Sepsis Susceptibility Research Articles

Plasma Proteome, Metabolome Mendelian Randomization Identifies Sepsis Therapeutic Targets.

The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Our investigation used public genome-wide association study (GWAS) data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample MR established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative MR analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. Post p-value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility (p-value = 2.14E-05, OR = 1.10, 95% CI = 1.05-1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. Following p-value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk (p-value = 3.37E-05, OR = 1.18, 95% CI = 1.09-1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein (p-value = 3.52E-04, OR = 1.11, 95% CI = 1.04-1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated MR revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)'s total effect on sepsis progression. This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.

Dissecting the mediating role of cytokines in the interaction between immune traits and sepsis: insights from comprehensive mendelian randomization.

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection, yet the potential causal relationship between the immunophenotype and sepsis remains unclear. Genetic variants associated with the immunophenotype served as instrumental variables (IVs) in Mendelian randomization (MR) to elucidate the causal impact of the immunophenotype on three sepsis outcomes. Additionally, a two-step MR analysis was conducted to identify significant potential mediators between the immunophenotype and three sepsis outcomes. Our MR analysis demonstrated a significant association between the immunophenotype and sepsis outcome, with 36, 36, and 45 the immunophenotype associated with the susceptibility, severity, and mortality of sepsis, respectively. Specifically, our analysis highlighted the CD14+ CD16+ monocyte phenotype as a significant factor across all three sepsis outcomes, with odds ratios (ORs) and corresponding confidence intervals (CIs) indicating its impact on sepsis (OR = 1.047, CI: 1.001-1.096), sepsis in Critical Care Units (OR = 1.139, CI: 1.014-1.279), and sepsis-related 28-day mortality (OR = 1.218, CI: 1.104-1.334). Mediation analyses identified seven cytokines as significant mediators among 91 potential cytokines, including interleukin-5 (IL-5), S100A12, TNF-related apoptosis-inducing ligand (TRAIL), T-cell surface glycoprotein CD6 isoform, cystatin D, interleukin-18 (IL-18), and urokinase-type plasminogen activator (uPA). Furthermore, reverse MR analysis revealed no causal effect of sepsis outcomes on the immunophenotype. Our MR study suggests that the immunophenotype is significantly associated with the susceptibility, severity, and mortality of patient with sepsis, providing, for the first time, robust evidence of significant associations between immune traits and their potential risks. This information is invaluable for clinicians and patients in making informed decisions and merits further attention.

Carnitine is causally associated with susceptibility and severity of sepsis: a Mendelian randomization study

Abstract Background Energy metabolism disorders contribute to the development of sepsis. Carnitine is essential for fatty acid metabolism and energy production. Therefore, we aimed to explore whether there is a causal relationship between carnitine levels and sepsis. Methods Two-sample Mendelian randomization (MR) analysis was performed. The single nucleotide polymorphisms (SNPs) of carnitine from the genome-wide association (GWAS) study were used as exposure instrumental variables, and the susceptibility and severity of sepsis in the UK Biobank were used as outcomes. The inverse-variance weighted (IVW), MR-Egger, and weighted median methods were used to evaluate the causal relationship between exposure and outcomes. Heterogeneity was assessed using IVW and MR-Egger’s and Cochran’s Q tests, and pleiotropy was tested using the MR-Egger intercept and MR-PRESSO. Results Using the IVW method, a one-standard-deviation increase in genetically determined carnitine levels was found to be associated with increased susceptibility to sepsis in populations under 75 years of age (odds ratio [OR]: 2.696; 95% confidence interval [CI]: 1.127–6.452; P = 0.026) and increased severity of sepsis (OR: 22.31; 95% CI: 1.769–281.282; P = 0.016). Sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy; therefore, the results indicated robustness. Conclusion Genetic susceptibility to increased carnitine levels in the blood may increase the susceptibility and severity of sepsis. Therefore, interventions at an early stage in patients with high carnitine levels may reduce the risk of developing sepsis.

Circulating micronutrient levels and their association with sepsis susceptibility and severity: a Mendelian randomization study.

