Draft Genome Sequence of Candida saopaulonensis from a Very Premature Infant with Sepsis.

The rare fungus Candida saopaulonensis has never been reported to be associated with human infection. We report the draft genome sequence of the first clinical isolate of C. saopaulonensis, which was isolated from a very premature infant with sepsis. This is the first genome assembly reaching the near-complete chromosomal level with structural annotation for this species, opening up avenues for exploring evolutionary patterns and genetic mechanisms of pathogenesis.

Nivolumab-Induced Cytokine Release Syndrome: A Case Report and Literature Review.

BACKGROUND CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra-physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. CASE REPORT We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. CONCLUSIONS The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines.

The Dual Role of Neutrophil Extracellular Traps (NETs) in Sepsis and Ischemia-Reperfusion Injury: Comparative Analysis across Murine Models.

A better understanding of the function of neutrophil extracellular traps (NETs) may facilitate the development of interventions for sepsis. The study aims to investigate the formation and degradation of NETs in three murine sepsis models and to analyze the production of reactive oxygen species (ROS) during NET formation. Murine sepsis was induced by midgut volvulus (720° for 15 min), cecal ligation and puncture (CLP), or the application of lipopolysaccharide (LPS) (10 mg/kg body weight i.p.). NET formation and degradation was modulated using mice that were genetically deficient for peptidyl arginine deiminase-4 (PAD4-KO) or DNase1 and 1L3 (DNase1/1L3-DKO). After 48 h, mice were killed. Plasma levels of circulating free DNA (cfDNA) and neutrophil elastase (NE) were quantified to assess NET formation and degradation. Plasma deoxyribonuclease1 (DNase1) protein levels, as well as tissue malondialdehyde (MDA) activity and glutathione peroxidase (GPx) activity, were quantified. DNase1 and DNase1L3 in liver, intestine, spleen, and lung tissues were assessed. The applied sepsis models resulted in a simultaneous increase in NET formation and oxidative stress. NET formation and survival differed in the three models. In contrast to LPS and Volvulus, CLP-induced sepsis showed a decreased and increased 48 h survival in PAD4-KO and DNase1/1L3-DKO mice, when compared to WT mice, respectively. PAD4-KO mice showed decreased formation of NETs and ROS, while DNase1/1L3-DKO mice with impaired NET degradation accumulated ROS and chronicled the septic state. The findings indicate a dual role for NET formation and degradation in sepsis and ischemia-reperfusion (I/R) injury: NETs seem to exhibit a protective capacity in certain sepsis paradigms (CLP model), whereas, collectively, they seem to contribute adversely to scenarios where sepsis is combined with ischemia-reperfusion (volvulus).

The Association between the rs3747406 Polymorphism in the Glucocorticoid-Induced Leucine Zipper Gene and Sepsis Survivals Depends on the SOFA Score.

The variability in mortality in sepsis could be a consequence of genetic variability. The glucocorticoid system and the intermediate TSC22D3 gene product-glucocorticoid-induced leucine zipper-are clinically relevant in sepsis, which is why this study aimed to clarify whether TSC22D3 gene polymorphisms contribute to the variance in sepsis mortality. Blood samples for DNA extraction were obtained from 455 patients with a sepsis diagnosis according to the Sepsis-III criteria and from 73 control subjects. A SNP TaqMan assay was used to detect single-nucleotide polymorphisms (SNPs) in the TSC22D3 gene. Statistical and graphical analyses were performed using the SPSS Statistics and GraphPad Prism software. C-allele carriers of rs3747406 have a 2.07-fold higher mortality rate when the sequential organ failure assessment (SOFA) score is higher than eight. In a multivariate COX regression model, the SNP rs3747406 with a SOFA score ≥ 8 was found to be an independent risk factor for 30-day survival in sepsis. The HR was calculated to be 2.12, with a p-value of 0.011. The wild-type allele was present in four out of six SNPs in our cohort. The promoter of TSC22D3 was found to be highly conserved. However, we discovered that the C-allele of rs3747406 poses a risk for sepsis mortality for SOFA Scores higher than 6.

