Factor In Sepsis Research Articles

CHANGES OF HISTIDINE-RICH GLYCOPROTEIN LEVELS IN CRITICALLY ILL SEPTIC PATIENTS.

Background: Histidine-rich glycoprotein (HRG), a potential prognostic factor in sepsis, lacks clarity regarding its relevance in septic-induced shock, disseminated intravascular coagulation (DIC), and acute respiratory distress syndrome (ARDS) pathogenesis. This study investigated the association between HRG concentrations and these critical conditions. Methods: Blood samples were collected from 53 critically ill patients on days 1, 3, 5, and 7 after ICU admission at the Kyushu University Hospital. Daily clinical and laboratory data were recorded, and patient survival was assessed 28 days after ICU admission. Results: Serum HRG concentrations were significantly reduced on days 3, 5, and 7 in patients with septic shock and DIC but not in those with ARDS. While initial HRG levels on day one were not correlated with survival, nonsurvivors displayed decreased HRG levels, notably on days 3, 5, and 7 post-ICU admissions. The HRG levels remained stable in survivors. A progressive decrease was associated with higher mortality rates, particularly on days 5 and 7. On day 5, an HRG level with a cutoff of 25.5 μg/mL showed a sensitivity of 0.77 and a specificity of 0.75, indicating significantly lower survival rates (log-rank test, P < 0.05). Conclusion: HRG presents a potential intervention for critically ill sepsis patients, providing a novel strategy to enhance outcomes. Further research is needed to explore the therapeutic potential of HRG in sepsis management.

Clinical biomarker profiles reveals gender differences and mortality factors in sepsis.

Sepsis is a major contributor to global morbidity and mortality, affecting millions each year. Notwithstanding the decline in sepsis incidence and mortality over decades, gender disparities in sepsis outcomes persist, with research suggesting higher mortality rates in males. This retrospective study aims to delineate gender-specific clinical biomarker profiles impacting sepsis progression and mortality by examining sepsis cases and related clinical data from the past three years. Propensity score matching was used to select age-matched healthy controls for comparison. Among 265 sepsis patients, a significantly higher proportion were male (60.8%, P<0.001). While mortality did not significantly differ by gender, deceased patients were significantly older (mean 69 vs 43 years, P=0.003), more likely to have hypertension (54% vs 25%, P=0.019), and had higher SOFA scores (mean ~10 vs 4, P<0.01) compared to survivors. Principal Component Analysis (PCA) showed clear separation between sepsis patients and healthy controls. 48 serum biomarkers were significantly altered in sepsis, with Triiodothyronine, Apolipoprotein A, and Serum cystatin C having the highest diagnostic value by ROC analysis. Gender-stratified comparisons identified male-specific (e.g. AFP, HDLC) and female-specific (e.g. Rheumatoid factor, Interleukin-6) diagnostic biomarkers. Deceased patients significantly differed from survivors, with 22 differentially expressed markers; Antithrombin, Prealbumin, HDL cholesterol, Urea nitrogen and Hydroxybutyrate had the highest diagnostic efficiency for mortality. These findings enhance our understanding of gender disparities in sepsis and may guide future therapeutic strategies. Further research is warranted to validate these biomarker profiles and investigate the molecular mechanisms underlying these gender differences in sepsis outcomes.

Blood urea nitrogen to serum albumin ratio: a novel mortality indicator in intensive care unit patients with coronary heart disease

The blood urea nitrogen to albumin ratio (BAR) has been demonstrated as a prognostic factor in sepsis and respiratory diseases, yet its role in severe coronary heart disease (CHD) remains unexplored. This retrospective study, utilizing data from the Medical Information Mart for Intensive Care-IV database, included 4254 CHD patients, predominantly male (63.54%), with a median age of 74 years (IQR 64–83). Primary outcomes included in-hospital, 28-day and 1-year all-cause mortality after ICU admission. The Kaplan–Meier curves, Cox regression analysis, multivariable restricted cubic spline regression were employed to assess association between BAR index and mortality. In-hospital, within 28-day and 1-year mortality rates were 16.93%, 20.76% and 38.11%, respectively. Multivariable Cox proportional hazards analysis revealed associations between the increased BAR index and higher in-hospital mortality (HR 1.11, 95% CI 1.02–1.21), 28-day mortality (HR 1.17, 95% CI 1.08–1.27) and 1-year mortality (HR 1.23, 95% CI 1.16–1.31). Non-linear relationships were observed for 28-day and 1-year mortality with increasing BAR index (both P for non-linearity < 0.05). Elevated BAR index was a predictor for mortality in ICU patients with CHD, offering potential value for early high-risk patient identification and proactive management by clinicians.