Background: Sepsis, a global health challenge, necessitates a nuanced understanding of modifiable factors for effective prevention and intervention. The role of trace micronutrients in sepsis pathogenesis remains unclear, and their potential connection, especially with genetic influences, warrants exploration. Methods: We employed Mendelian randomization (MR) analyses to assess the causal relationship between genetically predicted blood levels of nine micronutrients (calcium, β-carotene, iron, magnesium, phosphorus, vitamin C, vitamin B6, vitamin D, and zinc) and sepsis susceptibility, severity, and subtypes. The instrumental variables for circulating micronutrients were derived from nine published genome-wide association studies (GWAS). In the primary MR analysis, we utilized summary statistics for sepsis from two independent databases (UK Biobank and FinnGen consortium), for initial and replication analyses. Subsequently, a meta-analysis was conducted to merge the results. In secondary MR analyses, we assessed the causal effects of micronutrients on five sepsis-related outcomes (severe sepsis, sepsis-related death within 28days, severe sepsis-related death within 28days, streptococcal septicaemia, and puerperal sepsis), incorporating multiple sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. Results: The study revealed a significant causal link between genetically forecasted zinc levels and reduced risk of severe sepsis-related death within 28days (odds ratio [OR] = 0.450; 95% confidence interval [CI]: 0.263, 0.770; p = 3.58 × 10-3). Additionally, suggestive associations were found for iron (increased risk of sepsis), β-carotene (reduced risk of sepsis death) and vitamin C (decreased risk of puerperal sepsis). No significant connections were observed for other micronutrients. Conclusion: Our study highlighted that zinc may emerges as a potential protective factor against severe sepsis-related death within 28days, providing theoretical support for supplementing zinc in high-risk critically ill sepsis patients. In the future, larger-scale data are needed to validate our findings.

Increased Mortality Risk at Septic Condition in Inflammatory Skin Disorders and the Effect of High-Fat Diet Consumption.

In recent years, attention has increasingly focused on various infectious diseases. Although some fatalities are directly attributed to the causative virus, many result from complications and reactive inflammation. Patients with comorbidities are at a higher risk of mortality. Refractory skin conditions such as atopic dermatitis, psoriasis, and epidermolysis bullosa, known for an elevated risk of sepsis, partly owe this to compromised surface barrier function. However, the detailed mechanisms underlying this phenomenon remain elusive. Conversely, although the detrimental effects of a high-fat diet on health, including the onset of metabolic syndrome, are widely recognized, the association between diet and susceptibility to sepsis has not been extensively explored. In this study, we examined the potential causes and pathogenesis of increased sepsis susceptibility in inflammatory skin diseases using a mouse dermatitis model: keratin 14-driven caspase-1 is overexpressed (KCASP1Tg) in mice on a high-fat diet. Our findings reveal that heightened mortality in the dermatitis mouse model is caused by the inflamed immune system due to the chronic inflammatory state of the local skin, and administration of LPS causes a rapid increase in inflammatory cytokine levels in the spleen. Intake of a high-fat diet exacerbates these cytokine levels. Interestingly, we also observed a reduced expression of Toll-like receptor 4 (TLR4) in monocytes from KCASP1Tg mice, potentially predisposing these animals to heightened infection risks and associated complications. Histological analysis showed a clear decrease in T and B cells in the spleen of KCASP1Tg mice fed a high-fat diet. Thickening of the alveolar wall, inflammatory cell infiltration, and alveolar hemorrhage were more prominent in the lungs of KCASP1Tg and KCASP1Tg with fat mice. We postulate that the chronic, non-infectious inflammation induces a negative feedback loop within the inflammatory cascade, and the suppressed expression of TLR4 renders the mice more susceptible to infections. Therefore, it is imperative for individuals with chronic skin inflammation to closely monitor disease progression upon infection and seek timely and appropriate treatment. Additionally, chronic inflammation of adipose tissue, induced by high-fat food intake, combined with dermatitis inflammation, may exacerbate infections, necessitating a review of dietary habits.

Decoding the Genomic Complexity of Sepsis: Paving the Way for Future Advances

Sepsis, a life-threatening condition resulting from the body's extreme response to infection, remains a global health challenge with high morbidity and mortality rates. The primary aim of this article is to unravel the intricate genetic factors contributing to sepsis susceptibility, severity, and patient outcomes. By understanding the genomic landscape of sepsis and its pathogenic infiltrations, this article tries to contribute to the development of novel diagnostic tools and therapeutic interventions, additionally it tries to integrate genomic data with clinical information to develop personalized approaches for sepsis management, including targeted therapies, drug development and precision medicine, and improving overall outcomes for individuals affected by Sepsis.

