Non-septic Shock Research Articles

Protection by selective mTORC2 inhibition of Zymosan-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB activation

Non-septic shock is a serious condition leading to multiple organ dysfunction. Although targeting the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway exerts potent anti-inflammatory activity, little is known about mTORC2’s contribution to non-septic shock. Thus, our research aims to investigate mTORC2's contribution and associated changes of IκB kinase (IKKα)/inhibitor κB (IκB-α)/nuclear factor-ĸB (NF-κB) pathway on Zymosan (ZYM)-induced non-septic rat model using the novel mTORC2 selective inhibitor JR-AB2-011. Rats were given saline (4ml/kg), dimethylsulfoxide (DMSO) (4ml/kg), ZYM (500mg/kg), and (or) JR-AB2-011 (1mg/kg). Mean arterial pressure (MAP) and heart rate (HR) of rats were recorded. JR-AB2-011 reversed both ZYM-induced reduction in MAP and increase in HR. Protein expression and/or phosphorylation of rictor, protein kinase B (Akt), IκB-α, IKKα, NF-κB p65, inducible nitric oxide synthase (iNOS), nitrotyrosine, cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, besides prostaglandin (PG) E2 levels were measured. The enhanced expression of the proteins mentioned above has been inhibited by JR-AB2-011. These data suggest mTORC2’s promising role in ZYM-induced hypotension and systemic inflammation mediated via IKKα/IκB-α/NF-κB pathway.

Discovery of the therapeutic potential of PPARδ agonist bearing 1,3,4- thiadiazole in inflammatory disorders

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11’s potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

Severe hyperlactatemia in the emergency department: clinical characteristics, etiology and mortality

BackgroundSevere hyperlactatemia (lactate level ≥ 10 mmol/L) is associated with high mortality rates in critically ill patients. However, there is limited data on emergency department (ED) patients. We aimed to investigate the clinical characteristics, etiology and outcomes of patients with severe hyperlactatemia in the ED setting.MethodsA retrospective cohort study was conducted at a tertiary care hospital in Thailand. We included adult patients with a venous lactate sample taken in the ED within one hour. We excluded patients after out-of-hospital cardiac arrest, transferred to/from another hospital or those with missing clinical data. Mortality rates were evaluated among patients with increasing degrees of lactate elevation and among patients with severe hyperlactatemia, stratified by causative etiology.ResultsWe analyzed venous lactate levels in 40,047 patients, with 26,680 included in the analysis. Among these, 1.7% had severe hyperlactatemia (lactate ≥ 10 mmol/L), 10.5% moderate (4–9.99 mmol/L), 28.8% mild (2—3.99 mmol/L), and 59.0% normal levels (< 2 mmol/L). Severe hyperlactatemia was associated with high mortality rates of 29%, 37%, and 38% at 7, 28, and 60 days respectively, significant ICU admissions and mechanical ventilation rates. Patients with severe hyperlactatemia were stratified into high (> 50% mortality), moderate (21–50%), and low (< 20%) 28-day mortality risk groups. High-risk conditions included non-septic shock, traumatic injuries/burns, and neurological issues, with mortality rates of 51.1%, 61.8%, and 57.1%, respectively. In the moderate risk group, namely infection without shock showed a high prevalence, with a mortality rate of 36%. In the low-risk group, seizures and fainting were associated with lower mortality, exhibiting mortality rates of 0%.ConclusionsSevere hyperlactatemia is associated with higher rates of ICU admission and mortality compared to other degrees of lactate elevation in a general ED population. However, mortality rates can vary considerably, depending on the underlying etiology associated with different primary diagnoses.

Putative mRNA Biomarkers for the Eradication of Infection in an Equine Experimental Model of Septic Arthritis.

