GLOBAL SIGNATURES OF THE MICROBIOME AND METABOLOME DURING HOSPITALIZATION OF SEPTIC PATIENTS.

ABSTRACT: Background: The gut plays an important role in the development of sepsis and acts as one of the possible drivers of multiple-organ dysfunction syndrome. This study aimed to explore the dynamic alterations in the gut microbiota and its metabolites in septic patients at different stages of intensive care unit (ICU) admission. Methods: In this prospective observational study, a total of 109 fecal samples from 23 septic patients, 16 nonseptic ICU patients and 10 healthy controls were analyzed. 16S rRNA gene sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry targeted metabolomics were used for microbiota and metabolome analysis. A prediction model combining the Sequential Organ Failure Assessment score, Klebsiella , taurocholic acid, and butyric acid was used to predict the prognosis of sepsis. Results: The diversity and dominant species of the gut microbiota of septic patients were significantly disturbed. The proportions of normal gut microbiota, such as Firmicutes on the phylum level, as well as Faecalibacterium, Subdoligranulum , Ruminococcus , Agathobacter , and Blautia on the genus level, were decreased at different stages of ICU admission, while the proportions of potential pathogenic bacteria, such as Proteobacteria on the phylum level, and Enterococcus and Stenotrophomonas on the genus level were significantly increased. In addition, the amount of short-chain fatty acids and secondary bile acids decreased in septic patients, while that of the primary bile acids increased markedly. Bacterial richness and diversity were lower in the nonsurviving patients than those in the surviving patients in the later stage of ICU admission. In the nomogram model, the higher abundance of Klebsiella , concentration of taurocholic acid, and Sequential Organ Failure Assessment score, combined with a lower butyric acid concentration, could predict a higher probability of death from sepsis. Conclusions: Our study indicated that the dynamical alterations of gut microbiota and its metabolites were associated with the prognosis of the sepsis. Based on these alterations and clinical indicators, a nomogram model to predict the prognosis of septic patients was performed.

Testosterone and soluble ST2 as mortality predictive biomarkers in male patients with sepsis-induced cardiomyopathy.

Sepsis-induced cardiomyopathy (SIC) is characterized by high mortality and poor outcomes. This study aimed to explore the relationship between testosterone and soluble ST2 (sST2) and all-cause mortality in patients with SIC. Clinical data from SIC patients at Renmin Hospital of Wuhan University from January 2021 and March 2023 were reviewed. Serum testosterone and sST2 were measured at admission. Kaplan-Meier analysis and receiver operative characteristic curve (ROC) were used to estimate the predictive values of testosterone and sST2 on 28 days and 90 days mortality of SIC. A total of 327 male subjects with SIC were enrolled in this study. During the 28 days and 90 days follow-up, 87 (26.6%) and 103 deaths (31.5%) occurred, respectively. Kaplan-Meier analysis showed significantly higher 28 days and 90 days survival in patients with higher testosterone and decreased sST2 levels (p < 0.001). Testosterone, sST2, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were significantly associated with 28 days and 90 days mortality (p < 0.05). Partial correlation analysis showed strong positive correlation between testosterone and left ventricular ejection fraction (LVEF) (p < 0.001), and negative correlation between testosterone and sST2 (p < 0.001), high-sensitivity troponin I (hs-TnI) levels (p < 0.001) and smoke history (p < 0.01). The concentrations of sST2 were positively related with E/e' ratio (p < 0.001), and negatively correlated with TAPSE (p < 0.001). The combination of testosterone and sST2 enhanced the prediction of both 28 days [area under the ROC curve (AUC), 0.805] and 90 days mortality (AUC, 0.833). Early serum testosterone and sST2 levels could predict mortality of SIC independently and jointly. Further research is needed to determine the utility of biochemical markers in identifying high-risk patients with SIC.

Gpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells.

