PURPOSE: Early mortality in major trauma has decreased, but MODS remains a leading cause of poor outcomes, driven by trauma-induced cytokine storms that exacerbate injuries and organ damage. METHODS: This prospective cohort study included 79 major trauma patients (ISS >15) treated in the National Center for Trauma Medicine, Peking University People's Hospital, from September 1, 2021, to July 31, 2023. Patients (1) with ISS >15 (according to AIS 2015), (2) aged 15-80 years, (3) admitted within 6 h of injury, (4) having no prior treatment before admission, were included. Exclusion criteria were (1) GCS score <9 or AIS score ≥3 for TBI, (2) confirmed infection, infectious disease, or high infection risk, (3) pregnancy, (4) severe primary diseases affecting survival, (5) recent use of immunosuppressive or cytotoxic drugs within the past 6 months, (6) psychiatric patients, (7) participation in other clinical trials within the past 30 days, (8) patients with incomplete data or missing blood samples. Admission serum inflammatory cytokines and pathophysiological data were analyzed to develop machine learning models predicting MODS within 7 days. LR, DR, RF, SVM, NB, and XGBoost were evaluated based on the area under the AUROC. The SHAP method was used to interpret results. RESULTS: This study enrolled 79 patients with major trauma, and the median (Q₁, Q₃) age was 51 (35, 59) years (52 males, 65.8%). The inflammatory cytokine data were collected for all participants. Among these patients, 35 (44.3%) developed MODS, and 44 (55.7%) did not. Additionally, 2 patients (2.5%) from the MODS group succumbed. The logistic regression model showed strong performance in predicting MODS. Ten key cytokines, IL-18, Eotaxin, MCP-4, IP-10, CXCL12, MIP-3α, MCP-1, IL-1RA, Cystatin C, and MRP8/14 were identified as critical to the trauma-induced cytokine storm and MODS development. Early elevation of these cytokines achieved high predictive accuracy, with an AUROC of 0.887 (95% CI 0.813-0.976). CONCLUSION Trauma-induced cytokine storms are strongly associated with MODS. Early identification of inflammatory cytokine changes enables better prediction and timely interventions to improve outcomes.
Humans ; Prospective Studies ; Middle Aged ; Male ; Female ; Adult ; Aged ; Cytokine Release Syndrome/etiology* ; Adolescent ; Young Adult ; Aged, 80 and over ; Wounds and Injuries/complications* ; Cytokines/blood* ; Multiple Organ Failure/diagnosis* ; Machine Learning

Purpose To investigate the effect of autophagy intervention on ferroptosis and drug resistance of colorectal canc-er cells and its molecular mechanism.Methods The human colorectal cancer cell lines HCT-8,COLO205,HCT-116,SW620,and SW480 were cultured.HCT-116 cells with moder-ate expression of LC3 were screened,and the expression differ-ences of LC3,p62,Keap1,Nrf2,GPX4 proteins,Fe2+,GSH,and MDA between them and OXA-resistant HCT-116/OXA cell lines were detected.The expression levels of LC3,p62,Keap1,Nrf2,GPX4,Fe2+,GSH and MDA were assessed in HCT-116/OXA cells through the intervention of autophagy and ferroptosis intervention agent combined with oxaliplatin.The proliferative activity and sensitivity to oxaliplatin in each group were detected by CCK-8 assay.Cell growth and invasion ability of each group were detected by plate cloning and Trans well assay.Results LC3,p62 and GPX4 expression levels of HCT-116 cells in the 5 groups were moderate.Compared with HCT-116 cells,HCT-116/OXA was less sensitive to oxaliplatin,and the proteins of p62,Nrf2 and GPX4 were highly expressed,LC3 and Keap1 were lowly expressed,and the expression of Fe2+,GSH and MDA were increased(P＜0.05).The levels of LC3,Keap1 protein,Fe2+and MDA in Rapa and Rapa+Fer-1 groups were higher than those in Fer-1 and control groups,while p62,Nrf2,GPX4 and GSH levels were lower.The expressions of GPX4 pro-tein and GSH in Rapa+Fer-1 group were lower than those in Rapa group(P＜0.05).In the autophagy inhibitor group,LC3,p62,Nrf2,GPX4 and GSH were highly expressed in the CQ and CQ+Erastin groups compared with the control and Eras-tin groups,while Keap1 protein,Fe2+and MDA were low.The levels of GPX4 protein and GSH in Erastin group were lower than those in the other three groups,and the levels of Fe2+and MDA were higher than those in the other three groups(P＜0.05).The combination of autophagy activator OXA showed that Rapa intervention group had higher chemical sensitivity to OXA,less number of migrating cells and lower cell proliferation activity than the other three groups.The sensitivity of Rapa+Fer-1 group to oxaliplatin was lower than that of Rapa group,but higher than that of Fer-1 group and control group(P＜0.05).There was no significant difference between Fer-1 group and con-trol group(P＜0.05).Compared with the control group,the cell activity,migration capacity and clonogenesis capacity of Erastin,CQ+Erastin and CQ groups were decreased when auto-phagy inhibitor was combined with OXA,and the Erastin group was the lowest,while the CQ+Erastin group was higher than the Erastin group,and lower than the CQ group(P＜0.05).Con-clusion In colorectal cancer,autophagy is involved in the regu-lation of ferroptosis,and intervention in autophagy can regulate ferroptosis in colorectal cancer cells through the p62-Keap1/Nrf2-GPX4 pathway,thereby reversing oxaliplatin resistance.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin’s lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