ASSESSING THE CAUSAL RELATIONSHIP BETWEEN SEPSIS AND AUTOIMMUNE: A MENDELIAN RANDOMIZATION STUDY.

Objective : Numerous epidemiological studies have identified a potential link between sepsis and a variety of autoimmune disorders. The primary objective of this study is to delve deeper into this connection, investigating the potential causal relationship between sepsis and autoimmune disorders through the application of Mendelian randomization (MR). Methods : To assess the potential genetic impact on sepsis risk relating to susceptibility toward immune-related outcomes, we used summary data from the largest European genome-wide association studies (GWAS) on these conditions using a two-sample MR framework. Single nucleotide polymorphisms-which had strong associations with the nine traits-were extracted from the GWAS and examined their effects in an extensive European sepsis GWAS (486,484 cases and 474,841 controls). We used inverse-variance weighted MR, weighted median, and MR Egger for analyses, supplementing these with sensitivity analyses and assessing level pleiotropy using MR methodologies. We also executed a reverse MR analysis to test sepsis' causal effects on the designated autoimmune traits. Results : With primary sclerosing cholangitis being the exception, our MR analysis suggests that susceptibility toward most autoimmune diseases does not affect sepsis risks. The reverse MR analysis did not validate any influence of sepsis susceptibility over other autoimmune diseases. Our primary inverse-variance weighted MR analysis outcomes found general confirmation through our sensitivity MR examinations. Variance in the exposures, as dictated by the single nucleotide polymorphism sets used as MR instruments, ranged between 4.88 × 10 -5 to 0.005. Conclusion : Our MR research, centered on a European population, does not validate a correlation between susceptibility to the majority of autoimmune disorders and sepsis risk. Associations discerned in epidemiological studies may owe partly to shared biological or environmental confounders. The risk susceptibility for primary sclerosing cholangitis does relate to sepsis risk, opening doors for personalized precision treatments in the future.

Bacterial patterns and antibiotic susceptibility among neonatal sepsis in Prof. Dr. I.G.N.G. Ngoerah Hospital, Bali, Indonesia

Background: Neonatal sepsis has the main cause of mortality and morbidity in neonates worldwide; the most frequent cause is bacteria. This study examined the bacterial patterns and antibiotic susceptibility in neonatal sepsis at Prof Ngoerah Hospital, Bali. Methods: This observational, descriptive study was conducted in Prof Ngoerah Hospital, Bali, Indonesia involving neonatal sepsis confirmed with blood culture. Data on antibiotic susceptibility and bacterial patterns were collected retrospectively from the registry of neonates patients with neonatal sepsis from January 2021 to August 2022. Results: The predominance of gram-negative bacteria was Acinetobacter baumannii (29.17%), Klebsiella pneumonia (10.42%), and the predominance of gram-positive bacteria was Staphylococcus haemolyticus (14.58%), Staphylococcus epidermidis (8.35%). The susceptibility was Gentamicin (57.29%), Ciprofloxacin (56.84%), Levofloxacin (55.21%), Trimethoprim/sulfamethoxazole (54.17%), Amikacin (50%), Meropenem (39.58%), Ampicilin/sulbactam (34.38%), Cefepim (32.29%), Piperacillin/Tazobactam (28.13%), Cefoperazone sulbactam (25%), Tigecycline (25%), Ceftriaxone (23.96%), and Vancomycin (22.92%). Conclusion: Gram-negative bacteria were a common infection. This study suggests that the reconsideration of gentamicin still can be an option as an empirical antibiotic, but ampicillin has low sensitivity; another broad-spectrum antibiotic with better sensitivity is another option due to its significantly higher susceptibility.

A narrative review of precision medicine in neonatal sepsis: genetic and epigenetic factors associated with disease susceptibility.