Background: Dysfunction of the immune system would disturb the intestinal homeostasis and lead to inflammatory bowel disease (IBD). Dendritic cells (DCs) help maintain intestinal homeostasis and immediately respond to pathogens or injuries once the mucosa barriers are destroyed during IBD. G protein-coupled receptors(GPR)174 is an essential regulator of immunity that is widely expressed in most immune cells, including DCs. However, the role of GPR174 in regulating the immune function of DC in colitis has not been investigated. Methods: Dextran sodium sulfate (DSS) was administered to establish the mice colitis model. Data of weight, length of colon, disease activity index (DAI), and macroscopic scores were collected. The flow cytometry was used to detect the infiltrations of T cells and DCs, the mean fluorescence intensity (MFI) of CD80, CD86, CD40, and major histocompatibility complex-II (MHC-II). And T cells proliferataion was measured by carboxyfluorescein diacetate succinimidyl ester (CFSE). The expression of cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), interleukin -4 (IL-4)) and GPR174 mRNA were measured by Elisa, quantitative polymerase chain reaction (qPCR), and immunofluorescence. RNA of bone-marrow-derived dendritic cells (BMDCs) was extracted for sequencing. Adoptive transfer of BMDCs was administrated intravenously. Results: Gpr174-/- mice exposed to 3% DSS showed significant alleviation characterized by reduced loss of weight, more minor colon damage, and better DAI and macroscopic scores. The expression of pro-inflammatory cytokines (TNF-α, IL-6) decreased, while anti-inflammatory cytokine (IL-10) increased compared with WT mice. In vitro, Gpr174-/- BMDCs showed less maturity, with a declined expression of MHC-II, CD80, CD86 and reduced TNF-α, higher IL-10 after LPS stimulation. Gpr174-/- BMDCs were less capable of activating OT-II naïve CD4+ T cells than WT BMDCs and induced more Th0 cells to differentiate into Treg while less into Th1. Furthermore, the transcriptome sequencing analysis exhibited that Gpr174 participated in TNF-α (NF-κB) signaling, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways. Adoptive transfer of Gpr174-/- BMDCs to WT mice ameliorated DSS-induced colitis. Conclusion: Our study indicated that GPR174 was involved in the pathogenesis of IBD by regulating the maturation of the dendritic cells to maintain immune homeostasis. TNF-α (NF-κB) signaling pathway, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways may be the target pathway.

The pathogens of secondary infection in septic patients share a similar genotype to those that predominate in the gut.

BACKGROUND: Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. METHODS: In this prospective, observational case-control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. RESULTS: The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. CONCLUSION: Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

Artificial intelligence computed tomography helps evaluate the severity of COVID-19 patients: A retrospective study.

BACKGROUND: Computed tomography (CT) is a noninvasive imaging approach to assist the early diagnosis of pneumonia. However, coronavirus disease 2019 (COVID-19) shares similar imaging features with other types of pneumonia, which makes differential diagnosis problematic. Artificial intelligence (AI) has been proven successful in the medical imaging field, which has helped disease identification. However, whether AI can be used to identify the severity of COVID-19 is still underdetermined. METHODS: Data were extracted from 140 patients with confirmed COVID-19. The severity of COVID-19 patients (severe vs. non-severe) was defined at admission, according to American Thoracic Society (ATS) guidelines for community-acquired pneumonia (CAP). The AI-CT rating system constructed by Hangzhou YITU Healthcare Technology Co., Ltd. was used as the analysis tool to analyze chest CT images. RESULTS: A total of 117 diagnosed cases were enrolled, with 40 severe cases and 77 non-severe cases. Severe patients had more dyspnea symptoms on admission (12 vs. 3), higher acute physiology and chronic health evaluation (APACHE) II (9 vs. 4) and sequential organ failure assessment (SOFA) (3 vs. 1) scores, as well as higher CT semiquantitative rating scores (4 vs. 1) and AI-CT rating scores than non-severe patients (P<0.001). The AI-CT score was more predictive of the severity of COVID-19 (AUC=0.929), and ground-glass opacity (GGO) was more predictive of further intubation and mechanical ventilation (AUC=0.836). Furthermore, the CT semiquantitative score was linearly associated with the AI-CT rating system (Adj R 2=75.5%, P<0.001). CONCLUSIONS: AI technology could be used to evaluate disease severity in COVID-19 patients. Although it could not be considered an independent factor, there was no doubt that GGOs displayed more predictive value for further mechanical ventilation.

