture-dislocation (CSCIWFD) is referred to as a special type of cervical spinal cord injury characterized by traumatic spinal cord dysfunction and no significant bony structural abnormalities on imagines. Duo to the high risk of missed diagnosis during the initial consultation, CSCIWFD may lead to progressive neurological deterioration or even complete paralysis, severely impacting patients′ prognosis. Currently, there are no established consensuses over the diagnosis and treatment of CSCIWFD, such as the lack of evidence-based standards for indications of non-surgical treatment and risk of secondary neurological injury, as well as debates over the optimal timing for surgical intervention and indications for different surgical approaches. To address these issues, the Spine Trauma Group of the Orthopedic Branch of the Chinese Medical Doctor Association organized experts in the relevant fields to formulate Diagnosis and treatment guideline for acute cervical spinal cord injury without fracture- dislocation in adults ( version 2025) . Based on evidence-based medicine and the principles of scientific rigor and clinical applicability, the guidelines proposed 11 recommendations covering terminology, diagnosis, evaluation treatment, and rehabilitation, etc., aiming to standardize the management of CSCIWFD.

Objective:The serum ferritin-to-albumin ratio(FAR)has been proposed as a novel prognostic marker for sepsis,but its predictive role in outcomes among critically ill patients remains unclear.This study aimed to investigate the correlation between FAR and in-hospital mortality among critically ill patients.Methods:Based on the Medical Information Mart for Intensive Care-Ⅳ(MIMIC-Ⅳ),8,136 Intensive Care Unit(ICU)patients were included.Multivariate logistic regression was used to evaluate the predictive value of FAR for in-hospital mortality,and receiver operating characteristic(ROC)curve analysis was performed to compare its predictive performance with other parameters.Results:The overall in-hospital mortality was 2.31％.Multivariate logistic regression analysis showed that FAR was an independent predictor of in-hospital death(OR=2.190,95％CI=1.730-2.780,P=0.000).ROC analysis revealed that FAR achieved a significantly higher area under the curve(AUC)value(0.72)compared to ferritin(0.69)and albumin(0.26),with an optimal cutoff value of 80.57.Subgroup analysis demonstrated no significant interaction effects between FAR and most subgroups(P＞0.05),except for the hypertension subgroup.Conclusion:FAR is significantly associated with in-hospital mortality in critically ill patients,and elevated FAR values indicate an increased risk of death.

Objective:To explore the effect of evidence-based standardized procedures(SOP)on urinary incontinence manage-ment in patients with radical prostatectomy.Methods:Sixty-three patients who underwent radical prostatectomy from October 2022 to September 2023 were included in the control group.And 63 patients who underwent radical prostatectomy from October 2023 to Sep-tember 2024 were included in the observation group.The patients in the control group received routine perioperative care.As an addi-tion,the SOP on urinary incontinence management was performed in the patients of observation group.The incidence of urinary inconti-nence,severity of urinary incontinence(1 h urine pad test),quality of life(Incontinence Quality of Life Questionnaire)and comfort level(General Comfort Question)of the two groups were compared after 3 and 6 months of surgery.Results:The incidence of urina-ry incontinence at 3 and 6 months after operation in the observation group was 36.51％and 19.05％,respectively,which were lower than those(53.97％and 38.10％)of the control group,respectively.And the incidence rates of the two groups decreased significant-ly(P＜0.05).The score of life quality after 3 months of operation was(56.17±12.75)in the control group,which was lower than that(70.41±14.50)of the observation group.The 3-month postoperative comfort score was(52.73±11.26)in the control group and(63.49±13.52)in the observation group.The 6-month postoperative incontinence quality of life score was(64.70±11.38)in the control group and(85.41±12.04)in the observation group.And the 6-month postoperative comfort score was(60.96±8.04)in the control group and(83.49±12.04)in the observation group.The quality of life and comfort scores of the two groups 6 months after operation were significantly improved than those 3 months after operation,and the improvement of the observation group was more obvi-ous than that of the control group(P＜0.05).There were significant differences in the degree of urinary incontinence between the two groups at 3 months and 6 months after operation(P＜0.05).Conclusion:SOP management for the patients underwent radical pros-tatectomy can be an effective method for reducing the incidence of postoperative urinary incontinence,which promotes the recovery of postoperative urinary control.

Wastewater-based epidemiology has emerged as a transformative surveillance tool for estimating substance consumption and monitoring disease prevalence, particularly during the COVID-19 pandemic. It enables the population-level monitoring of illicit drug use, pathogen prevalence, and environmental pollutant exposure. In this perspective, we summarize the key challenges specific to the Chinese context: (1) Sampling inconsistencies, necessitating standardized 24-hour composite protocols with high-frequency autosamplers (≤ 15 min/event) to improve the representativeness of samples; (2) Biomarker validation, requiring rigorous assessment of excretion profiles and in-sewer stability; (3) Analytical method disparities, demanding inter-laboratory proficiency testing and the development of automated pretreatment instruments; (4) Catchment population dynamics, reducing estimation uncertainties through mobile phone data, flow-based models, or hydrochemical parameters; and (5) Ethical and data management concerns, including privacy risks for small communities, mitigated through data de-identification and tiered reporting platforms. To address these challenges, we propose an integrated framework that features adaptive sampling networks, multi-scale wastewater sample banks, biomarker databases with multidimensional metadata, and intelligent data dashboards. In summary, wastewater-based epidemiology offers unparalleled scalability for equitable health surveillance and can improve the health of the entire population by providing timely and objective information to guide the development of targeted policies.
China/epidemiology* ; Humans ; Wastewater/analysis* ; COVID-19/epidemiology* ; Public Health ; Wastewater-Based Epidemiological Monitoring ; SARS-CoV-2