Neonatal sepsis is a dysregulated host response to an infectious agent that results in severe morbidity and mortality among neonates worldwide. Given the complex and heterogenous nature of neonatal sepsis, early diagnosis and individualized treatment remain challenges for clinicians despite clinical advance. Epidemiological studies on twins suggest that hereditary factors act in conjunction with environmental factors to affect neonatal sepsis susceptibility. However, little is known about hereditary risks at present. This review aims to elucidate neonatal hereditary predisposition to sepsis and outline thoroughly the genomic landscape underlying neonatal sepsis, which may, to a large extent, facilitate precision medicine in this area. PubMed was searched for all published literature relating to neonatal sepsis using Medical Subject Headings (MeSH) terms, with a focus on hereditary factors. Without any restriction on article type, articles published in English prior to June 1, 2022, were retrieved. Additionally, pediatric, adult, and animal- and laboratory-based studies were reviewed wherever possible. This review provides a detailed introduction regarding the hereditary risk of neonatal sepsis in terms of genetics and epigenetics. Its findings demonstrate the potential for translation to precision medicine, where risk stratification, early diagnosis, and individualized interventions might be matched to the certain population. This review delineates the comprehensive genomic landscape underpinning inherent susceptibility to neonatal sepsis, allowing future studies to integrate hereditary information into a routine protocol and drive precision medicine from the bench to the bedside.

Causal relationship between type 1 diabetes mellitus and six high-frequency infectious diseases: A two-sample mendelian randomization study.

Type 1 diabetes mellitus (T1DM) is associated with different types of infections; however, studies on the causal relationship between T1DM and infectious diseases are lacking. Therefore, our study aimed to explore the causalities between T1DM and six high-frequency infections using a Mendelian randomization (MR) approach. Two-sample MR studies were conducted to explore the causalities between T1DM and six high-frequency infections: sepsis, acute lower respiratory infections (ALRIs), intestinal infections (IIs), infections of the genitourinary tract (GUTIs) in pregnancy, infections of the skin and subcutaneous tissues (SSTIs), and urinary tract infections (UTIs). Data on summary statistics for T1DM and infections were obtained from the European Bioinformatics Institute database, the United Kingdom Biobank, FinnGen biobank, and Medical Research Council Integrative Epidemiology Unit. All data obtained for summary statistics were from European countries. The inverse-variance weighted (IVW) method was employed as the main analysis. Considering the multiple comparisons, statistical significance was set at p< 0.008. If univariate MR analyses found a significant causal association, multivariable MR (MVMR) analyses were performed to adjust body mass index (BMI) and glycated hemoglobin (HbA1c). MVMR-IVW was performed as the primary analysis, and the least absolute shrinkage and selection operator (LASSO) regression and MVMR-Robust were performed as complementary analyses. MR analysis showed that susceptibility to IIs increased in patients with T1DM by 6.09% using the IVW-fixed method [odds ratio (OR)=1.0609; 95% confidence interval (CI): 1.0281-1.0947, p=0.0002]. Results were still significant after multiple testing. Sensitivity analyses did not show any significant horizontal pleiotropy or heterogeneity. After adjusting for BMI and HbA1c, MVMR-IVW (OR=1.0942; 95% CI: 1.0666-1.1224, p<0.0001) showed significant outcomes that were consistent with those of LASSO regression and MVMR-Robust. However, no significant causal relationship was found between T1DM and sepsis susceptibility, ALRI susceptibility, GUTI susceptibility in pregnancy, SSTI susceptibility, and UTI susceptibility. Our MR analysis genetically predicted increased susceptibility to IIs in T1DM. However, no causality between T1DM and sepsis, ALRIs, GUTIs in pregnancy, SSTIs, or UTIs was found. Larger epidemiological and metagenomic studies are required to further investigate the observed associations between the susceptibility of certain infectious diseases with T1DM.

Pregnancy-induced changes to the gut microbiota drive macrophage pyroptosis and exacerbate septic inflammation

The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae (P.merdae) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P.merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.

Genetic polymorphisms associated with sepsis incidence, severity, and outcomes among neonates: A mini-review.

Genetic variation remains a topic of great interest due to its potential as a risk factor for various diseases. Interactions between genes contribute to diverse phenotypes in response to factors such as infection. The impact of genetic background on susceptibility and clinical outcomes, particularly in neonatal sepsis, has gained recognition. The variability in sepsis susceptibility and outcomes can be attributed to the genetic diversity in coding regions and regulatory elements of genes related to innate immune response. Recent advances in genomics and technology have shed light on genetic polymorphisms among humans, often represented by single-nucleotide polymorphisms (SNPs). These SNPs encode proteins crucial for recognizing and responding to pathogenic bacteria, including Toll-like receptor 4, CD14, tumor necrosis factor-alpha, as well as interleukin-1-10. This literature review specifically discusses the involvement of genetic polymorphism during the pathogenesis stage of sepsis, with an emphasis on previous research findings in neonatal sepsis cases, aiming to discuss the implications of polymorphism in sepsis susceptibility and outcomes.