Septic arthritis (SA) in horses has long-term health implications. The success of its resolution hinges on the implementation of early, aggressive treatment, which is often sustained over a prolonged period. Common diagnostic methods do not allow for the reliable detection of the eradication of joint infection. A potential alternative is the discovery and characterization of mRNA biomarkers. The purpose of this study was to identify potential mRNA biomarkers for the eradication of joint infection in equine SA and to compare their expression with our previously published proteomics data. In addition, the transcriptomics data were compared to the mRNA biomarker panel, SeptiCyte Lab, used to distinguish sepsis from non-septic shock in humans. A comparative transcriptomics analysis of synovial fluid from the SA joints of five horses with active infection and subsequent post-treatment eradicated infection in the same joints and five horses with non-septic synovitis was performed. Eight novel mRNA transcripts were identified that were significantly upregulated (>3-fold) in horses with active SA compared to horses post-eradication of infection after treatment and horses with non-septic synovitis. Two proteins in our proteomics data corresponded to these mRNA transcripts, but were not statistically different. The transcripts used in the SeptiCyte test were not differentially expressed in our study. Our results suggest that mRNA may be a useful source of biomarkers for the eradication of joint infection in horses and warrants further investigation.

Exploring the optimal range of central venous pressure in sepsis and septic shock patients: A retrospective study in 208 hospitals

BackgroundThe aim of this study was to investigate the optimal CVP range in sepsis and septic shock patients admitted to intensive care unit. MethodsWe performed a retrospective study with adult sepsis patients with CVP records based on the eICU Collaborative Research Database. Multivariable logistic regression was performed to explore the associations between CVP level and hospital mortality. Non-linear correlations and optimal CVP range were explored using restricted cubic splines (RCS). ResultsA total of 5302 sepsis patients were included in this study. Patients in 4-8 mmHg group owned the lowest odds ratio for raw hospital mortality (19.7%). The logistic regression analyses revealed that hospital death risk increased significantly when mean CVP level exceeds 12 mmHg compared to 4-8 mmHg level. U-shaped association of CVP with hospital mortality was revealed by RCS model in septic shock patients and the optimal range was 5.6-12 mmHg. While, there was a J-shaped trend for non-septic shock patients. For non-septic shock patients, patients had an increased risk of hospital death only if CVP exceeded 11 mmHg. ConclusionsWe observed U-shaped association between mean CVP level and hospital mortality in septic shock patients and J-shaped association in non-septic shock patients. This may imply that patients with different severity of sepsis have different CVP requirements. We need to monitor and manage CVP according to the circulatory status of the sepsis patient.

Presepsin as a predictor of septic shock and mortality in patients with urinary tract infection according to the Sepsis-3 definitions

The objective of this study was to investigate whether presepsin can serve as a useful biomarker for predicting septic shock and mortality rates in patients with urinary tract infections (UTI) as defined by the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). This single-center and prospective observational study was carried out between December 2019 and December 2022 and included 171 UTI patients divided into two groups: a non-septic shock group (n = 121) and a septic shock group (n = 50). The primary outcome of this study was the development of septic shock; the secondary outcome was 30-day hospital mortality. Receiver operating characteristic (ROC) curves and multivariate regression analyses were performed to investigate the predictive value of presepsin levels for septic shock and the Cox proportional hazards model was used to determine the risk factors for 30-day hospital mortality in UTI patients. Septic shock patients had significantly higher serum levels of presepsin when compared to the non-septic shock group (p &lt; 0.001). In multivariate logistic regression analysis, presepsin demonstrated its independent role as a risk factor for septic shock (odds ratio (OR): 1.002; 95% confidence interval (CI): 1.001–1.002; p &lt; 0.001). The multivariate Cox proportional hazards model indicated that presepsin represents a significant predictor of 30-day hospital mortality in septic shock patients (hazard ratio (HR): 1.0005; 95% CI: 1.0001–1.001; p &lt; 0.05). The ROC curve for diagnosing septic shock had an area under the curve (AUC) of 0.739 with a cutoff value of 447 pg/mL for presepsin. For the prediction of 30-day hospital mortality in patients with UTI, an optimal presepsin cutoff of 709 pg/mL was determined; ROC curve analysis yielded an AUC of 0.744. When applying the Sepsis-3 criteria, presepsin levels represented a significant independent risk factor for septic shock and 30-day hospital mortality in UTI patients.