Microbial Community Changes in Silkworms Suspected of Septicemia and Identification of Serratia sp.

Diseases that occur in silkworms include soft rot, hardening disease, digestive diseases, and sepsis. However, research on the causes of bacterial diseases occurring in silkworms and the resulting changes in the microbial community is lacking. Therefore, we examined the morphological characteristics of sepsis and changes in the microbial community between silkworms that exhibit a unique odor and healthy silkworms; thus, we established a relationship between disease-causing microorganisms and sepsis. After producing a 16S rRNA amplicon library for samples showing sepsis, we obtained information on the microbial community present in silkworms using next-generation sequencing. Compared to that in healthy silkworms, in silkworms with sepsis, the abundance of the Firmicutes phylum was significantly reduced, while that of Proteobacteria was increased. Serratia sp. was dominant in silkworms with sepsis. After bacterial isolation, identification, and reinfection through the oral cavity, we confirmed this organism as the disease-causing agent; its mortality rate was 1.8 times higher than that caused by Serratia marcescens. In summary, we identified a new causative bacterium of silkworm sepsis through microbial community analysis and confirmed that the microbial community balance was disrupted by the aberrant proliferation of certain bacteria.

Clinical Impact of Supplementation with Pasteurized Donor Human Milk by High-Temperature Short-Time Method versus Holder Method in Extremely Low Birth Weight Infants: A Multicentre Randomized Controlled Trial.

Nosocomial infections are a frequent and serious problem in extremely low birth weight (ELBW) infants. Donor human milk (DHM) is the best alternative for feeding these babies when mother's own milk (MOM) is not available. Recently, a patented prototype of a High-Temperature Short-Time (HTST) pasteurizer adapted to a human milk bank setting showed a lesser impact on immunologic components. We designed a multicentre randomized controlled trial that investigates whether, in ELBW infants with an insufficient MOM supply, the administration of HTST pasteurized DHM reduces the incidence of confirmed catheter-associated sepsis compared to DHM pasteurized with the Holder method. From birth until 34 weeks postmenstrual age, patients included in the study received DHM, as a supplement, pasteurized by the Holder or HTST method. A total of 213 patients were randomized; 79 (HTST group) and 81 (Holder group) were included in the analysis. We found no difference in the frequency of nosocomial sepsis between the patients of the two methods-41.8% (33/79) of HTST group patients versus 45.7% (37/81) of Holder group patients, relative risk 0.91 (0.64-1.3), p = 0.62. In conclusion, when MOM is not available, supplementing during admission with DHM pasteurized by the HTST versus Holder method might not have an impact on the incidence of catheter-associated sepsis.

[Key microbial monitoring and clinical analysis of bloodstream infections and CRO colonization after hematopoietic stem cell transplantation in hematological patients].