HERPES SIMPLEX VIRUS-1 SUSCEPTIBILITY AS A RISK FACTOR FOR SEPSIS, WITH CYTOMEGALOVIRUS SUSCEPTIBILITY ELEVATING SEVERITY: INSIGHTS FROM A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY.

Objective: We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causal relationships between herpes viruses and sepsis. Methods: Publicly available genome-wide association study data were used. Four viruses, HSV-1, HSV-2, EBV, and CMV, were selected, with serum positivity and levels of antibody in serum as the herpes virus data. Results: In forward MR, susceptibility to HSV-1 was a risk factor for sepsis. The susceptibility to CMV showed a severity-dependent effect on sepsis and was a risk factor for the 28-day mortality from sepsis, and was also a risk factor for 28-day sepsis mortality in critical care admission. The EBV EA-D antibody level after EBV infection was a protective factor for 28-day sepsis mortality in critical care admission, and CMV pp28 antibody level was a risk factor for 28-day sepsis mortality in critical care admission. No statistically significant causal relationships between HSV-2 and sepsis were found. No exposures having statistically significant association with sepsis critical care admission as an outcome were found. In reverse MR, the sepsis critical care admission group manifested a decrease in CMV pp52 antibody levels. No causal relationships with statistical significance between sepsis exposure and other herpes virus outcomes were found. Conclusion: Our study identifies HSV-1 susceptibility as a sepsis risk, with CMV susceptibility elevating severity. Varied effects of EBV and CMV antibodies on sepsis severity are noted. Severe sepsis results in a decline in CMV antibody levels. Our results help prognostic and predictive enrichment and offer valuable information for precision sepsis treatment.

Single-Cell Sequencing Reveals MYOF-Enriched Monocyte/Macrophage Subcluster as a Favorable Prognostic Factor in Sepsis.

This research utilized single-cell RNA sequencing to map the immune cell landscape in sepsis, revealing 28 distinct cell clusters and categorizing them into nine major types. Delving into the monocyte/macrophage subclusters, 12 unique subclusters are identified and pathway enrichment analyses are conducted using KEGG and GO, discovering enriched pathways such as oxidative phosphorylation and antigen processing. Further GSVA and AUCell assessments show varied activation of interferon pathways, especially in subclusters 4 and 11. The clinical correlation analysis reveals genes significantly linked to survival outcomes. Additionally, cellular differentiation in these subclusters is explored. Building on these insights, the differential gene expression within these subclusters is specifically scrutinized, which reveal MYOF as a key gene with elevated expression levels in the survivor group. This finding is further supported by in-depth pathway enrichment analysis and the examination of cellular differentiation trajectories, where MYOF's role became evident in the context of immune response regulation and sepsis progression. Validating the role of the MYOF gene in sepsis, a dose-dependent response to LPS in THP-1 cells and C57 mice is observed. Finally, inter-cellular communications are analyzed, particularly focusing on the MYOF+Mono/Macro subcluster, which indicates a pivotal role in immune regulation and potential therapeutic targeting.

The implication of targeting PD-1:PD-L1 pathway in treating sepsis through immunostimulatory and anti-inflammatory pathways.

Sepsis currently remains a major contributor to mortality in the intensive care unit (ICU), with 48.9 million cases reported globally and a mortality rate of 22.5% in 2017, accounting for almost 20% of all-cause mortality worldwide. This highlights the urgent need to improve the understanding and treatment of this condition. Sepsis is now recognized as a dysregulation of the host immune response to infection, characterized by an excessive inflammatory response and immune paralysis. This dysregulation leads to secondary infections, multiple organ dysfunction syndrome (MODS), and ultimately death. PD-L1, a co-inhibitory molecule expressed in immune cells, has emerged as a critical factor in sepsis. Numerous studies have found a significant association between the expression of PD-1/PD-L1 and sepsis, with a particular focus on PD-L1 expressed on neutrophils recently. This review explores the role of PD-1/PD-L1 in immunostimulatory and anti-inflammatory pathways, illustrates the intricate link between PD-1/PD-L1 and sepsis, and summarizes current therapeutic approaches against PD-1/PD-L1 in the treatment and prognosis of sepsis in preclinical and clinical studies.