Gene Co-Expression Networks Offer New Perspectives on Sepsis Pathophysiology.

Sepsis is among the most common causes of death in intensive care units. Septic shock is a type of circulatory shock that shows signs and symptoms that are similar to non-septic shock. Despite the impact of shock on patients and the economic burden, knowledge of the pathophysiology of septic shock is scarce. In this context, weighted gene co-expression network analysis can help to elucidate the molecular mechanisms of this condition. The gene expression dataset used in this study was downloaded from the Gene Expression Omnibus, which contains 80 patients with septic shock, 33 patients with non-septic shock, and 15 healthy controls. Our novel analysis revealed five gene modules specific for patients with septic shock and three specific gene modules for patients with non-septic shock. Interestingly, genes related to septic shock were mainly involved in the immune system and endothelial cells, while genes related to non-septic shock were primarily associated with endothelial cells. Together, the results revealed the specificity of the genes related to the immune system in septic shock. The novel approach developed here showed its potential to identify critical pathways for the occurrence and progression of these conditions while offering new treatment strategies and effective therapies.

Red Blood Cell Distribution Width (RDW) as a predictor of septic shock in children

Link of Video Abstract: https://youtu.be/Exh1T2szfoE Background: Septic shock is a prevalent PICU condition requiring prompt intervention. Using the PELOD II score, which has multiple characteristics to examine, it is challenging to predict prognosis in healthcare-limited settings. A link has recently been shown between red blood cell distribution width (RDW) and mortality risk in critically ill patients, albeit the exact mechanism is unknown. Methods: This retrospective observational study examined RDW values in pediatric septic or non-septic shock patients. This study examined patient clinical features, RDW hematological markers (RDW-CV, RDW-SD, and RDW/albumin ratio), and the area under the curve to determine the cut-off for the hematological marker, sensitivity, and specificity. Results: Sixty-one pediatric patients met the inclusion criteria (33 with septic shock and 28 with non-septic shock). The red cell distribution width coefficient variation (RDW-CV) (p=0,058), red cell distribution width standard deviation (RDW-SD) (p=0,05), and RDW Albumin Ratio (RAR) (p=0,014) were shown to be significantly different between the septic shock and non-septic shock groups. The cut-off value for RDW-CV was 15.3% (53.6% sensitivity and 97% specificity), 47.4 fl for RDW-SD (64.3% sensitivity and 84.8% specificity), and 5.65 for RDW/albumin ratio (71.4% sensitivity and 84.8% specificity). RDW-CV odd ratio was 36.9 (95% confidence interval (CI) 4.41-308.96, p 0.001), RDW-SD odd ratio was 10.08 (95% confidence interval (CI) 2.95-34.34, p 0,001), and RDW/albumin ratio was 14.00 (95% confidence interval (CI) 3.98-49.16, p 0,001). Conclusion: Increased RDW can be one marker in pediatric patients with septic shock. Increased levels of RDW/albumin ratio are significantly associated with the incidence of septic shock. Through the (ROC) area under the curve, the RDW/albumin ratio has better capabilities compared to other predictor markers.

PD-L1 Blockade Improves Survival in Sepsis by Reversing Monocyte Dysfunction and Immune Disorder

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 −) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction.

Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy.

Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required. We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria. After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29-0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20-35 or SOFA score 8-12). Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.

Uncovering the Burden of Immune-Related Adverse Events in Immunotherapy: Insights from a Nationally Representative Sample.