Objective: To investigate the distribution and clinical characteristics of pathogenic bacteria following hematopoietic stem cell transplantation (HSCT), as well as to provide a preliminary research foundation for key microbial monitoring, and clinical diagnosis and treatment of infections after HSCT in hematological patients. Methods: We retrospectively analyzed the clinical data of 190 patients who tested positive for microbial testing [G-bacteria blood culture and/or carbapenem-resistant organism (CRO) screening of perianal swabs] at our center from January 2018 to December 2022. Patients were divided into blood culture positive, perianal swab positive, and double positive groups based on the testing results. The three patient groups underwent statistical analysis and comparison. Results: The top four pathogenic bacteria isolated from sixty-three patients with G-bacteria bloodstream infection (BSI) were Escherichia coli (28 strains, 43.75% ), Klebsiella pneumonia (26 strains, 40.63% ), Pseudomonas aeruginosa (3 strains, 4.69% ), and Enterobacter cloacae (3 strains, 4.69% ). The top three pathogenic bacteria isolated from 147 patients with CRO perianal colonization were carbapenem-resistant Klebsiella pneumoniae (58 strains, 32.58% ), carbapenem-resistant Escherichia coli (49 strains, 27.53% ), and carbapenem-resistant Enterobacter cloacae (20 strains, 11.24% ). The 3-year disease-free survival (DFS ) and overall survival (OS) of double positive group patients were significantly lower compared to those in the blood culture and perianal swab positive groups (DFS: 35.6% vs 53.7% vs 68.6%, P=0.001; OS: 44.4% vs 62.4% vs 76.9%, P<0.001), while non-relapse mortality (NRM) was significantly higher (50.0% vs 34.9% vs 10.6%, P<0.001). Failed engraftment of platelets and BSI are independent risk factors for NRM (P<0.001). Using polymyxin and/or ceftazidime-avibactam for more than 7 days is an independent protective factor for NRM (P=0.035) . Conclusion: This study suggests that the occurrence of BSI significantly increases the NRM after HSCT in patients with hematological diseases; CRO colonization into the bloodstream has a significant impact on the DFS and OS of HSCT patients.

Using Mendelian randomization provides genetic insights into potential targets for sepsis treatment.

Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20-1.45, p = 1.66E-08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.

New findings on CD16brightCD62Ldim neutrophil subtypes in sepsis-associated ARDS: an observational clinical study.

Background: The CD16brightCD62Ldim neutrophil subtype is a recently identified neutrophil subtype. The aim of this study was to evaluate changes of peripheral blood CD16brightCD62Ldim neutrophils in patients with sepsis-associated ARDS. Methods: We prospectively recruited adult patients with sepsis-associated ARDS in the intensive care unit (ICU). Patient demographic data, medical history information, and laboratory data were collected within 48 hours of enrollment, and flow cytometry was applied to analyze the CD16brightCD62Ldim neutrophil subtype in the patients' peripheral blood. Multifactor COX regression models were used to analyze factors affecting prognosis, and Spearman correlation coefficients were used to analyze clinical and laboratory indicators affecting complications of infection. Results: Of the 40 patients, 9 patients died by the 28-day follow-up, indicating a mortality rate of 22.5%. Patients in the nonsurvival group had higher CD16brightCD62Ldim neutrophil levels. Patients with sepsis-associated ARDS who had a baseline proportion of CD16brightCD62Ldim neutrophil subtypes to total neutrophils in peripheral blood >3.73% had significantly higher 28-day mortality, while patients with CD16brightCD62Ldim neutrophil subtypes counts >2.62×109/L were also associated with significantly higher 28-day mortality. The percentage of the CD16brightCD62Ldim neutrophil subtype (HR=5.305, 95% CI 1.986-14.165, p=0.001) and IL-8 (HR=3.852, 95% CI 1.561-9.508, p=0.003) were independent risk factors for the development of infectious complications in patients with sepsis-related ARDS. The percentage of CD16brightCD62Ldim neutrophil subtypes predicted an AUC of 0.806 (95% CI 0.147-0.964, P=0.003) for the development of infectious complications, and 0.742 (95% CI 0.589-0.895, P=0.029) for the prediction of death within 28 days. Conclusion: We identified for the first time that CD16brightCD62Ldim neutrophils are elevated in patients with sepsis-associated ARDS and are associated with infectious complications and poor prognosis. The percentage of CD16brightCD62Ldim neutrophil subtypes may serve as a predictor of the development of infectious complications in patients with ARDS.

Long-term risk of death in patients with infection attended by prehospital emergency services. / Modelo de riesgo de mortalidad a largo plazo en pacientes con infección atendidos por servicios de emergencias prehospitalarios.