Construction and validation of a mitochondria-associated genes prognostic signature and immune microenvironment characteristic of sepsis

BackgroundSepsis is a common critical condition seen in clinical settings, with mitochondrial dysfunction playing an important role in the progression of sepsis. However, a mitochondrial prognosis model related to sepsis has not been established yet, and the relationship between the sepsis immune microenvironment and mitochondria remains unclear. MethodsSepsis prognostic mitochondria-associated genes (MiAGs) were screened by univariate Cox, multivariate Cox, and LASSO analysis from the GEO dataset. Consensus Cluster was used to analyze MiAGs-based molecular subtypes for sepsis. The ESTIMATE and ssGSEA algorithms were used to analyze the situation of sepsis immune cell infiltration and its relation to MiAGs. Further, MiAGs score was calculated to construct a sepsis prognosis risk model to predict the prognosis of sepsis patients. Clinical blood samples were used to investigate the expression level of selected MiAGs in sepsis. Single-cell sequencing analysis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and ATP detection were used to verify the influence of MiAGs on mitochondrial dysfunction in sepsis. ResultsA total of 5 MiAGs of sepsis were screened. Based on MiAGs, sepsis MiAGs subtypes were analyzed, where Cluster A had a better prognosis than Cluster B, and there were significant differences in immune infiltration between the two clusters. The sepsis mitochondrial prognosis model suggested that the high MiAG score group had a shorter survival time compared to the low MiAG score group. Significant differences were also observed in the immune microenvironment between the high and low MiAG score groups. Prognostic analysis and the Nomogram indicated that the MiAG score is an independent prognostic factor in sepsis. Single-cell sequencing analysis exhibited the possible influence of MiAGs on the mitochondrial function of monocytes. Finally, the downregulation of the COX7B could effectively improve mitochondrial function in the LPS-stimulated sepsis model. ConclusionOur findings suggest that MiAGs can be used to predict the prognosis of sepsis and that regulating the mitochondrial prognostic gene COX7B can effectively improve the mitochondrial function of immune cells in sepsis.

A simplified machine learning model utilizing platelet-related genes for predicting poor prognosis in sepsis.

Thrombocytopenia is a known prognostic factor in sepsis, yet the relationship between platelet-related genes and sepsis outcomes remains elusive. We developed a machine learning (ML) model based on platelet-related genes to predict poor prognosis in sepsis. The model underwent rigorous evaluation on six diverse platforms, ensuring reliable and versatile findings. A retrospective analysis of platelet data from 365 sepsis patients confirmed the predictive role of platelet count in prognosis. We employed COX analysis, Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) techniques to identify platelet-related genes from the GSE65682 dataset. Subsequently, these genes were trained and validated on six distinct platforms comprising 719 patients, and compared against the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ-Failure Assessment (SOFA) score. A PLT count <100×109/L independently increased the risk of death in sepsis patients (OR = 2.523; 95% CI: 1.084-5.872). The ML model, based on five platelet-related genes, demonstrated impressive area under the curve (AUC) values ranging from 0.5 to 0.795 across various validation platforms. On the GPL6947 platform, our ML model outperformed the APACHE II score with an AUC of 0.795 compared to 0.761. Additionally, by incorporating age, the model's performance was further improved to an AUC of 0.812. On the GPL4133 platform, the initial AUC of the machine learning model based on five platelet-related genes was 0.5. However, after including age, the AUC increased to 0.583. In comparison, the AUC of the APACHE II score was 0.604, and the AUC of the SOFA score was 0.542. Our findings highlight the broad applicability of this ML model, based on platelet-related genes, in facilitating early treatment decisions for sepsis patients with poor outcomes. Our study paves the way for advancements in personalized medicine and improved patient care.