Immune checkpoint inhibitors have shown promising efficacy in multiple malignancies and, therefore, have been increasingly used over the past decade. Clinical data have suggested anti-cancer efficacy associated with immune-related adverse events that could have added healthcare resource utilization and costs. We used a nationwide dataset to investigate the association between immune-related adverse events and healthcare resource utilization, charges, and mortality among patients receiving various immune checkpoint inhibitors for indicated cancers. We performed a retrospective analysis of the National Inpatient Sample to identify patients hospitalized in the USA for immunotherapy between October 2015 and 2018. Data between patients who developed immune-related adverse events were compared to those who did not. Baseline characteristics, inpatient complications, and associated charges were collected and analyzed between these two groups. Patients who developed immune-related adverse events in the hospital had high incidences of acute kidney injury, non-septic shock, and pneumonia, and managing these complications significantly contributed to higher healthcare resource utilization. The average charge of admission was highest in patients who developed an infusion reaction, followed by colitis, and adrenal insufficiency. In terms of cancer type, renal cell carcinoma had the highest charges, followed by Merkel cell carcinoma. Immune checkpoint inhibitor-based regimens have shifted the treatment landscape among multiple malignancies and their use continues to expand. However, a significant proportion of patients still develop severe adverse effects leading to increased healthcare costs and impacting patients' quality of life. Closer attention should be given to recognizing and managing immune-related adverse events according to guidelines across healthcare facilities and clinical practice settings.

Factors Associated with in-Hospital Mortality in Patients with Hemophagocytic Lymphohistiocytosis: A 5-Year Analysis from the National Inpatient Sample

Background: Haemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome caused by a robust and excessive immune response leading to multi-organ failure. HLH can be due to a myriad of etiologies that range from primary disorders related to genetic defects or secondary to infections, autoimmune conditions, malignancies, etc. HLH has been broadly recognized in the pediatric population. Most of the clinical guidelines and evidence are based on this population; thus, more literature is needed amongst the adult population, especially on what factors increase mortality. Therefore, our study aims to evaluate factors associated with mortality in HLH Among Hospitalized Patients in the US using a Large Nation-wide Database. Methods: We performed a retrospective survey analysis of the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify adult patients hospitalized with a primary or secondary diagnosis of HLH between October 2015 and December 2019. We compared patients who survived the illness as a control group versus patients who died during the hospitalization. A comparison was done between demographic variables including age, race, sex, median income, among other factors. Data regarding past medical history was also included. The most common causes of HLH were queried and compared between the two groups. Lastly, we performed a final comparison between multiple inpatient complications and outcomes between the two groups. We used qui-square and fisher exact test for categorical variables and student t-test or Mann-Whitney U test for continuous variables. All analysis was done using R studio utilizing the survey package. Results: Data from 8,660 admissions with HLH were included, of which 21% of patients died during the hospitalization. Patients with HLH who died tended to be males (61%), slightly older at age 53 years, and a higher percentage of white patients (55%), though not statistically significant than those who did not die. On the other hand, increased mortality was associated with hematological malignancies (37% vs 24%, p<0.05), baseline chronic kidney, heart, and liver disease. Additionally, these patients were also more likely to develop renal failure, non-septic shock, and pneumonia. Interestingly, patients with rheumatological disorders had statistically lower deaths (13% vs 17% p<0.05). Patients in the lowest percentile of income had the highest percentage of deaths at 30% and the highest percentile of income had a lower percentage of deaths at 22%. The length of inpatient stay was significantly longer in patients who died (18 vs 14 days, p<0.05). In terms of location, larger academic hospitals had higher mortality (77% vs 71%, p=0.02), with no difference between regions. Conclusions: This nationwide data analysis demonstrates the high mortality rates that persist in patients with HLH. Our study contributes to the growing literature on HLH, an intricate and complex topic that is not yet fully understood. Increased attention should be placed on the older population with pre-existent co-morbidities as well as patients with hematological malignancies and low socioeconomic status who are at potentially higher risk of death, to elucidate the mechanisms leading to poor outcomes and potential treatments of this condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Study on the value of prothrombin time for predicting the severity and prognosis of septic patients