Protective role of (5R)-5-hydroxytriptolide in lipopolysaccharide-induced acute lung injury by suppressing dendritic cell activation.

(5R)-5-hydroxytriptolide (LLDT-8) is a triptolide derivative with potent immunosuppressive property. This study aimed to investigate whether LLDT-8 manifests anti-inflammatory effects and influences dendritic cell function in early phase of lipopolysaccharide (LPS)-induced acute lung injury (ALI). C57BL/6 mice were administrated with LPS (6 mg/kg) to induce ALI and LLDT-8 were administrated at different doses (0.125 mg, 0.25 mg, 0.5 mg/kg). Histological changes were demonstrated by hematoxylin and eosin staining. Activation of dendritic cells were measured by flow cytometry. The concentrations of cytokines were measured by enzyme-linked immunosorbent assay. Bone marrow-derived dendritic cells (BMDCs) were acquired to explore immunosuppressive effects of LLDT-8 in vitro. Expression of Toll-like receptor 4 (TLR4), phosphorylation of inhibitor kappa B alpha (IκBα) and nuclear translocation of nuclear factor kappa B (NF-κB) were explored by immunoblot. Immunosuppressive property of LLDT-8-treated BMDCs were measured by adoptive transfer. The survival rate of ALI mice was significantly improved by LLDT-8 at the dose of 0.25 mg/kg. Moreover, systemic inflammatory response was suppressed and lung injury was relieved. LLDT-8 inhibited the activation of dendritic cells in vivo and influenced maturation, apoptosis and cytokine secretion capacity of BMDCs in vitro. Additionally, LLDT-8-treated BMDCs manifested reduced expression of TLR4, phosphorylation of IκBα and nuclear translocation of NF-κB. Adoptive transfer of LLDT-8-treated BMDCs alleviated LPS-induced lung injury. LLDT-8 also had protective effects on Pseudomonas aeruginosa-induced ALI. In conclusion, LLDT-8 played a protective role against ALI and suppressed dendritic cell activation potentially through affecting TLR4 expression and NF-κB signaling.

Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation.

BACKGROUND: Endothelium injury and coagulation dysfunction play an important role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), tissue plasminogen activator-inhibitor complex (t-PAIC), thrombin-antithrombin complex (TAT) and α2-plasmin inhibitor-plasmin complex (PIC) are biomarkers of endothelium injury and coagulation dysfunction. This study aimed to explore the prognostic values and diagnostic performance for septic shock and sepsis-induced disseminated intravascular coagulation (DIC) of endothelial biomarkers. METHODS: We conducted an observational study on patients with sepsis admitted to intensive care unit (ICU) at a teaching hospital from January 2016 to December 2018. Levels of sTM, t-PAIC, TAT and PIC were measured at admission day and day 5-7 after admission and detected by qualitative chemiluminescence enzyme immunoassay performed on HISCL automated analyzers. RESULTS: A total of 179 septic patients and 125 non-septic ICU controls were enrolled. The level of sTM was higher in septic patients compared to ICU controls (OR =1.093, 95% CI: 1.045-1.151, P<0.001). Moreover, higher levels of sTM and t-PAIC were independent predictors of poor 60-day prognosis for septic patients (HR =1.012, 95% CI: 1.003-1.022, P=0.012; HR =1.014, P=0.009). Level of sTM was also higher in patients with septic shock as revealed by multivariate analysis (OR =1.049, 95% CI: 1.020-1.078, P=0.001), as well as in patients with sepsis-induced DIC (OR =1.109, 95% CI: 1.065-1.158, P<0.001). sTM was considered as a sensitive biomarker for the early prediction of septic shock and sepsis-induced DIC, with AUC up to 0.765 (0.687-0.842) and 0.864 (0.794-0.935) of receiver operating characteristic curve. CONCLUSIONS: Most patients developed coagulopathy which was closely linked to endothelial injury in initial phase of sepsis, which was demonstrated by abnormalities in endothelial biomarkers and their strong association with poor 60-day prognosis and development of septic shock and sepsis-induced DIC.

Predictive Significance of the Prognostic Nutritional Index (PNI) in Patients with Severe COVID-19.