Potential Neuroprotective Role of Melatonin in Sepsis-Associated Encephalopathy Due to Its Scavenging and Anti-Oxidative Properties.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of septic patients. SAE has a very wide spectrum of clinical symptoms, ranging from mild behavioral changes through cognitive disorders to disorders of consciousness and coma. The presence of SAE increases mortality in the population of septic patients and may lead to chronic cognitive dysfunction in sepsis survivors. Therefore, therapeutic interventions with neuroprotective effects in sepsis are needed. Melatonin, a neurohormone responsible for the control of circadian rhythms, exerts many beneficial physiological effects. Its anti-inflammatory and antioxidant properties are well described. It is considered a potential therapeutic factor in sepsis, with positive results from studies on animal models and with encouraging results from the first human clinical trials. With its antioxidant and anti-inflammatory potential, it may also exert a neuroprotective effect in sepsis-associated encephalopathy. The review presents data on melatonin as a potential drug in SAE in the wider context of the pathophysiology of SAE and the specific actions of the pineal neurohormone.

The Impact of Thrombocytopenia and Lymphopenia on Mortality in Patients Infected with Influenza Virus: A Retrospective Cohort Study

Introduction: Influenza virus causes significant global annual morbidity and mortality. Thrombocytopenia is recognized as a poor prognostic factor in sepsis and is associated with mortality, while lymphopenia has been established as a poor prognostic factor in other viral infections. We aimed to assess the incidence of thrombocytopenia and lymphopenia in seasonal influenza and their effect on clinical outcomes. Methods: This single-center, retrospective, cohort study included consecutive adult patients, hospitalized in Rabin Medical Center between October 2017 and April 2018, with laboratory-confirmed influenza. Patients were grouped according to blood counts on admission: (1) thrombocytopenia (<150 K/mL), (2) lymphopenia (<0.5 K/mL), and (3) both thrombocytopenia and lymphopenia. Patients without thrombocytopenia and lymphopenia were designated as controls. The primary outcome was 30-day all-cause mortality. Risk factors were identified by univariable and multivariable analyses, using logistic regression and reported as odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 625 patients were included, 112 (18%) had thrombocytopenia, 98 (15.6%) had lymphopenia, and 107 (17%) had both. The crude 30-day all-cause mortality was 7.6% (48/625). Mortality rates were 7.1% (8/112) for the thrombocytopenia group, 11.2% (11/98) for the lymphopenia group, and 14.9% (16/107) for patients with both versus 4.2% (13/308) in the control (p = 0.000 for all). In a multivariable regression model, significant thrombocytopenia (<100 K/μL) [OR 5.07 (95% CI 1.5–16.2)], age [OR 1.07 (95% CI 1.02–1.11)], time to oseltamivir [OR 1.006 (95% CI 1.002–1.11)], and significant respiratory support [OR 8.85 (3.4–22.6)] were associated with 30-day all-cause mortality. Conclusion: Patients hospitalized with seasonal influenza and thrombocytopenia <100 K/mL on admission, have an increased 30-day all-cause mortality.

Unraveling novel crosstalk between distinct neutrophil subsets and soluble plasma factors in sepsis and ARDS

Abstract Sepsis is a life-threatening condition caused by an aberrant immune response to infection and subsequent organ dysfunction. Further, due to shared mechanisms such as severe inflammation and endothelial dysfunction, sepsis remains the most common etiology in acute respiratory distress syndrome (ARDS) patients. Despite multiple efforts to identify a distinct signature to support the development of new therapeutics, sepsis remains a significant unmet clinical need. While singular components of the dysregulated immune response have been explored, studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and related changes in soluble plasma factors in sepsis versus healthy donors. Results from our studies identify differentially expressed mature and immature neutrophil subsets in sepsis patients. Further, we show that expression of neutrophil CD10 is associated with factors such as pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in the sepsis cohort. These findings detail a novel correlation between increased presence of immature neutrophils and endothelial dysfunction/metabolic alterations in sepsis patients. Additionally, we profiled the neutrophil landscape and evaluated levels of soluble plasma factors, in a subset of ARDS patients and healthy donors. Here, we present distinct findings that reveal a novel crosstalk between neutrophil subsets and parameters indicative of endothelial dysfunction, in sepsis and ARDS patients. Overall, our study reinforces the importance of data integration and provides novel insights that could help inform future mechanistic studies, early patient stratification and treatment options.