Bacteriological profiles and antibiotic susceptibility of neonatal sepsis in a university hospital of Northern India.

Knowledge of epidemiology of bacterial isolates and their anti-biograms in hospital settings is necessary for prompt empirical anti-microbial therapy of neonatal sepsis. To study risk factors, bacteriological profiles, and anti-biograms of blood culture isolates of both early and late onset neonatal sepsis. It is a prospective observational study conducted from January 2020 till July 2021 at our tertiary care center. Neonates (0-28 days) admitted to this neonatal intensive care unit clinically suspected with sepsis were subjected to blood cultures, and the isolates were identified both biochemically and by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry system. Antibiotic susceptibility testing (AST) was performed as per CLSI guidelines. Chi-square test was used. Out of 280 suspected cases of neonatal sepsis, 43 (15.3%) cases showed positive blood culture. Of these, the majority (30, 69.8%) had late-onset neonatal sepsis. Major pre-disposing risk factors were pre-term birth and a low birth weight (26, 60.5%). Gram-negative bacteria and Gram-positive bacteria were isolated in 25 (58.1%) and 18 (41.9%) blood cultures, respectively. Klebsiella pneumoniae (37.5%) was the most predominant pathogen in both early-onset (23.1%) and late-onset (46.7%) sepsis. Coagulase negative Staphylococcus (34.8%) was the second most common organism and was more common in late onset (23.2%) neonatal sepsis. A high level of antibiotic resistance was noted in Klebsiella pneumoniae isolates, even to amikacin (76.5%) and carbapenems (66.7%). Increased resistance in bacterial isolates of neonatal sepsis emphasizes the need of AST of bacterial isolates for proper antibiotic administration.

FK506 impairs neutrophil migration that results in increased polymicrobial sepsis susceptibility.

This study aimed to investigate the effects of FK506 on experimental sepsis immunopathology. It investigated the effect of FK506 on leukocyte recruitment to the site of infection, systemic cytokine production, and organ injury in mice with sepsis. Using a murine cecal ligation and puncture (CLP) peritonitis model, the experiments were performed with wild-type (WT) mice and mice deficient in the gene Nfat1 (Nfat1-/-) in the C57BL/6 background. Animals were treated with 2.0mg/kg of FK506, subcutaneously, 1h before the sepsis model, twice a day (12h/12h). The number of bacteria colony forming units (CFU) was manually counted. The number of neutrophils in the lungs was estimated by the myeloperoxidase (MPO) assay. The expression of CXCR2 in neutrophils was determined using flow cytometry analysis. The expression of inflammatory cytokines in macrophage was determined using ELISA. The direct effect of FK506 on CXCR2 internalization was evaluated using HEK-293T cells after CXCL2 stimulation by the BRET method. FK506 treatment potentiated the failure of neutrophil migration into the peritoneal cavity, resulting in bacteremia and an exacerbated systemic inflammatory response, which led to higher organ damage and mortality rates. Failed neutrophil migration was associated with elevated CXCL2 chemokine plasma levels and lower expression of the CXCR2 receptor on circulating neutrophils compared with non-treated CLP-induced septic mice. FK506 did not directly affect CXCL2-induced CXCR2 internalization by transfected HEK-293 cells or mice neutrophils, despite increasing CXCL2 release by LPS-treated macrophages. Finally, the CLP-induced response of Nfat1-/- mice was similar to those observed in the Nfat1+/+ genotype, suggesting that the FK506 effect is not dependent on the NFAT1 pathway. Our data indicate that the increased susceptibility to infection of FK506-treated mice is associated with failed neutrophil migration due to the reduced membrane availability of CXCR2 receptors in response to exacerbated levels of circulating CXCL2.

Investigation of TLR2 and TLR4 Polymorphisms and Sepsis Susceptibility: Computational and Experimental Approaches.