BACKGROUND: The prognostic nutritional index (PNI) has been reported to significantly correlate with poor survival and postoperative complications in patients with various diseases, but its relationship with mortality in COVID-19 patients has not been addressed. METHOD: A multicenter retrospective study involving patients with severe COVID-19 was conducted to investigate whether malnutrition and other clinical characteristics could be used to stratify the patients based on risk. RESULTS: A total of 395 patients were included in our study, with 236 patients in the training cohort, 59 patients in the internal validation cohort, and 100 patients in the external validation cohort. During hospitalization, 63/236 (26.69%) and 14/59 (23.73%) patients died in the training and validation cohorts, respectively. PNI had the strongest relationships with the neutrophil-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level but was less strongly correlated with the CURB65, APACHE II, and SOFA scores. The baseline PNI score, platelet (PLT) count, LDH level, and PaO2/FiO2 (P/F) ratio were independent predictors of mortality in COVID-19 patients. A nomogram incorporating these four predictors showed good calibration and discrimination in the derivation and validation cohorts. A PNI score less than 33.405 was associated with a higher risk of mortality in severe COVID-19 patients in the Cox regression analysis. CONCLUSION: These findings have implications for predicting the risk of mortality in COVID-19 patients at the time of admission and provide the first direct evidence that a lower PNI is related to a worse prognosis in severe COVID-19 patients.

MicroRNA-145 plays a role in mitochondrial dysfunction in alveolar epithelial cells in lipopolysaccharide-induced acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) causes substantial mortalities. Alveolar epithelium is one of the main sites of cell injuries in ARDS. As an important kind of microRNAs (miRNAs), microRNA-145 (miR-145) has been studied in various diseases, while its role in ARDS has not been investigated. METHODS: Lipopolysaccharide (LPS) was intratracheally instilled to establish a rat ARDS model. Cytokines from bronchoalveolar lavage fluid (BALF) were measured using rat tumor necrosis factor-α and interleukin-6 enzyme-linked immunosorbent assay kits (R&D Systems), and the pathological structures were evaluated using hematoxylin and eosin (H&E) staining and transmission electron microscope; the lung miR-145 messenger RNA (mRNA) was detected using quantitative polymerase chain reaction. Bioinformatics focused on the target genes and possible pathways of gene regulation. RESULTS: A rat model of LPS-induced ARDS was successfully established. The miR-145 was down-regulated in the LPS-induced ARDS lung, and mitochondrial dysfunction was observed in alveolar epithelial cells, most obviously at 72 hours after LPS. TargetScan and miRDB databases were used to predict the target genes of miR-145. A total of 428 overlapping genes were identified, seven genes were associated with mitochondrial function, and Ogt, Camk2d, Slc8a3, and Slc25a25 were verified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, and Gene Ontology (GO) biological process was mainly enriched in signal transduction and transcription regulation. CONCLUSIONS: The miR-145 is down-regulated in LPS-induced ARDS, and affects its downstream genes targeting mitochondrial functions.

GPR174 mRNA Acts as a Novel Prognostic Biomarker for Patients With Sepsis via Regulating the Inflammatory Response.

