BACKGROUND: There is little literature describing the artificial intelligence (AI)-aided diagnosis of severe pneumonia (SP) subphenotypes and the association of the subphenotypes with the ventilatory treatment efficacy. The aim of our study is to illustrate whether clinical and biological heterogeneity, such as ventilation and gas-exchange, exists among patients with SP using chest computed tomography (CT)-based AI-aided latent class analysis (LCA). METHODS: This retrospective study included 413 patients hospitalized at Xinhua Hospital diagnosed with SP from June 1, 2015 to May 30, 2020. AI quantification results of chest CT and their combination with additional clinical variables were used to develop LCA models in an SP population. The optimal subphenotypes were determined though evaluating statistical indicators of all the LCA models, and clinical implications of them such as guiding ventilation strategies were further explored by statistical methods. RESULTS: The two-class LCA model based on AI quantification results of chest CT can describe the biological characteristics of the SP population well and hence yielded the two clinical subphenotypes. Patients with subphenotype-1 had milder infections ( P <0.001) than patients with subphenotype-2 and had lower 30-day ( P <0.001) and 90-day ( P <0.001) mortality, and lower in-hospital ( P = 0.001) and 2-year ( P <0.001) mortality. Patients with subphenotype-1 showed a better match between the percentage of non-infected lung volume (used to quantify ventilation) and oxygen saturation (used to reflect gas exchange), compared with patients with subphenotype-2. There were significant differences in the matching degree of lung ventilation and gas exchange between the two subphenotypes ( P <0.001). Compared with patients with subphenotype-2, those with subphenotype-1 showed a relatively better match between CT-based AI metrics of the non-infected region and oxygenation, and their clinical outcomes were effectively improved after receiving invasive ventilation treatment. CONCLUSIONS A two-class LCA model based on AI quantification results of chest CT in the SP population particularly revealed clinical heterogeneity of lung function. Identifying the degree of match between ventilation and gas-exchange may help guide decisions about assisted ventilation.
Humans ; Tomography, X-Ray Computed/methods* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Artificial Intelligence ; Aged ; Pneumonia/diagnosis* ; Latent Class Analysis ; Adult

G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.
Intervertebral Disc Displacement/metabolism* ; Humans ; Aging/pathology* ; Nucleus Pulposus/pathology* ; Male ; Female ; Transcriptome ; Middle Aged ; Lumbar Vertebrae/pathology* ; Adult ; Cellular Senescence ; Stem Cells/pathology* ; Aged ; Intervertebral Disc Degeneration/metabolism*

Glioma, the most prevalent primary tumor of the central nervous system (CNS), is also the most lethal primary malignant tumor. Currently, there are limited chemotherapeutics available for glioma treatment, necessitating further research to identify and develop new chemotherapeutic agents. A significant approach to discovering anti-glioma drugs involves isolating antitumor active ingredients from natural products (NPs) and optimizing their structures. Additionally, targeted drug delivery systems (TDDSs) are employed to enhance drug solubility and stability and overcome the blood-brain barrier (BBB). TDDSs can penetrate deep into the brain, increase drug concentration and retention time in the CNS, and improve the targeting efficiency of NPs, thereby reducing adverse effects and enhancing anti-glioma efficacy. This paper reviews the research progress of anti-glioma activities of NPs, including alkaloids, polyphenols, flavonoids, terpenoids, saponins, quinones, and their synthetic derivatives over the past decade. The review also summarizes anti-glioma mechanisms, such as suppression of related protein expression, regulation of reactive oxygen species (ROS) levels, control of apoptosis signaling pathways, reduction of matrix metalloproteinases (MMPs) expression, blocking of vascular endothelial growth factor (VEGF), and reversal of immunosuppression. Furthermore, the functions and advantages of NP-based TDDSs in anti-glioma therapy are examined. The key information presented in this review will be valuable for the research and development of NP-based anti-glioma drugs and related TDDSs.
Humans ; Glioma/metabolism* ; Biological Products/therapeutic use* ; Animals ; Brain Neoplasms/genetics* ; Drug Delivery Systems ; Antineoplastic Agents/therapeutic use* ; Blood-Brain Barrier/metabolism* ; Apoptosis/drug effects*