Toll-like receptors (TLR) play an eminent role in the regulation of immune responses to invading pathogens during sepsis. TLR genetic variants might influence individual susceptibility to developing sepsis. The current study aimed to investigate the association of genetic polymorphisms of the TLR2 and TLR4 with the risk of developing sepsis with both a pilot study and in silico tools. Different in silico tools were used to predict the impact of our SNPs on protein structure, stability, and function. Furthermore, in our prospective study, all patients matching the inclusion criteria in the intensive care units (ICU) were included and followed up, and DNA samples were genotyped using real-time polymerase chain reaction (RT-PCR) technology. There was a significant association between TLR2 Arg753Gln polymorphisms and sepsis under the over-dominant model (p = 0.043). In contrast, we did not find a significant difference with the TLR4 Asp299Gly polymorphism with sepsis. However, there was a significant association between TLR4 Asp299Gly polymorphisms and Acinetobacter baumannii infection which is quite a virulent organism in ICU (p = 0.001) and post-surgical cohorts (p = 0.033). Our results conclude that the TLR2 genotype may be a risk factor for sepsis in adult patients.

MicroRNAs combined with the TLR4/TDAG8 mRNAs and proinflammatory cytokines are biomarkers for the rapid diagnosis of sepsis.

The early diagnosis and treatment of sepsis are of particular importance to patient survival. To obtain novel biomarkers that serve as prompt indicators of sepsis, the current study screened the differentially expressed microRNAs (DEMs) that were associated with sepsis susceptibility. The correlation between the elucidated DEMs and the inflammatory response was also examined. The present study included 40 patients with sepsis and 40 healthy controls. RNA-sequencing technology and bioinformatics analysis were applied to screen the DEMs between the two cohorts. The expression of these DEMs was subsequently verified by performing reverse transcription-quantitative PCR (RT-qPCR). In addition, IL-6, IL-21, C-X-C motif chemokine ligand-8 (CXCL8) and monocyte chemoattractant protein-1 (MCP-1) levels, along with T-cell death-associated gene 8 (TDAG8) and toll-like receptor 4 (TLR4) mRNA expression levels were assessed. The association between microRNA (miRNA/miR)-3663-3p and the secretion of various proinflammatory cytokines or TDAG8 and TLR4 mRNA expressions were subsequently evaluated by linear correlation analysis. The results revealed 305 DEMs (P<0.05; fold change >2) between patients with sepsis and healthy controls. Among these, the top 18 up- and downregulated miRNAs were selected for RT-qPCR verification. In addition, the serum content of IL-6, IL-21, CXCL8 and MCP-1, and the expression of TDAG8 and TLR4 mRNAs were significantly increased in patients with sepsis compared with healthy controls. Moreover, in patients with sepsis, a positive correlation was identified between miR-3663-3p and the secretion of inflammatory cytokines or TDAG8 and TLR4 mRNA expression. A positive correlation was also elucidated between TDAG8 and TLR4 mRNA expression and proinflammatory cytokine/chemokine secretion. Receiver operating characteristic curve analysis of miR-3663-3p expression, IL-6, IL-21, CXCL8 and MCP-1 secretion and TDAG8 and TLR4 mRNA expression demonstrated that miRNA analysis may be invaluable for the diagnosis of sepsis. Collectively, the results determined that miR-3663-3p may be a potentially powerful diagnostic and predictive biomarker of sepsis and that the combined and simultaneous detection of several biomarkers, including proteins, miRNAs and mRNA may be a reliable approach for the fast diagnosis and early identification of sepsis.

Effect of TLR-4 gene polymorphisms on sepsis susceptibility in neonates: a systematic review and meta-analysis.

Aim: To clarify the role of polymorphisms rs4986790 and rs4986791 in TLR-4with susceptibility to neonatal sepsis. Methods: To evaluate the possible correlation of polymorphisms rs4986790 and rs4986791 with sepsis risk, odds ratios (ORs) were calculated. The heterogeneity was evaluated by χ2-based Q-test. Results: For rs4986790, ORs were 1.36 (95% CI: 1.05-1.79, p=0.017) and 1.84 (95% CI: 0.04-7.9, p=0.410) under AG+GG versus AA and G vs A models, respectively. For rs4986791, ORs were 2.22 (95% CI: 1.25-3.94, p=0.006) and 2.20 (95% CI: 1.26-3.85, p=0.005) under CT+TT versusCC and of T versus C models, respectively. Conclusion: The rs4986790 and rs4986791 polymorphisms in TLR-4 could influence the sepsis susceptibility in neonates.

The rs8506 TT Genotype in lincRNA-NR_024015 Contributes to the Risk of Sepsis in a Southern Chinese Child Population.