ИНФОРМАТИВНОСТЬ ТРАДИЦИОННОГО МИКРОБИОЛОГИЧЕСКОГО АНАЛИЗА ПРИ СЕПСИСЕ У ПАЦИЕНТОВ НЕЙРОРЕАНИМАЦИОННОГО ПРОФИЛЯ

Background. The existing routine methods of identification of microbes in various biological environments of the body have not led to a radical improvement in the target selection of antimicrobials and the outcomes of septic conditions. The purpose of the study: to analyze the effectiveness of standard microbiological studies in sepsis in patients with brain damage of various origins. Material and methods. A retrospective cohort study included 40 patients (male – 23, female – 17, average age – 50.43±2.84 years) neuro-resuscitation profile. The importance of the most important microbiological patterns of biological media in survived and deceased patients from sepsis has been studied. Results. Acinetobacter baumani, Escherichia coli in urine, Providencia stuartii in tracheobronchial aspirate were detected only in deceased patients, which the presence of these microorganisms can be considered adverse prognostic factors in sepsis and septic shock. Conclusion: A decrease in the clinical significance of the traditional method of verification of microbiological cultures in sepsis was revealed.

Serum Lactate, an Independent Prognostic Marker in Normotensive Patients With Acute Pulmonary Thromboembolism

Abstract Objective Serum lactate, a marker of tissue hypoxia, is an important prognostic factor in sepsis, trauma, and cardiogenic shock. Data on the direct correlation of serum lactate and in-hospital mortality in normotensive acute pulmonary thromboembolism (APE) patients, however, remains scarce. Material and methods We analyzed normotensive APE patients admitted to our clinic from January 1, 2014, to December 31, 2021. Serum lactate was collected from arterial blood at admission. Results The study sample included 161 patients with an average age of 68.61 ± 11.54 years. 54.94% were female. In-hospital mortality was 19.88%. In ROC analysis, serum lactate was a predictor of in-hospital mortality with an AUC of 0.662 (95%CI 0.584 – 0.735, p = 0.005). The cut-off level identified by the Youden index-associated criterion was &gt; 38 mg/dL (34.38% sensitivity, 94.57% specificity). In multivariable analysis for in-hospital mortality alongside the biomarkers proposed by the 2019 ESC guidelines for severity assessment, lactate &gt; 38 mg/dL was an independent predictor of mortality (OR 10.92, 95%CI 3.04 – 39.29, p &lt; 0.001). The prediction model including PESI score, right ventricular dysfunction, troponin I, and lactate &gt; 38 mg/dL had the best predictive performance for in-hospital mortality (AUC 0.807, p &lt; 0.001). Conclusions Elevated serum lactate is an independent predictor of all-cause in-hospital mortality of normotensive APE patients, with the optimal cut-off &gt; 38 mg/dL. Adding the lactate level for mortality prediction outperformed the 2019 ESC guidelines algorithm for severity assessment of normotensive APE patients.

Red blood cell distribution width as prognostic factor in sepsis: A new use for a classical parameter.

To evaluate Red blood cell distribution width (RDW) as a sepsis prognostic biomarker. 203 septic patients admitted to the ICU. Analysis of RDW dynamics, hospital mortality discrimination ability and the added value when incorporated to the SOFA, LODS, SAPS-II and APACHE-II scores using the AUC-ROC. Non-survivors presented higher RDW values during the first week after ICU admission (p = 0.048). Only SOFA and RDW were independently associated with mortality when adjusted by Charlson, immunosuppression, nosocomial infection, NEWS2, SAPS-II, septic shock and haemoglobin (p < 0.05). After adjustment, AUC-ROC was 0.827, 0.822, 0.824, 0.834 and 0.812 for each model including admission, 24, 48 and 72-h and 7-days RDW, respectively. When added to the scores, 24-h RDW and admission RDW improved their discrimination ability (SOFA AUC-ROC = 0.772 vs 0.812 SOFA + admission RDW, p = 0.041; LODS AUC-ROC = 0.687 vs 0.710, p = 0.002; SAPS-II AUC-ROC = 0.734 vs 0.785, p = 0.021; APACHE-II AUC-ROC = 0.672 vs 0.755, p = 0.003). Admission RDW with SOFA presented the better discrimination ability for mortality. RDW is an independent prognostic marker of death in septic patients admitted in the ICU that improves SOFA, LODS, APACHE-II and SAPS-II discrimination ability. This parameter could be incorporated to the prognostic scores as a marker of systemic dysfunction and dysregulated inflammatory response.