Objective:To evaluate the relationship between physical activity (PA) and postoperative delirium (POD) in elderly patients undergoing knee or hip arthroplasty.Methods:The study was conducted as part of the Perioperative Neurocognitive Impairment and Biomarkers Lifestyle Cohort, which was a nested case-control study. Medical records from elderly patients undergoing elective knee or hip arthroplasty under spinal-epidural anesthesia at Qingdao Municipal Hospital from August 2022 to August 2023 were collected. The patients were divided into a POD group ( n=89) and a non-POD group ( n=221) based on the occurrence of POD. Peripheral blood samples were collected before surgery, and the cerebrospinal fluid (CSF) 2 ml was extracted after successful puncture under spinal-epidural anesthesia for determination of the concentrations of amyloid-β 42 (Aβ 42), total tau protein (t-tau), and phosphorylated tau protein (p-tau) by enzyme-linked immunosorbent assay. Logistic regression was used to analyze the influencing factors of POD, and the mediation analysis was conducted to examine the mediating role of CSF biomarker in the relationship between PA and POD. Results:Logistic regression analysis showed that the increased concentration of CSF biomarkers Aβ 42 ( OR=0.997, P=0.006), elevated ratio of Aβ 42/t-tau ( OR=0.642, P=0.003), elevated ratio of Aβ 42/p-tau ratio ( OR=0.872, P=0.001) and PA ( OR=0.374, P=0.001) were protective factors for POD, while the elevated concentrations of t-tau ( OR=1.006, P=0.001) and p-tau ( OR=1.030, P=0.011) were risk factors for POD after adjusting for multi-confounders such as hypertension, diabetes, history of drinking, years of education and Mini-Mental State Examination score. The results of the mediation analysis showed that Aβ 42 (20%), t-tau (16%), Aβ 42/t-tau (23%) and Aβ 42/p-tau (28%) played mediating roles in the relationship between PA and POD. Conclusions:PA is a protective factor for POD in elderly patients undergoing knee or hip arthroplasty and CSF biomarkers may play a mediating role in the relationship between PA and POD.

Objective:To evaluate the relationship between the preoperative sleep quality and postoperative delirium (POD) in elderly patients.Methods:Three hundred and eighty-nine patients of either sex, aged 65-90 yr, with American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ, who underwent elective knee/hip arthroplasty under combined spinal-epidural anesthesia in Qingdao Municipal Hospital from May 2022 to October 2023, were selected. The Pittsburgh Sleep Quality Index scale was applied at 1 day before surgery to assess the sleep quality within 1 month before surgery. The cerebrospinal fluid (CSF) specimens 2 ml were withdrawn from the subarachnoid space before anesthesia for determination of the concentrations of biomarkers (β-amyloid), total tau protein [t-tau], and phosphorylated tau protein [p-tau]) by enzyme-linked immunosorbent assay. Patients were divided into POD group and non-POD group based on whether delirium occurred within 7 days after surgery. Logistic regression was used to identify the risk factors for POD, and the sensitivity analysis was used to test the stability of the regression models. The mediation model was used to examine whether CSF biomarkers mediated the link between sleep quality and POD. The accuracy of preoperative sleep quality and CSF biomarker concentrations in predicting the occurrence of POD was evaluated by plotting the receiver operating characteristic curve and calculating the area under the curve.Results:Two hundred and seventy-nine patients were finally included, with 33 patients in POD group and 246 patients in non-POD group. The results of logistic regression analysis showed that shorter sleep duration, use of hypnotics, daytime dysfunction within 1 month before surgery, elevated t-tau concentrations in CSF, and elevated p-tau concentrations in CSF were risk factors for POD after adjusting for multiple confounding factors such as age, sex, body mass index, years of education, Mini-Mental State Examination score, and VAS score. The results of mediating effect showed that the effect of use of hypnotics and daytime dysfunction within 1 month before surgery on POD was partially mediated by p-tau concentrations in CSF (>10%). The area under the curve of combination of daytime dysfunction, sleep duration, use of hypnotics within 1 month before surgery, and CSF biomarker concentrations in predicting POD was 0.979.Conclusions:Shortened sleep duration, use of hypnotic, and daytime dysfunction with 1 month before surgery are risk factors for POD in elderly patients, and the association between use of hypnotics and daytime dysfunction and POD is partially mediated by p-tau in CSF.