OBJECTIVES: To develop and validate a risk model for 1-year mortality based on variables available from early prehospital emergency attendance of patients with infection. MATERIAL AND METHODS: Prospective, observational, noninterventional multicenter study in adults with suspected infection transferred to 4 Spanish hospitals by advanced life-support ambulances from June 1, 2020, through June 30, 2022. We collected demographic, physiological, clinical, and analytical data. Cox regression analysis was used to develop and validate a risk model for 1-year mortality. RESULTS: Four hundred ten patients were enrolled (development cohort, 287; validation cohort, 123). Cumulative mortality was 49% overall. Sepsis (infection plus a Sepsis-related Organ Failure Assessment score of 2 or higher) was diagnosed in 29.2% of survivors vs 56.7% of nonsurvivors. The risk model achieved an area under the receiver operating characteristic curve of 0.89 for 1-year mortality. The following predictors were included in the model: age; institutionalization; age-adjusted Charlson comorbidity index; PaCO2; potassium, lactate, urea nitrogen, and creatinine levels; fraction of inspired oxygen; and diagnosed sepsis. CONCLUSION: The model showed excellent ability to predict 1-year mortality based on epidemiological, analytical, and clinical variables, identifying patients at high risk of death soon after their first contact with the health care system.

OBJETIVO: Diseñar y validar un modelo de riesgo con variables determinadas a nivel prehospitalario para predecir el riesgo de mortalidad a largo plazo (1 año) en pacientes con infección. METODO: Estudio multicéntrico, observacional prospectivo, sin intervención, en pacientes adultos con sospecha infección atendidos por unidades de soporte vital avanzado y trasladados a 4 hospitales españoles entre el 1 de junio de 2020 y el 30 de junio de 2022. Se recogieron variables demográficas, fisiológicas, clínicas y analíticas. Se construyó y validó un modelo de riesgo para la mortalidad a un año usando una regresión de Cox. RESULTADOS: Se incluyeron 410 pacientes, con una tasa de mortalidad acumulada al año del 49%. La tasa de diagnóstico de sepsis (infección e incremento sobre el SOFA basal $ 2 puntos) fue del 29,2% en supervivientes frente a un 56,7% en no supervivientes. El modelo predictivo obtuvo un área bajo la curva de la característica operativa del receptor para la mortalidad a un año fue de 0,89, e incluyó: edad, institucionalización, índice de comorbilidad de Charlson ajustado por edad, presión parcial de dióxido de carbono, potasio, lactato, nitrógeno ureico en sangre, creatinina, saturación en relación con fracción inspirada de oxígeno y diagnóstico de sepsis. CONCLUSIONES: El modelo desarrollado con variables epidemiológicas, analíticas y clínicas mostró una excelente capacidad predictiva, y permitió identificar desde el primer contacto del paciente con el sistema sanitario, a modo de evento centinela, casos de alto riesgo.

Monocytic myeloid-derived suppressor cells as an immune indicator of early diagnosis and prognosis in patients with sepsis.

BACKGROUND: Immunosuppression is a leading cause of septic death. Therefore, it is necessary to search for biomarkers that can evaluate the immune status of patients with sepsis. We assessed the diagnostic and prognostic value of low-density neutrophils (LDNs) and myeloid-derived suppressor cells (MDSCs) subsets in the peripheral blood mononuclear cells (PBMCs) of patients with sepsis. METHODS: LDNs and MDSC subsets were compared among 52 inpatients with sepsis, 33 inpatients with infection, and 32 healthy controls to investigate their potential as immune indicators of sepsis. The percentages of LDNs, monocytic MDSCs (M-MDSCs), and polymorphonuclear MDSCs (PMN-MDSCs) in PBMCs were analyzed. Sequential organ failure assessment (SOFA) scores, C-reactive protein (CRP), and procalcitonin (PCT) levels were measured concurrently. RESULTS: The percentages of LDNs and MDSC subsets were significantly increased in infection and sepsis as compared to control. MDSCs performed similarly to CRP and PCT in diagnosing infection or sepsis. LDNs and MDSC subsets positively correlated with PCT and CRP levels and showed an upward trend with the number of dysfunctional organs and SOFA score. Non-survivors had elevated M-MDSCs compared with that of patients who survived sepsis within 28 days after enrollment. CONCLUSIONS: MDSCs show potential as a diagnostic biomarker comparable to CRP and PCT, in infection and sepsis, even in distinguishing sepsis from infection. M-MDSCs show potential as a prognostic biomarker of sepsis and may be useful to predict 28-day hospital mortality in patients with sepsis.