To explore the predictive efficacy of prothrombin time (PT) with regarding for the severity and prognosis of septic patients, along with comparing with other routine coagulation parameters. A retrospective analysis was conducted. The clinical data of 302 septic patients who were admitted to the intensive care unit (ICU) of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology from January 1 to December 31 in 2019 were enrolled. Demographic and basic clinical data were collected. Laboratory data, including PT, activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer, fibrin (fibrinogen) degradation product (FDP), antithrombin (AT), platelet count (PLT) at ICU admission were recorded, and sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score within 24 hours of admission to ICU were also collected. What's more, some major clinical events, such as septic shock, disseminated intravascular coagulation (DIC), etc. during ICU stay were also monitored. A follow-up 28 days observation of prognosis was performed. The patients were divided into the septic shock group and the non-septic shock group according to the occurrence of septic shock, and they were divided into the survival group and the non-survival group according to the 28-day prognosis. The differences in terms of above parameters between each two groups were compared. Spearman correlation method was used to analyze the correlation between routine coagulation parameters and SOFA score or APACHE II score. Receiver operator characteristic curve (ROC curve) was plotted to determine the predictive efficacy of each routine coagulation parameter with regarding to predict septic shock and 28-day mortality. Based on the cut-off value of PT, the septic patients were divided into two risk stratifications, and then the major clinical and end point outcome were compared. Kaplan-Meier survival curve analysis was applied to investigate the difference of the 28-day cumulated survival rate based on the different risk stratifications of PT level. Finally, multivariate Logistic regression analysis was used to explore whether prolonged PT level was an independent risk factor for septic shock and 28-day mortality. The 302 patients were all enrolled, including 120 patients with septic shock and 182 patients without. Seventy-five patients died within 28 days, while 227 survived. Comparing with the non-septic shock group or the survival group, the septic shock group or the non-survival group patients both had longer PT, APTT and TT, higher D-dimer, FDP and lower PLT, FIB and AT. Correlation analysis revealed that PT and PLT were better correlated with SOFA score (r values were 0.503 and -0.524, both P < 0.01), and PT was better correlated with APACHE II score (r = 0.407, P < 0.01). ROC curve analysis showed that PT had the most powerful predictive efficacy for septic shock and 28-day mortality. The area under the ROC curve (AUC) and 95% confidence interval (95%CI) were 0.831 (0.783-0.879) and 0.739 (0.674-0.805), respectively. The cut-off value were 16.8 s and 16.3 s, respectively, with the sensitivity of 64.2%, 72.0% and the specificity of 89.0%, 70.9%, respectively. Risk stratification based on PT level revealed that the patients with PT > 16.5 s (n = 103) had higher rate of 28-day mortality, incidence of septic shock and DIC, and score of SOFA and APACHE II comparing to those with PT ≤ 16.5 s (n = 199). Kaplan-Meier survival curve analysis showed that the 28-day cumulative survival rate was significantly lower in the patients with PT > 16.5 s than those with PT ≤ 16.5 s (52.43% vs. 86.93%; Log-Rank test: χ2 = 49.428, P < 0.001). Multivariate Logistic regression analysis revealed that PT > 16.5 s was an independent risk factor both for septic shock and 28-day mortality [model 1 (enrolled SOFA score): odds ratio (OR) and 95%CI were 6.003 (3.040-11.855), 4.842 (2.114-11.089); model 2 (enrolled APACHE II score): OR and 95%CI were 7.675 (4.007-14.702), 5.160 (2.258-11.793)]. Compared with other routine coagulation parameters, PT has the potential best predictive value for evaluating the severity of sepsis and the prognosis. When a patient is diagnosed with sepsis and has a result of PT longer than 16.5 s at ICU admission, the patient may have a higher risk of progression to septic shock and short-term death.

ARG1 as a promising biomarker for sepsis diagnosis and prognosis: evidence from WGCNA and PPI network

BackgroundSepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication.MethodsPreliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results.ResultsFour hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally.ConclusionsWe identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Analysis of influencing factors of community-acquired pneumonia with deep venous thrombosis in elderly communities