Objective:To evaluate the association between preoperative serum β 2-microglobulin (β 2MG) concentrations and postoperative delirium (POD) in elderly patients. Methods:The study selected patients who underwent knee or hip arthroplasty under spinal-epidural anesthesia on an elective basis at Qingdao Municipal Hospital from May 2021 to November 2022. The patients were divided into a POD group and a non-POD group based on the occurrence of POD. The study was conducted as part of the Perioperative Neurocognitive Impairment and Biomarkers Lifestyle Cohort, which was a nested case-control study. The study collected baseline data from two groups of patients and analyzed the differences between them. Logistic regression was used to identify the risk factors for POD. The stability of the regression model was tested using sensitivity analysis. The mediation model was used to examine whether cerebrospinal fluid (CSF) biomarkers mediated the relationship between β 2MG and POD. The receiver operating characteristic curve was drawn and the area under the curve was calculated to evaluate the accuracy of preoperative β 2MG concentrations and CSF biomarker concentration in predicting POD. Results:There were 57 cases in POD group and 449 cases in non-POD group. The results of logistic regression analysis showed that the increased β 2MG and CSF total tau protein (t-tau) concentrations were risk factors for POD, and the increased CSF β-amyloid 42 concentration was a protective factor for POD after adjustment for multiple confounders such as age, gender, education, Mini-Mental State Examination, history of hypertension and infusion volume ( P<0.05). The results of mediation analysis showed that the serum β 2MG′s effect on POD was partly mediated by t-tau (18.1%). The results of the receiver operating characteristic curve showed that the area under the curve of the β 2MG concentration combined with the CSF biomarker concentration was 0.742. Conclusions:Elevated preoperative serum β 2MG concentration is a risk factor for POD in elderly patients, and the relationship may be partly mediated by CSF t-tau.

Objective:To evaluate the relationship between preoperative serum bilirubin concentrations and postoperative delirium (POD) in the patients undergoing knee or hip replacement.Methods:Medical records from 413 patients undergoing knee or hip arthroplasty were selected from August 2020 to October 2023 at Qingdao Municipal Hospital using a nested case-control design based on the PNDABLE study cohort. The patients were divided into POD group ( n=77) and non-POD group ( n=336) according to whether POD occurred. Univariate analysis was used to analyze the influencing factors. Logistic regression was used to identify the risk factors for POD. The significance of mediation effect was tested. The receiver operating characteristic curve was drawn to evaluate the accuracy of risk factors in predicting POD. Results:There were significant differences in age, education time, ratio of diabetes history, Memorial Delirium Assessment Scale score, total bilirubin concentration, direct bilirubin concentration, indirect bilirubin concentration, Aβ 42 concentration, p-tau concentration, t-tau concentration, Aβ 42/p-tau ratio and Aβ 42/t-tau ratio between POD group and non-POD group ( P<0.05). The results of logistic regression analysis showed that preoperative serum total bilirubin, direct bilirubin and indirect bilirubin were risk factors for POD ( P<0.05). The results of mediation effects showed that the concentration of total tau protein in CSF partly mediated the relationship between high serum total bilirubin, direct bilirubin and indirect bilirubin concentrations and POD. The area under the receiver operating characteristic curve of total bilirubin, direct bilirubin and indirect bilirubin combined with CSF biomarker concentrations in predicting POD was 0.83 ( P<0.001). Conclusions:Preoperative elevated concentrations of total bilirubin, direct bilirubin and indirect bilirubin are risk factors for POD in the patients undergoing knee or hip replacement. CSF t-tau concentration has a partly mediating role in the association between serum total bilirubin, direct bilirubin and indirect bilirubin concentrations and the development of POD.