An observational study on the impact of overcrowding towards door-to-antibiotic time among sepsis patients presented to emergency department of a tertiary academic hospital.

BACKGROUND: The latest Surviving Sepsis Campaign 2021 recommends early antibiotics administration. However, Emergency Department (ED) overcrowding can delay sepsis management. This study aimed to determine the effect of ED overcrowding towards the management and outcome of sepsis patients presented to ED. METHODS: This was an observational study conducted among sepsis patients presented to ED of a tertiary university hospital from 18th January 2021 until 28th February 2021. ED overcrowding status was determined using the National Emergency Department Overcrowding Score (NEDOCS) scoring system. Sepsis patients were identified using Sequential Organ Failure Assessment (SOFA) scores and their door-to-antibiotic time (DTA) were recorded. Patient outcomes were hospital length of stay (LOS) and in-hospital mortality. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 26. P-value of less than 0.05 for a two-sided test was considered statistically significant. RESULTS: Total of 170 patients were recruited. Among them, 33 patients presented with septic shock and only 15% (n = 5) received antibiotics within one hour. Of 137 sepsis patients without shock, 58.4% (n = 80) received antibiotics within three hours. We found no significant association between ED overcrowding with DTA time (p = 0.989) and LOS (p = 0.403). However, in-hospital mortality increased two times during overcrowded ED (95% CI 1-4; p = 0.041). CONCLUSION: ED overcrowding has no significant impact on DTA and LOS which are crucial indicators of sepsis care quality but it increases overall mortality outcome. Further research is needed to explore other factors such as lack of resources, delay in initiating fluid resuscitation or vasopressor so as to improve sepsis patient care during ED overcrowding.

Neo-epitope detection identifies extracellular matrix turnover in systemic inflammation and sepsis: an exploratory study.

BACKGROUND: Sepsis is associated with high morbidity and mortality, primarily due to systemic inflammation-induced tissue damage, resulting organ failure, and impaired recovery. Regulated extracellular matrix (ECM) turnover is crucial for maintaining tissue homeostasis in health and in response to disease-related changes in the tissue microenvironment. Conversely, uncontrolled turnover can contribute to tissue damage. Systemic Inflammation is implicated to play a role in the regulation of ECM turnover, but the relationship between the two is largely unclear. METHODS: We performed an exploratory study in 10 healthy male volunteers who were intravenously challenged with 2 ng/kg lipopolysaccharide (LPS, derived from Escherichia coli) to induce systemic inflammation. Plasma samples were collected before (T0) and after (T 1 h, 3 h, 6 h and 24 h) the LPS challenge. Furthermore, plasma was collected from 43 patients with septic shock on day 1 of ICU admission. Circulating neo-epitopes of extracellular matrix turnover, including ECM degradation neo-epitopes of collagen type I (C1M), type III (C3M), type IV (C4Ma3), and type VI (C6M), elastin (ELP-3) and fibrin (X-FIB), as well as the ECM synthesis neo-epitopes of collagen type III (PRO-C3), collagen type IV (PRO-C4) and collagen type VI (PRO-C6) were measured by ELISA. Patient outcome data were obtained from electronic patient records. RESULTS: Twenty-four hours after LPS administration, all measured ECM turnover neo-epitopes, except ELP-3, were increased compared to baseline levels. In septic shock patients, concentrations of all measured ECM neo-epitopes were higher compared to healthy controls. In addition, concentrations of C6M, ELP-3 and X-FIB were higher in patients with septic shock who ultimately did not survive (N = 7) compared to those who recovered (N = 36). CONCLUSION: ECM turnover is induced in a model of systemic inflammation in healthy volunteers and was observed in patients with septic shock. Understanding interactions between systemic inflammation and ECM turnover may provide further insight into mechanisms underlying acute and persistent organ failure in sepsis.