Community-acquired pneumonia (CAP) is one of the common infectious diseases that threaten human health, venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE), is a global health care problem. Acute infection and age ≥70 years are important risk factors for VTE in internal medicine inpatients. There is increasing evidence that acute infectious diseases caused by bacterial and viral infections can induce coagulation, platelet (PLT) activation and inhibit the activity of anticoagulant factors. However, there is no consensus on whether patients with CAP suffer from DVT. Finding out the clinical characteristics and risk factors of DVT in elderly patients with CAP is helpful for early identification of high-risk patients with VTE and timely prevention, which can significantly reduce the occurrence of VTE in hospitals. Data was collected from 505 patients with CAP aged ≥70 years old hospitalized in the Department of Respiratory and Critical Care Medicine. 133 patients with DVT were selected as the DVT group. DVT score and risk grading were performed for all patients using Padua. Fifty-seven cases were diagnosed as having severe pneumonia, including 50 cases diagnosed as having septic shock. Padua, D-dimer, between the DVT group and the control group, the severe pneumonia group and the non-severe pneumonia group, and the severe pneumonia DVT group and the control group were compared. (I) The incidence of DVT with severe pneumonia was much higher than with non-severe pneumonia (P<0.001). The incidence of DVT in patients with septic shock and non-septic shock was 74.0% (37/50) and 28.6% (2/7) respectively (P=0.0154). (II) There were significant differences in Padua scores between the DVT group and the control group and between the severe pneumonia group and non-severe pneumonia group (P<0.001). (III) There were significant differences in D-dimer level between the DVT group and the control group and between the severe pneumonia group and the non-severe pneumonia group (P<0.001). (IV) Regression analysis indicated the central venous catheter (CVC), D-dimer value, and Padua score were significantly correlated with thrombosis (P=0.042, <0.001, 0.043). Severe pneumonia in elderly patients and septic shock may be complicated by DVT, and central venous catheterization and D-dimer are closely related to thrombosis.

Inpatient complications of immunotherapy-associated colitis in solid malignancies: Real-world data analysis.

2657 Background: Immune checkpoint inhibitors (ICPis) and their containing regimens have been proven beneficial for the treatment of multiple malignancies, while immune-related adverse events (IrAEs) have become constant safety challenges in their clinical management through all ICPi therapies. Diarrhea resulted from immune-mediated colitis has been one of the most common IrAEs. The Aim of this study is to evaluate the real-world incidence and factors that contributed to colitis among patients hospitalized for anti-neoplastic immunotherapy using a large nation-wide database. Methods: We performed a retrospective analysis with the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify patients with solid tumors hospitalized for immunotherapy between October 2015 and 2018. A comparison analysis was made between patients who developed diarrhea (or colitis) or not during their hospitalizations. Patient characteristics included past medical history, location, charges, length of stay (LOS) and inpatient complications variables, data were compared between the two groups. Results: The data from 5,795 admissions for immunotherapy were included, of which 615 (10.61%) inpatient events were complicated by diarrhea (colitis). Patients with diarrhea tended to be males (60%), slightly older at age 57 years, higher percentage of white patients (78%) though not statistically significant from those who did not have colitis. On the other hand, the length of inpatient stay was statistically longer (7 vs 5 days, p &lt; 0.05), and associated with higher expenses ($214,612 vs $ 134,195, p &lt; 0.05). In addition, inpatient admissions with colitis were more towards larger academic hospitals (80% vs 67%, p = 0.01). ICPi-treated patients with genitourinary (GU) cancers were observed more with colitis among these admissions (27% vs 15%, p &lt; 0.05). Though no difference from mortalities observed, serious complications, such as acute kidney injury (AKI) (44% vs 20%, p &lt; 0.05) and non-septic shock rates were higher (7% vs 2%, p = 0.01) among colitis admissions. Conclusions: This real-world data analysis of inpatient admissions from ICPi-treated cancer patients demonstrated colitis with diarrhea as a common safety concern over ICPi-therapies, a higher risk among patients of GU primaries, higher risk with serious medical complications: acute renal dysfunction and non-septic shock, led to increased length of stays (LOS) and financial burden. Special attention and further study may be placed among ICPi-treated GU cancer patients. [Table: see text]

Association of Blood Glucose Level and Glycemic Variability With Mortality in Sepsis Patients During ICU Hospitalization.