Previous studies indicated that G-protein coupled receptor 174 (GPR174) is involved in the dysregulated immune response of sepsis, however, the clinical value and effects of GPR174 in septic patients are still unknown. This study is aimed to evaluate the potential value of GPR174 as a prognostic biomarker for sepsis and explore the pathological function of GPR174 in cecal ligation and puncture (CLP)-induced septic mice. In this prospective longitudinal study, the expressions of peripheral GPR174 mRNA were measured in 101 septic patients, 104 non-septic ICU controls, and 46 healthy volunteers at Day 1, 7 after ICU (Intensive Care Unit) admission, respectively. Then, the clinical values of GPR174 for the diagnosis, severity assessment, and prognosis of sepsis were analyzed. Moreover, the expressions of GPR174 mRNA in CLP-induced septic mice were detected, and Gpr174-knockout (KO) mice were used to explore its effects on inflammation. The results showed that the levels of GPR174 mRNA were significantly decreased in septic patients compared with non-septic ICU and healthy controls. In addition, the expressions of GPR174 mRNA were correlated with the lymphocyte (Lym) counts, C-reactive protein (CRP), and APACHE II and SOFA scores. The levels of GPR174 mRNA at Day 7 had a high AUC in predicting the death of sepsis (0.83). Further, we divided the septic patients into the higher and lower GPR174 mRNA expression groups by the ROC cut-off point, and the lower group was significantly associated with poor survival rate (P = 0.00139). Similarly, the expressions of peripheral Gpr174 mRNA in CLP-induced septic mice were also significantly decreased, and recovered after 72 h. Intriguingly, Gpr174-deficient could successfully improve the outcome with less multi-organ damage, which was mainly due to an increased level of IL-10, and decreased levels of IL-1ß and TNF-α. Further, RNA-seq showed that Gpr174 deficiency significantly induced a phenotypic shift toward multiple immune response pathways in septic mice. In summary, our results indicated that the expressions of GPR174 mRNA were associated with the severity of sepsis, suggesting that GPR174 could be a potential prognosis biomarker for sepsis. In addition, GPR174 plays an important role in the development of sepsis by regulating the inflammatory response.

Gut microbiota modulation and anti-inflammatory properties of Xuanbai Chengqi decoction in septic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanbai Chengqi decoction (XBCQ), a traditional Chinese medicine formulation, was reported to have a protective role in a variety of pulmonary infection diseases. However, its mechanism remains uncertain. In the current study, we investigated the potential mechanism of XBCQ, its therapeutic effects on organ injuries induced by sepsis and gut microbiota modulation. MATERIAL AND METHODS: 80 Male Sprague Dawley rats were performed cecal ligation and puncture (CLP) for sepsis model and 60 of them were treated with different doses of XBCQ (3.78, 7.56, 15.12 g/Kg, 20 rats per group) twice per day. After the most valid dose was determined, another 40 rats were divided randomly into four groups: sham group, sham + XBCQ group, sepsis group, sepsis + XBCQ group. The sepsis + XBCQ group was treated with XBCQ by intragastric administration and then twice per day. Feces of the rats were collected and the gut microbiota constituents were analyzed by 16S rDNA sequencing. Histological changes were observed by H&E staining. Occludin content in the colon was determined by immunohistochemical analysis. The concentrations of cytokines were determined by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: The survival rate of septic rats was increased significantly at the dose of 7.56 g/Kg from 50% to 80% at 72 h. The gut microbiota richness and composition were disturbed in septic rats. XBCQ altered the gut microbiota, involving alpha diversity changes, significantly reducing the relative abundance of Bacteroidaceae and ClostridiumXI and increasing that of Firmicutes and Actinobacteria. Furthermore, the relative abundances of Lactobacillus, Butyricicoccus and Bifidobacterium were increased by XBCQ. Moreover, the gut barrier dysfunction was improved by XBCQ through restoring the impaired tight conjunction protein Occludin. The concentration of diamine oxidase was decreased, while the D-lactate level was elevated. Meanwhile, the level of myeloperoxidase (MPO) in the lung tissue of the XBCQ-treated group was reduced. Lung injury was also alleviated by decreased levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 10 (IL-10) in bronchoalveolar lavage fluids (BALFs). The relative abundance of potential microbial biomarkers in four groups significantly correlated with the concentration of inflammatory factors in BALFs. CONCLUSIONS: Our results suggested that XBCQ had a protective role against sepsis by modulating the gut microbiota, restoring the intestinal epithelial barrier and decreasing inflammatory responses.

Risk factors for COVID-19 patients with cardiac injury: pulmonary ventilation dysfunction and oxygen inhalation insufficiency are not the direct causes.