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

OBJECTIVE To understand the disinfectant-resistant genes in the gram-negative bacteria isolated from the dirt retention on air recure filters of air conditioners and observe the drug resistance.METHODS The dirt re-tention samples were collected from the air return filters of air conditioners of some wards in 3 hospitals of Wuhan(Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology,Wuhan Central Hospital,and Hubei Provincial Maternal and Child Health Hospital)from 2018 to 2024.The gram-negative bac-teria were screened out,the disinfectant-resistant genes in the strains were detected by polymerase chain reaction(PCR),and the results of drug susceptibility test were analyzed.RESULTS Of 354 dirt retention samples that were collected from the air return filers of air conditioners,77 were detected with 138 strains of gram-negative bacteria,87 of which were Acinetobacter baumannii,50 were Enterobacteriaceae,and 1 was Pseudomonas aerug-inosa.The detection rates of qacEΔ1,qacEΔ1-sul1,aceI and qacA/B were 73.19％,82.61％,69.57％and 2.90％,respectively.None of the strains were detected with qacC,qacH or qacJ.The result of drug susceptibility test showed that 76.81％of the gram-negative bacteria were resistant to at least 1 type of antibiotic;93 strains of multidrug-resistant gram-negative bacteria were isolated,most of which were isolated from intensive care unit(ICU).The detection rates of qacEΔ1 and qacEΔ1-sul1 were higher in the drug-resistant strains than those in the non-drug-resistant strains;there were significant differences in the drug resistance rates to carbapenems,quin-olones and β-lactams between the qacEΔ1-sul 1-positive strains and the qacEΔ1-sul1-negative strains(P＜0.05).CONCLUSIONS There are drug-resistant gram-negative bacteria contaminations in some wards of the 3 hospitals in Wuhan.The carrying rates of disinfectant-resistant genes of the strains are high,and the strains show varying degree of resistance to the commonly used antibiotics;the strains carrying the qacEΔ1-sul1 have certain statistical association with the drug resistance.It is suggested that the hospital should take targeted disinfec-tion measures for the environment and reasonably use antibiotics.

Thoracic anesthesia with spontaneous respiration represents a form of precision anesthesia meticulously customized to individual patients.Considering the more stringent requirements this anesthesia approach imposes on the regulation of respiratory function,the writing group of the"Consensus of Experts on the Management of Thoracic Anesthesia with Spontaneous Respiration"has formulated elaborate guidelines regarding indications and contraindications,preoperative evaluation,anesthesia implementation,common complications,and treatment strategies.This was accomplished by referencing relevant domestic and international literature and integrating it with actual clinical requirements.The objective is to standardize the rational application of this anesthesia method.

Objective:To analyze the predictive factors associated with late-onset sepsis(LOS) in very low birth weight infants,and to develop a risk prediction score scale applicable to these infants three days postnatal.This will provide valuable insights for early diagnosis and timely intervention.Methods:Very low birth weight infants admitted to the Children's Hospital of Fudan University from January 1,2022,to June 30,2024,were selected as research subjects.These infants were categorized into two groups:the LOS group and the non-LOS group,based on whether they developed LOS.LASSO regression analysis,alongside univariate and multivariate regression analyses,was employed to identify predictive factors for LOS in this population.A Logistic model was constructed using the optimal combination of predictive variables,and a risk assessment scale was subsequently developed.The prediction performance of the model was evaluated using the Hosmer-Lemeshow chi-square test and the receiver operating characteristic curve.Results:A total of 444 cases of very low birth weight infants were included,of which 185 had LOS and 259 did not.After screening the variables,seven independent factors were included into the model:birth weight,gestational age,tracheal intubation,abnormal skin color,abdominal distension,elevated C-reactive protein levels,and right hand perfusion index.A predictive scoring scale was developed based on the regression coefficients of each variable,with corresponding risk scores assigned as follows:1,4,3,2,1,1,and 2; a score of ≥3.5 indicated high-risk groups.The Hosmer-Lemeshow test results demonstrated that χ2 = 7.602( P = 0.473).The area under the receiver operating characteristic curve was 0.792 ( P<0.001),with a sensitivity of 73.5% and specificity of 71.0%. Conclusion:The risk score scale developed in this study exhibits significant predictive capability,providing valuable insights for clinical medical personnel to assess the risk of LOS in very low birth weight infants during the early postnatal period.