BackgroundThere was considerable debate regarding the effect of mean blood glucose (MBG) and glycemic variability (GV) on the mortality of septic patients. This retrospective cohort study aimed to assess the association between MBG and GV with ICU mortality of sepsis patients and to explore the optimal MBG range.MethodsSepsis patients were enrolled from the Medical Information Mart for Intensive Care IV database (MIMIC-IV). MBG and glycemic coefficient of variation (GluCV) were, respectively, calculated to represent the overall glycemic status and GV during ICU stay. The associations between MBG, GluCV, and ICU mortality of the septic patients were assessed by using multivariate logistic regression in different subgroups and the severity of sepsis. Restricted cubic splines evaluated the optimal MBG target.ResultsA total of 7,104 adult sepsis patients were included. The multivariate logistic regression results showed that increased MBG and GluCV were significantly correlated with ICU mortality. The adjusted odds ratios were 1.14 (95% CI 1.09–1.20) and 1.05 (95% CI 1.00–1.12). However, there was no association between hyperglycemia and ICU mortality among diabetes, liver disease, immunosuppression, and hypoglycemia patients. And the impact of high GluCV on ICU mortality was not observed in those with diabetes, immunosuppression, liver disease, and non-septic shock. The ICU mortality risk of severe hyperglycemia (≧200 mg/dl) and high GluCV (>31.429%), respectively, elevated 2.30, 3.15, 3.06, and 2.37, 2.79, 3.14-folds in mild (SOFA ≦ 3), middle (SOFA 3–7), and severe group (SOFA ≧ 7). The MBG level was associated with the lowest risk of ICU mortality and hypoglycemia between 120 and 140 mg/dl in the subgroup without diabetes. For the diabetic subset, the incidence of hypoglycemia was significantly reduced when the MBG was 140–190 mg/dl, but a glycemic control target effectively reducing ICU mortality was not observed.ConclusionMBG and GluCV during the ICU stay were associated with all-cause ICU mortality in sepsis patients; however, their harms are not apparent in some particular subgroups. The impact of hyperglycemia and high GV on death increased with the severity of sepsis. The risk of ICU mortality and hypoglycemia in those with no pre-existing diabetes was lower when maintaining the MBG in the range of 120–140 mg/dl.

Association of Septic Shock with Mortality in Hospitalized COVID-19 Patients in Wuhan, China.

Purpose Septic shock is a severe complication of COVID-19 patients. We aim to identify risk factors associated with septic shock and mortality among COVID-19 patients. Methods A total of 212 COVID-19 confirmed patients in Wuhan were included in this retrospective study. Clinical outcomes were designated as nonseptic shock and septic shock. Log-rank test was conducted to determine any association with clinical progression. A prediction model was established using random forest. Results The mortality of septic shock and nonshock patients with COVID-19 was 96.7% (29/30) and 3.8% (7/182). Patients taking hypnotics had a much lower chance to develop septic shock (HR = 0.096, p=0.0014). By univariate logistic regression analysis, 40 risk factors were significantly associated with septic shock. Based on multiple regression analysis, eight risk factors were shown to be independent risk factors and these factors were then selected to build a model to predict septic shock with AUC = 0.956. These eight factors included disease severity (HR = 15, p < 0.001), age > 65 years (HR = 2.6, p=0.012), temperature > 39.1°C (HR = 2.9, p=0.047), white blood cell count > 10 × 10⁹ (HR = 6.9, p < 0.001), neutrophil count > 75 × 10⁹ (HR = 2.4, p=0.022), creatine kinase > 5 U/L (HR = 1.8, p=0.042), glucose > 6.1 mmol/L (HR = 7, p < 0.001), and lactate > 2 mmol/L (HR = 22, p < 0.001). Conclusions We found 40 risk factors were significantly associated with septic shock. The model contained eight independent factors that can accurately predict septic shock. The administration of hypnotics could potentially reduce the incidence of septic shock in COVID-19 patients.

How likely is septic shock to develop in a patient with Fournier's gangrene? A risk prediction model based on a 7-year retrospective study.