BACKGROUND: Cardiac injury in patients with coronavirus disease 2019 (COVID-19) has been reported in recent studies. However, reports on the risk factors for cardiac injury and their prognostic value are limited. RESULTS: In total, 15.9% of all cases were defined as cardiac injury in our study. Patients with severe COVID-19 were significantly associated with older age and higher respiratory rates, Sequential Organ Failure Assessment (SOFA) scores, cardiac injury biomarkers and PaO2/FiO2 ratios. Male patients with chest distress and dyspnea were more likely to have severe disease. Patients with cardiac injury were significantly more likely to have a severe condition and have an outcome of death. However, no significant difference was found in respiratory rates, dyspnea or PaO2/FiO2 ratio between patients with or without cardiac injury. In the logistic regression model, pre-existing hypertension and higher SOFA score were independent risk factors for patients with COVID-19 developing cardiac injury. CONCLUSIONS: Our study revealed that cardiac injury was an important predictor for patients having a severe or fatal outcome. Patients with pre-existing hypertension and higher SOFA scores upon admission were more likely to develop cardiac injury. Nevertheless, pulmonary ventilation dysfunction and oxygen inhalation insufficiency were not the main causes of cardiac injury in patients with COVID-19. METHODS: A total of 113 confirmed cases were included in our study. Severe patients were defined according to American Thoracic Society guidelines for community-acquired pneumonia. Cardiac injury was defined as a serum cTnI above the 99th-percentile of the upper reference limit. Patient characteristics, clinical laboratory data and treatment details were collected and analyzed. The risk factors for patients with and without cardiac injury were analyzed.

Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: a retrospective and observational study.

BACKGROUND: The World Health Organization has declared coronavirus disease 2019 (COVID-19) a public health emergency of global concern. Updated analysis of cases might help identify the risk factors of illness severity. RESULTS: The median age was 63 years, and 44.9% were severe cases. Severe patients had higher APACHE II (8.5 vs. 4.0) and SOFA (2 vs. 1) scores on admission. Among all univariable parameters, lymphocytes, CRP, and LDH were significantly independent risk factors of COVID-19 severity. LDH was positively related both with APACHE II and SOFA scores, as well as P/F ratio and CT scores. LDH (AUC = 0.878) also had a maximum specificity (96.9%), with the cutoff value of 344.5. In addition, LDH was positively correlated with CRP, AST, BNP and cTnI, while negatively correlated with lymphocytes and its subsets. CONCLUSIONS: This study showed that LDH could be identified as a powerful predictive factor for early recognition of lung injury and severe COVID-19 cases. METHODS: We extracted data regarding 107 patients with confirmed COVID-19 from Renmin Hospital of Wuhan University. The degree of severity of COVID-19 patients (severe vs. non-severe) was defined at the time of admission according to American Thoracic Society guidelines for community acquired pneumonia.

Survival outcomes of pancreaticoduodenectomy versus extended pancreaticoduodenectomy procedure for pancreatic head carcinoma: a propensity score matching study.

BACKGROUND: It is unclear if the modified extended pancreaticoduodenectomy (PD) has better outcome superior the conventional PD for patients with pancreatic head carcinoma (PHC). The objective of this study is to compare the survival outcomes of the classic PD procedure and the modified extended PD procedure for PHC. METHODS: A total of 7,084 resected PHC patients with PD and extended PD procedure from the SEER database from 2004 to 2014 were stratified. With the utilization of propensity score matching (PSM), patient baseline characteristics were balanced to decrease the bias. Overall survival (OS) and cancer-specific survival (CSS) were analyzed in both groups. RESULTS: Of the 7,084 patients, 6,541 (92.3%) and 543 (7.7%) patients received PD and extended PD surgical procedures, respectively. After 2:1 ratio of PSM, 543 patients with extended PD procedure and 1,084 patients with PD procedure were completely matched. The median CSS and OS for PD and extended PD group were 20.0 and 19.0 months, and 19.0 and 18.0 months, respectively. The 5-year CSS and OS rates for PD and extended PD group were 17.5% and 16.1%, and 13.9% and 13.1%, respectively. CONCLUSIONS: There is no distinct difference in survival outcomes between PD and extended PD procedure in patients with PHC.

The increased marginal zone B cells attenuates early inflammatory responses during sepsis in Gpr174 deficient mice.