Pneumococcal BgaA Promotes Host Organ Bleeding and Coagulation in a Mouse Sepsis Model

Streptococcus pneumoniae is a major cause of invasive diseases such as pneumonia, meningitis, and sepsis, with high associated mortality. Our previous molecular evolutionary analysis revealed that the S. pneumoniae gene bgaA, encoding the enzyme β-galactosidase (BgaA), had a high proportion of codons under negative selection among the examined pneumococcal genes and that deletion of bgaA significantly reduced host mortality in a mouse intravenous infection assay. BgaA is a multifunctional protein that plays a role in cleaving terminal galactose in N-linked glycans, resistance to human neutrophil-mediated opsonophagocytic killing, and bacterial adherence to human epithelial cells. In this study, we performed in vitro and in vivo assays to evaluate the precise role of bgaA as a virulence factor in sepsis. Our in vitro assays showed that the deletion of bgaA significantly reduced the bacterial association with human lung epithelial and vascular endothelial cells. The deletion of bgaA also reduced pneumococcal survival in human blood by promoting neutrophil-mediated killing, but did not affect pneumococcal survival in mouse blood. In a mouse sepsis model, mice infected with an S. pneumoniae bgaA-deleted mutant strain exhibited upregulated host innate immunity pathways, suppressed tissue damage, and blood coagulation compared with mice infected with the wild-type strain. These results suggest that BgaA functions as a multifunctional virulence factor whereby it induces host tissue damage and blood coagulation. Taken together, our results suggest that BgaA could be an attractive target for drug design and vaccine development to control pneumococcal infection.

Abstract 2002: A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group

Abstract Background: Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and are more likely to experience morbidity and mortality from infectious toxicities during treatment compared to those without DS. We sought to characterize genetic risk factors for sepsis among individuals with DS-ALL. Methods: We performed a germline genome-wide association (GWAS) study for sepsis among 264 subjects with DS-ALL treated on Children’s Oncology Group (COG) protocols AALL0932 (N=181) and AALL1131 (N=83), for newly-diagnosed standard risk and high risk B-ALL, respectively. Sepsis was defined using Common Terminology Criteria for Adverse Events (v4.0), with a microbiologically confirmed grade 4 or 5 sepsis event reported during any phase of treatment to define the case and comparison groups. Germline genotyping on the Affymetrix SNP 6.0 or Illumina Omni 2.5Exome arrays was imputed to the Haplotype Reference Consortium panel and filtered for quality control. Logistic regression models were used to compare individuals with DS-ALL who experienced sepsis to those who never developed sepsis during treatment. Models were adjusted for principal components of population structure and COG protocol. Analyses included autosomal variants with a minor allele frequency &amp;gt;1% and excluded chromosome 21. Results: We identified 29 individuals (10.9%) with DS-ALL who developed one or more sepsis events during treatment. In genome-wide analyses, we observed 52 variants in eight genomic loci associated with sepsis at P&amp;lt;10-5 among individuals with DS-ALL. Our top signal was rs77917748 (P=6.02x10-7), an intronic variant in a regulatory region of TMEM163, a protein that is essential for zinc homeostasis. Additionally, we identified a strong linkage signal at rs56288508 on chr6p21.2 (P=5.29x10-6). According to data from the Genotype-Tissue Expression (GTEx) project, this locus is associated with whole blood expression of ZFAND3, a zinc finger protein and transcriptional regulator. Additionally, this variant is associated with intestinal infections (P=0.012) in the UK Biobank. Finally, a third variant we identified in our GWAS is on chr6q24.2 (P=4.33x10-6) and shows strong linkage in GTEx with peripheral blood mononuclear cell expression of APOBEC3A, a viral deaminase that lacks zinc binding activity. Notably, this variant is associated with respiratory failure (P=0.0099) in the UK Biobank. Conclusion: We identified evidence of genetic associations for sepsis risk in DS-ALL. These findings suggest zinc homeostasis may be an important factor mediating risk of sepsis during treatment of individuals with DS-ALL. Confirmatory studies and validation in additional cohorts are ongoing. Citation Format: Melissa A. Richard, Meenakshi Devidas, Wenjian Yang, John P. Woodhouse, Vilmarie Rodriguez, Johann K. Hitzler, Reuven J. Schore, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2002.