BackgroundFournier’s gangrene (FG) is a rare life-threatening form of necrotizing fasciitis. The risk factors for septic shock in patients with FG are unclear. This study aimed to identify potential risk factors and develop a prediction model for septic shock in patients with FG.MethodsThis retrospective cohort study included patients who were treated for FG between May 2013 and May 2020 at the Sixth Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). The patients were divided into a septic shock group and a non-septic shock group. An L1-penalized logistic regression model was used to detect the main effect of important factors and a penalized Quadratic Discriminant Analysis method was used to identify possible interaction effects between different factors. The selected main factors and interactions were used to obtain a logistic regression model based on the Bayesian information criterion.ResultsA total of 113 patients with FG were enrolled and allocated to the septic shock group (n = 24) or non-septic shock group (n = 89). The best model selected identified by backward logistic regression based on Bayesian information criterion selected temperature, platelets, total bilirubin (TBIL) level, and pneumatosis on pelvic computed tomography/magnetic resonance images as the main linear effect and Na+ × TBIL as the interaction effect. The area under the ROC curve of the probability of FG with septic shock by our model was 0.84 (95% confidence interval, 0.78–0.95). The Harrell's concordance index for the nomogram was 0.864 (95% confidence interval, 0.78–0.95).ConclusionWe have developed a prediction model for evaluation of the risk of septic shock in patients with FG that could assist clinicians in identifying critically ill patients with FG and prevent them from reaching a crisis state.

Lactylated Histone H3K18 as a Potential Biomarker for the Diagnosis and Predicting the Severity of Septic Shock

ObjectiveTo date, there are no studies regarding the lactylation profile and its role in critically ill patients. Thus, we aimed to examine expression of histone H3 lysine 18 (H3K18) lactylation and its role in patients with septic shock.MethodsThirteen healthy volunteers and 35 critically ill patients from the Department of Surgical Intensive Care Medicine, Beijing Hospital were enrolled in our study. Baseline information and clinical outcomes were obtained prospectively. Lactylation levels of all proteins and H3K18 from peripheral blood mononuclear (PBMC) were determined by western blotting and serum levels of inflammatory cytokines by flow cytometry. Arginase-1 (Arg1) and Krüppel-like factor-4 (Klf4) mRNA expression was evaluated by quantitative real-time PCR (qRT-PCR).ResultsLactylation was found to be an all-protein post-translational modification and was detected in PBMCs from both healthy volunteers and critically ill patients, with a significantly higher relative density in shock patients (t=2.172, P=0.045). H3K18la was expressed in all subjects, including healthy volunteers, with the highest level in septic shock patients (compared with non-septic shock patients, critically ill without shock patients and healthy volunteers P=0.033, 0.000 and 0.000, respectively). Furthermore, H3K18la protein expression correlated positively with APACHE II scores, SOFA scores on day 1, ICU stay, mechanical ventilation time and serum lactate (ρ=0.42, 0.63, 0.39, 0.51 and 0.48, respectively, ρ=0.012, 0.000, 0.019, 0.003 and 0.003, respectively). When we matched patients with septic shock and with non-septic shock according to severity, we found higher H3K18la levels in the former group (t=-2.208, P =0.040). Moreover, H3K18la exhibited a close correlation with procalcitonin levels (ρ=0.71, P=0.010). Patients with high H3K18la expression showed higher IL-2, IL-5, IL-6, IL-8, IL-10, IL-17, IFN-α levels (ρ=0.33, 0.37, 0.62, 0.55, 0.65, 0.49 and 0.374 respectively, P=0.024, 0.011, 0.000, 0.000, 0.000 and 0.000 respectively). H3K18la expression also displayed a positive correlation with the level of Arg1 mRNA (ρ=0.561, P=0.005).ConclusionsLactylation is an all-protein post-translational modification occurring in both healthy subjects and critically ill patients. H3K18la may reflect the severity of critical illness and the presence of infection. H3K18la might mediate inflammatory cytokine expression and Arg1 overexpression and stimulate the anti-inflammatory function of macrophages in sepsis.