GPR174 plays a crucial role in immune responses, but the role of GPR174 in the pathological progress of sepsis remains incompletely understood. In this study, we generated a sepsis model by cecal ligation and puncture (CLP) to investigate the role of GPR174 in regulating functions and underlying mechanism of marginal zone B (MZ B) cells in sepsis. We found that in Gpr174 deficient mice, the number of splenic MZ B cells was increased. Moreover, Gpr174-/- MZ B cells exhibited an enhanced response to LPS stimulation in vitro. By using the CLP-induced sepsis model, we demonstrated that the increased MZ B cells attenuated early inflammatory responses during sepsis. RNA sequencing results revealed that the expression of c-fos in splenic B lymphocytes was upregulated in Gpr174 deficient mice. However, the protective role of increased MZ B cells in Gpr174 deficient mice was weakened by a c-fos-specific inhibitor. Collectively, these findings suggested that GPR174 plays an immunomodulatory role in early immune responses during sepsis through the regulation of MZ B cells.

Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice.

G protein-coupled receptor 174 (GPR174) is mainly expressed in thymus, spleen, lymph nodes, and leukocytes, and genetic variation in GPR174 is associated with susceptibility to autoimmune diseases, indicating that GPR174 is involved in the immune response. However, the function of GPR174 in regulating inflammatory responses against bacterial infection in sepsis remains unclear. In this study, we investigated the role of GPR174 in regulating suppressive function of regulatory T cells (Treg cells) and the underlying mechanism of Gpr174-deficient Treg cells in controlling cytokine storm of sepsis. We showed that Gpr174-dedicient mice were resistant to inflammatory shock induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). Moreover, Gpr174 was highly expressed in Treg cells, and its deficiency in mice promoted the expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and interleukin (IL)-10 in Treg cells. By using the LPS-induced sepsis model, we demonstrated that anti-inflammatory macrophages (M2 macrophages) induction was Treg cell-dependent and Gpr174-deficient Treg cells protected mice against sepsis-induced lung damage through prompting M2 macrophages polarization. In vitro, Gpr174-deficient Treg cells also promoted the polarization of macrophages toward M2 cells and dampened the secretions of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α (TNF-α)) in macrophages. In conclusion, these findings suggested that GPR174 plays an important role in the initial period of sepsis through the regulation of macrophage polarization and pro- and anti-inflammatory cytokine secretions. Therefore, GPR174 may be a promising target for therapeutic agents to regulate inflammatory disorders.

Clinical characteristics and prognosis of serous body cavity effusions in patients with sepsis: a retrospective observational study.

BACKGROUND: Cavity effusion is common in patients with infectious diseases. However, the incidence rate and characteristics of serous cavity effusions (SCE) in septic patients are not clear to date. The objective of this study was to investigate the incidence and characteristics of SCE in septic patients and to explore the correlations between the bloody effusions and the illness severity/prognosis in septic patients. METHODS: From January 2010 to January 2015, a total of 214 patients with severe sepsis and septic shock were enrolled in this retrospective observational study. Thoracentesis or abdominal paracentesis was performed in 45 septic patients because of massive pleural effusions or ascites. The serum concentrations of VEGF, VEGFR, Ang, sICAM-1, sVCAM-1, E-selectin, Serpine1 and VE-cadherin in 45 septic patients underwent paracentesis were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of the 214 septic patients, 155 (72.4%) had SCE according to imaging or ultrasound manifestations. 45 subjects with SCE underwent therapeutic thoracentesis or abdominal paracentesis. Effusion laboratory analysis showed that exudates were predominant when compared with transudates (95.6% vs. 4.4%), and 16 (35.6%) patients suffered bloody effusions. Compared with patients with non-bloody effusions, those with bloody effusions showed higher critical illness scores (13 vs. 17 for APACHE II; 7 vs. 9 for SOFA), and higher mortality (6.9% vs. 62.5%). Moreover, patients with bloody effusions had delayed TT and APTT, increased D-dimer concentration, and higher serum levels of CRP and PCT (P < 0.05). In addition, the serum levels of Ang2, sVCAM-1 and E-selectin were significantly higher in patients with bloody effusions than in those with non-bloody effusions (P < 0.05). However, the serum level of VEGFR2 was lower in patients with bloody fluids (P = 0.025). CONCLUSIONS: The incidence of serous cavity effusion is high in patients with sepsis. The septic patients with bloody effusions suffer a more inflammatory burden and a worse prognosis compared to septic patients with non-bloody effusions.