OBJECTIVES: This study aimed to remove occlusal veneers of varied thicknesses and compositions by Er:Yag laser in vitro and analyze the interfacial microstructure between veneers and tooth that irradiated by laser, by which experimental evidence could be provided to support the non-invasive removal of occlusal veneerby laser. METHODS: Fresh mandibular premolars extracted for orthodontic requirements were collected for tooth preparation. Three kinds of ceramic materials (Vita Suprinity, Vita Mark Ⅱ, and Upcera Hyramic) were selected to fabricate occlusal veneer with different thicknesses (1.0, 1.5, and 2.0 mm). One week later, Er:Yag laser (2.5 W and 3.5 W) was used to irradiate and remove the occlusal veneer and recorded the timespan. After the removal operation, the micro-morphologies of samples were examined by scanning electron microscope. RESULTS: Upcera Hyramic veneer failed to be removed (>20 min); the operation span at 2.5 W, Vita Suprinity (96.0 s±16.0 s) was longer than Vita MarkⅡ(84.5 s±19.5 s) in the 1.0 mm group (P<0.05), and Vita Suprinity (246.5 s±13.5 s) was longer than Vita MarkⅡ(170.0 s±14.0 s) in the 1.5 mm group (P<0.05). At 3.5 W, Vita Suprinity (381.0 s±24.0 s) was longer than Vita MarkⅡ(341.5 s±26.5 s) in the 2.0 mm group. CONCLUSIONS Increasing laser power could shorten the operation span and facilitate the removal of occlusal veneers with the same thickness and composition. The occlusal veneer was sustained when insufficient laser power was applied. With the same laser power and ceramic thickness, laser penetration could interfere with the integral of the ceramic structure when the laser interacted with the bonding layer. With the same ceramic composition and laser power, the operation span and laser power increased with the thickness of the occlusal veneer. However, the laser was incapable of removing occlusal resin veneer directly.
Lasers, Solid-State ; Materials Testing ; Dental Porcelain/chemistry* ; Ceramics/chemistry* ; Bicuspid ; Dental Veneers