BackgroundSepsis is a highly life-threatening heterogeneous syndrome and a global health burden. Studies have shown that many genetic variants could influence the risk of sepsis. Long non-coding RNA lincRNA-NR_024015 may participate in functional alteration of endothelial cell via vascular endothelial growth factor (VEGF) signaling, whereas its relevance between the lincRNA-NR_024015 polymorphism and sepsis susceptibility is still unclear.Methods474 sepsis patients and 678 healthy controls were enrolled from a southern Chinese child population in the present study. The polymorphism of rs8506 in lincRNA-NR_024015 was determined using Taqman methodology.ResultsOverall, a significant association was found between rs8506 polymorphism and the risk of sepsis disease (TT vs. CC/CT: adjusted OR = 1.751, 95%CI = 1.024–2.993, P = 0.0406). In the stratified analysis, the results suggested that the carriers of TT genotypes had a significantly increased sepsis risk among the children aged 12–60 months, females, early-stage sepsis and survivors (TT vs. CC/CT: ORage = 2.413; ORfemale = 2.868; ORsepsis = 2.533; ORsurvivor = 1.822; adjusted for age and gender, P < 0.05, respectively).ConclusionOur study indicated that lincRNA-NR_024015 rs8506 TT genotype might contribute to the risk of sepsis in a southern Chinese child population. Future research is required to elucidate the possible immunoregulatory mechanisms of this association and advance the development of novel biomarkers in sepsis.

Institutional Analysis of the Bacteriological Profile and Antibiotic Susceptibility of the Neonatal Sepsis in Eastern Nepal

Introduction: In the developing nations, neonatal sepsis account for the larger portion of the neonatal morbidity and mortality. Blood culture is considered as the gold standard for the diagnosis. Both, the conformation and management is difficult for clinicians in the resource limited nations like Nepal.&#x0D; Method: It is a retrospective observational study conducted at one of the tertiary care hospital in eastern Nepal over a year.&#x0D; Result: Incidence of neonatal sepsis was 12.9%. The incidence of blood culture positivity in the neonatal sepsis was 15%. Coagulase negative Staphylococcus species and Escherichia coli were two most predominant organism isolated. All of the isolated Klebsiella spp. and Pseudomonas spss.showed resistance to ampicillin whereas 100% of Coagulase Negative Staphylococcus spp. showed sensitivity to vancomycin.&#x0D; Conclusion: Isolated bacteria showed resistance to multiple antibiotics. This is an alarming moment for the pediatrician. Antibiotics should be used judiciously and continuous surveillance should be done to monitor the changing epidemiology of organisms and antibiotic sensitivity as the emergence of resistance to commonly used antibiotics is high.

The relationship between vitamin D receptor gene and TREM-1 gene polymorphisms and the susceptibility and prognosis of neonatal sepsis.

ObjectiveThe objective of this was to study the relationship between vitamin D receptor (VDR) and triggering receptor expressed on myeloid cells 1 (TREM‐1) gene single‐nucleotide polymorphisms (SNP) and neonatal sepsis susceptibility and prognosis.MethodsThe blood of 150 neonatal sepsis patients and 150 normal neonates was collected, and genomic DNA was extracted. Sanger sequencing was used to analyze the genotypes of VDR rs739837 and TREM‐1 rs2234246.ResultsVitamin D receptor rs739837 locus GT, TT genotype, dominant model, and recessive model were all protective factors for sepsis (0 < OR < 1, p < 0.05). The risk of sepsis in carriers of the rs739837 G allele was 0.65 times that of the rs739837 T allele (95% CI: 0.50–0.83, p < 0.001), CT, TT, dominant model, and recessive model at rs2234246 were risk factors for sepsis (OR > 1, p < 0.05). The risk of sepsis in carriers of the rs739837 T allele was 1.38 times that of carriers of the C allele (95% CI: 1.16–1.61, p < 0.001). The polymorphisms of VDR gene rs739837 and TREM‐1 gene rs2234246 were not significantly correlated with the survival of patients with neonatal sepsis (p > 0.05).Conclusion Vitamin D receptor gene rs739837 locus G>T is associated with a reduction in the risk of neonatal sepsis, TREM‐1 rs2234246 C>T is associated with the increased risk of neonatal sepsis, but none of them was significantly associated with the prognosis of neonatal sepsis.