The Novel Role of Metabolism-Associated Molecular Patterns in Sepsis.

Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host’s severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.

Sepsis Encephalopathy Is Partly Mediated by miR370-3p-Induced Mitochondrial Injury but Attenuated by BAM15 in Cecal Ligation and Puncture Sepsis Male Mice.

BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100β, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood–brain barrier (BBB) damage (Evan’s blue dye and the presence of green fluorescent E. coli in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (iNOS and IL-1β) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation.

The role of blood urea nitrogen to serum albumin ratio in the prediction of severity and 30‐day mortality in patients with COVID‐19

BackgroundConsidering the role of higher blood urea nitrogen and lower serum albumin (SA) levels in deceased coronavirus disease 2019 (COVID‐19) patients, an increased blood urea nitrogen to SA (B/A) ratio may help to determine those at higher risk of critical illness. This study aimed to evaluate the correlation of the B/A ratio with severity and 30‐day mortality in COVID‐19 patients.MethodsA total of 433 adult patients with COVID‐19 were enrolled. The laboratory markers were measured on admission. Disease severity was categorized into mild disease, severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and septic shock. The mortality was followed for 30 days after admission. χ 2 test, Fisher's exact test, and Mann–Whitney U test were performed, as appropriate. Also, logistic regression and the receiver operating characteristic (ROC) curve for the B/A ratio are included.ResultsThirty‐day mortality rate was 27.25%. The frequency of mild, severe pneumonia, ARDS, sepsis, and septic shock was 30.72%, 36.95%, 24.02%, 6.00%, and 2.31%, respectively. B/A ratio and SA levels were statistically different between alive and deceased patients. The mean B/A ratio was different among classified disease severities, except for mild disease. Logistic regression revealed the B/A ratio as an independent risk factor for sepsis after adjusting for age and sex. ROC analysis showed B/A ratio had an area under the curve (AUC) of 0.733 for mortality at the cutpoint of 4.944. AUC for sepsis was 0.617 which was greater than other disease severities.ConclusionThe results showed that B/A ratio and SA levels are associated with mortality of COVID‐19 patients. A higher B/A ratio is, additionally, associated with COVID‐19 severity, except in mild cases and it can act as an independent risk factor in sepsis. However, a greater B/A ratio is not a significant predictor of COVID‐19 severity, but it can predict mortality. Therefore, we suggest this marker for clinical assessment of patients with severe COVID‐19.

Identification of the robust predictor for sepsis based on clustering analysis

Sepsis is a life-threatening disorder with high incidence and mortality rate. However, the early detection of sepsis is challenging due to lack of specific marker and various etiology. This study aimed to identify robust risk factors for sepsis via cluster analysis. The integrative task of the automatic platform (i.e., electronic medical record) and the expert domain was performed to compile clinical and medical information for 2,490 sepsis patients and 16,916 health check-up participants. The subjects were categorized into 3 and 4 groups based on seven clinical and laboratory markers (Age, WBC, NLR, Hb, PLT, DNI, and MPXI) by K-means clustering. Logistic regression model was performed for all subjects including healthy control and sepsis patients, and cluster-specific cases, separately, to identify sepsis-related features. White blood cell (WBC), well-known parameter for sepsis, exhibited the insignificant association with the sepsis status in old age clusters (K3C3 and K4C3). Besides, NLR and DNI were the robust predictors in all subjects as well as three or four cluster-specific subjects including K3C3 or K4C3. We implemented the cluster-analysis for real-world hospital data to identify the robust predictors for sepsis, which could contribute to screen likely overlooked and potential sepsis patients (e.g., sepsis patients without WBC count elevation).