Objective Comprehensive mortality risk analyses and therapeutic assessment in real-world practice are beneficial to guide individual treatment in patients with Carbapenem-resistant Klebsiella pneumoniae bloodstream infections(CRKP-BSI).Methods Retrospective analysis of the clinical characteristics of 81 CRKP-BSI patients in our intensive care unit from July 2016 to June 2020,to indentify the risk factors of death and treatment effects of different antibiotic regimens.Results In 81 CRKP-BSI cases,the majority source were from abdominal and respiratory,accounting for 56.79%(46 cases)and 22.22%(18 cases),respectively.The 28-day mortality and hospitalization mortality of CRKP-BSI were 54.32%(44 cases)and 65.43%(53 cases).Multivariate regression analysis suggested that biliary tract disease before admission(P=0.026)and increased SOFA score at the onset of BSI(P=0.006)were independent risk factors for 28-day mortality.There was no statistically significant difference in 28-day mortality between the groups of antibiotic treatment based on tigecycline(44 cases)and polymyxin B(26 cases)[56.82%(25/44)vs.57.69%(15/26),P=0.943].Patients were evaluated based on their age(≤65 years vs.>65 years),gender,body mass index(≤25 kg/m2 vs.>25 kg/m2),and APACHEⅡ score(≤20 vs.>20),the use of renal replacement therapy and mechanical ventilation,there was no difference in the mortality among each subgroup.Conclusions Biliary tract disease before admission and SOFA score were independent risk factors for 28-day mortality.There was no significant difference outcomes between tigecycline-and polymyxin B-based therapy.

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

【Objective】 To analyze the clinical features of nonvalvular atrial fibrillation （NVAF） patients with left atrial/left atrial appendage spontaneous echo contrast （LA/LAASEC）， and investigate the correlation between LA/LAASEC and left atrial diameter. 【Methods】 Clinical data （including gender， age， and history of hypertension， diabetes， stroke or transient ischemic attack， vascular disease）， laboratory indexes （including coagulation indicators， blood routine， thyroid function）， and transthoracic echocardiogram parameters of 262 NVAF patients hospitalized in the Department of Cardiovascular Medicine of our hospital from November 2019 to January 2021 were collected and analyzed retrospectively. According to the results of transesophageal echocardiography， they were divided into control group and LA/LAASEC group. Logistic regression analysis was performed to investigate the influencing factors of LA/LAASEC. ROC curve analysis was used to evaluate the predictive value of left atrial diameter for LA/LAASEC. 【Results】 The proportion of non-paroxysmal atrial fibrillation was significantly higher in LA/LAASEC patients than the controls （65.9% vs. 32.2%， P<0.01）， and so was the CHA2DS2-VASC score （P=0.003）. Compared with the control group， left atrial diameter and left ventricular end-systolic/end-diastolic diameters were significantly increased， left ventricular ejection fraction was significantly decreased， and the level of NT-proBNP was significantly increased in LA/LAASEC group （P<0.05）. Logistic regression analysis showed that non-paroxysmal AF （OR=2.451， 95% CI： 1.260-4.766， P<0.05）， CHA2DS2-VASc score （OR=1.236， 95% CI： 1.023-1.494， P<0.05）， and left atrial diameter （OR=1.086， 95% CI： 1.019-1.157， P<0.05） were independent risk factors for LA/LAASEC. ROC curve analysis displayed that the AUC for left atrial diameter in predicting LA/LAASEC was 0.731 （95% CI： 0.668-0.794， P<0.001）. 【Conclusion】 Left atrial diameter is closely related to LA/LAASEC in NVAF patients. Combined with atrial fibrillation type and CHA2DS2-VASC score， it has a potential value in predicting the risk of thromboembolism in NVAF patients.

Objective:To explore the clinical efficacy of double opposing rhomboid flap in repairing facial skin defects.Methods:From January 2020 to December 2020, 30 cases of facial skin lesions were removed in the Department of Plastic and Aesthetic Surgery, the Affiliated Hospital of Qingdao University, including 12 males and 18 females, aged 14-65 years, with an average age of 34.2 years. The diameter of the facial skin defect wound was 0.5-2.0 cm. The patients with facial skin defect were repaired with double opposing rhomboid flap. All patients were followed up for 3-12 months.Results:The incisions of 30 patients were healed in one stage, and double opposing rhomboid flaps survived. Following-up for 3 to 12 months showed that the operation area was flat, the incision scar was not obvious, the texture and color of the operation area and the surrounding skin matched well, the surrounding organs were not deformed, the lesions were not recurrent, and the cosmetic effect was satisfactory.Conclusions:The double opposing rhomboid flap is an effective method to repair quasi-circular facial skin defects, which is worthy of clinical application.