ObjectiveTo explore the possible mechanisms of Shoutai Wan （寿胎丸） in treating recurrent miscarriage （RSA） from the perspective of immune tolerance under the acidic microenvironment at the maternal-fetal interface. MethodsFemale CBA/J mice were randomly divided into normal group， model group， progesterone group， and Shoutai Wan group， with 15 mice in each group. The mice in the normal group and model group were given 0.2 ml distilled water by gavage each day， the Shoutai Wan group given Shoutai Wan decoction 0.15 g/（10 g·d） by gavage， the progesterone group given progesterone tablets 0.44 mg/（10 g·d） by gavage. After gavage for 14 days， the mice were cohabited. Female CBA/J mice in the normal group were mated with male BALB/c mice at a ratio of 2∶1， and female CBA/J mice in the other groups were mated with male DBA/2 mice at a ratio of 2∶1 to establish the RSA mouse model. Vaginal smears were taken from the female mice the next morning， and the appearance of a large number of spermatozoa and the presence of a vaginal plug were considered as the first day of pregnancy. After the appearance of the plug， the mice were continued to be administered according to the previous method until the 10th day of pregnancy. On the 10th day of pregnancy， maternal-fetal interface tissues were collected from each group of mice， and lactate dehydrogenase colorimetric method was used to detect lactate （LA） content； qPCR method and Western blot method were used to detect the expression of immune-related factors interleukin-4 （IL-4）， interferon-gamma （IFN-γ）， transforming growth factor beta 1 （TGF-β1）， and forkhead box protein 3 （Foxp3） mRNA and protein； flow cytometry was used to detect the numbers of helper T lymphocyte 1 （Th1）， helper T lymphocyte 2 （Th2）， regulatory T cell （Treg）， classical macrophage （M1）， and alternative macrophage （M2）. The bivariate Pearson test was used to analyze the correlation between LA content and the numbers of Th1， Th2， Treg， M1， and M2 cells， as well as the correlation between LA content and the expression of IL-4， IFN-γ， TGF-β1， Foxp3 protein， and mRNA. ResultsOn the 10th day of pregnancy， compared with the normal group， the LA content decreased in the model group， and the expression of IL-4， TGF-β1， Foxp3 protein and mRNA in the maternal-fetal interface tissues decreased， while the expression of IFN-γ protein and mRNA increased. The numbers of Th1 and M1 cells increased， while the numbers of Th2， Treg， and M2 cells decreased （P＜0.05 or P＜0.01）. Compared with the model group， the LA content increased in the Shoutai Wan group and progesterone group. The expression of IL-4， TGF-β1， Foxp3 protein and mRNA in the maternal-fetal interface tissues increased， while the expression of IFN-γ protein and mRNA decreased. The numbers of Th1 and M1 cells decreased， while the numbers of Th2， Treg， and M2 cells increased （P＜0.05 or P＜0.01）. The LA content was positively correlated with the numbers of Th2， Treg， and M2 cells， and the expression of IL-4， TGF-β1， Foxp3 protein， and mRNA （P＜0.05 or P＜0.01）； the LA content was negatively correlated with the numbers of Th1， M1 cells， and the expression of IFN-γ protein and mRNA （P＜0.05 or P＜0.01）. ConclusionShoutai Wan may improve immune tolerance by regulating the expression of immune-related factors in the acidic microenvironment at the maternal-fetal interface of RSA model mice， thereby exerting its role in preventing miscarriage.