Inflammatory liver diseases and susceptibility to sepsis.

Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.

Pellino1 orchestrates gut-kidney axis to perpetuate septic acute kidney injury through activation of STING pathway and NLRP3 inflammasome.

AIMS: Intestinal barrier dysfunction is the initial and propagable factor of sepsis in which acute kidney injury (AKI) has been considered as a common life-threatening complication. Our recent study identifies the regulatory role of Pellino1 in tubular death under inflammatory conditions in vitro. The objective of our current study is to explore the impact of Pellino1 on gut-kidney axis during septic AKI and uncover the molecular mechanism (s) underlying this process. MATERIALS AND METHODS: Immunohistochemistry (IHC) was conducted to evaluate Pellino1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels in renal biopsies from critically ill patients with a clinical diagnosis of sepsis. Functional and mechanistic studies were characterized in septic models of the Peli-knockout (Peli1-/-) mice by histopathological staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, biochemical detection, CRISPR/Cas9-mediated gene editing and intestinal organoid. KEY FINDINGS: Pellino1, together with NLRP3, are highly expressed in renal biopsies from critically ill patients diagnosed with sepsis and kidney tissues of septic mice. The Peli1-/- mice with sepsis become less prone to develop AKI and have markedly compromised NLRP3 activation in kidney. Loss of Peli1 endows septic mice refractory to intestinal inflammation, barrier permeability and enterocyte apoptosis that requires stimulator of interferons genes (STING) pathway. Administration of STING agonist DMXAA deteriorates AKI and mortality of septic Peli1-/- mice in the presence of kidney-specific NLRP3 reconstitution. SIGNIFICANCE: Our studies suggest that Pellino1 has a principal role in orchestrating gut homeostasis towards renal pathophysiology, thus providing a potential therapeutic target for septic AKI.

Unraveling the immunological landscape in acute pancreatitis progression to sepsis: insights from a Mendelian randomization study on immune cell traits.

Background: Acute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression. Methods: Employing a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis. Results: Our investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis. Conclusion: This study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition.

Empowering Little Fighters: Post-Cardiotomy Pediatric ECMO and the Journey to Recovery.

INTRODUCTION: Extra Corporeal Membrane Oxygenation (ECMO) has long been used for cardiorespiratory support in the immediate post-paediatric cardiac surgery period with a 2-3% success as per the ELSO registry. Success in recovery depends upon the optimal delivery of critical care to paediatric patients and a comprehensive healthcare team. METHODOLOGY: The survival benefit of children placed on central veno arterial (VA) ECMO following elective cardiac surgeries for congenital heart disease (n = 672) was studied in a cohort of 29 (4.3%) cases from the period of Jan 2018 to Dec 2022 in our cardiac surgical centre. Indications for placing these patients on central VA ECMO included inability to wean from cardiopulmonary bypass (CPB), low cardiac output syndrome, severe pulmonary arterial hypertension, significant bleeding, anaphylaxis, respiratory failure and severe pulmonary edema. RESULTS: The mean time to initiation of ECMO was less than 5 h and the mean duration of ECMO support was 56 h with a survival rate of 58.3%. Amongst perioperative complications, sepsis and arrhythmia on ECMO were found to be negatively associated with survival. Improvements in the pH, PaO2 levels and serum lactate levels after initiation of ECMO were associated with survival benefits. CONCLUSION: The early initiation of ECMO for paediatric cardiotomies could be a beacon of hope for families and medical teams confronting these challenging situations. Improvement in indicators of adequate perfusion and ventricular recoveries like pH and serum lactate and absence of arrhythmia and sepsis are associated with good outcomes.

[Research progress on pathogenic mechanism of sepsis-induced liver injury and treatment with traditional Chinese medicine and its active components].

Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.

L-AP Alleviates Liver Injury in Septic Mice by Inhibiting Macrophage Activation via Suppressing NF-κB and NLRP3 Inflammasome/Caspase-1 Signal Pathways.

Liver injury and progressive liver failure are severe life-threatening complications in sepsis, further worsening the disease and leading to death. Macrophages and their mediated inflammatory cytokine storm are critical regulators in the occurrence and progression of liver injury in sepsis, for which effective treatments are still lacking. l-Ascorbic acid 6-palmitate (L-AP), a food additive, can inhibit neuroinflammation by modulating the phenotype of the microglia, but its pharmacological action in septic liver damage has not been fully explored. We aimed to investigate L-AP's antisepticemia action and the possible pharmacological mechanisms in attenuating septic liver damage by modulating macrophage function. We observed that L-AP treatment significantly increased survival in cecal ligation and puncture-induced WT mice and attenuated hepatic inflammatory injury, including the histopathology of the liver tissues, hepatocyte apoptosis, and the liver enzyme levels in plasma, which were comparable to NLRP3-deficiency in septic mice. L-AP supplementation significantly attenuated the excessive inflammatory response in hepatic tissues of septic mice in vivo and in cultured macrophages challenged by both LPS and ATP in vitro, by reducing the levels of NLRP3, pro-IL-1ß, and pro-IL-18 mRNA expression, as well as the levels of proteins for p-I-κB-α, p-NF-κB-p65, NLRP3, cleaved-caspase-1, IL-1ß, and IL-18. Additionally, it impaired the inflammasome ASC spot activation and reduced the inflammatory factor contents, including IL-1ß and IL-18 in plasma/cultured superannuants. It also prevented the infiltration/migration of macrophages and their M1-like inflammatory polarization while improving their M2-like polarization. Overall, our findings revealed that L-AP protected against sepsis by reducing macrophage activation and inflammatory cytokine production by suppressing their activation in NF-κB and NLRP3 inflammasome signal pathways in septic liver.

Bacterial etiology and antimicrobial resistance pattern of pediatric bloodstream infections: a 5-year experience in an Iranian referral hospital.

BACKGROUND: Bloodstream infections (BSI) are the major cause of morbidity and mortality in children in developing countries. The purpose of the current study was to establish the antimicrobial susceptibility pattern of bacterial isolates from bloodstream infections at Children's Medical Center Hospital (CMC), Tehran, Iran. METHODS: We retrospectively recorded all positive blood cultures and antimicrobial susceptibility of all bloodstream isolates among children admitted to CMC, during 5 years. Specimen culture, bacterial identification, and antimicrobial susceptibility testing were performed according to standard laboratory methods. RESULTS: From 3,179 pathogens isolated from the blood cultures 2,824 bacteria were cultured, with 1,312 cases being identified as Gram-positive bacteria (46%) and 1,512 cases as Gram-negative bacteria (54%). The most common Gram-negative bacteria isolated were as follows: Pseudomonas spp. (n = 266, 17.6%), Klebsiella pneumoniae (n = 242, 16%), Stenotrophomonas maltophilia (n = 204, 13.5%), Enterobacter spp. (n = 164, 10.8%), Escherichia coli (n = 159, 10.5%), Pseudomonas aeruginosa (n = 126, 8.3%), Serratia marcescens (n = 121, 8%), and Acinetobacter baumannii (n = 73, 4.8%). The most common Gram-positive bacteria isolated were coagulase-negative staphylococci (CONS) (n = 697, 53%), Streptococcus spp. (n = 237, 18%), Staphylococcus aureus (n = 202, 15%) and Enterococcus spp. (n = 167, 12.7%). 34% of bacterial strains were isolated from ICUs. The rates of methicillin resistance in S. aureus and CONS were 34% and 91%, respectively. E. coli isolates showed high resistance to cefotaxime (84%). All isolates of K. pneumoniae were susceptible to colistin and 56% were susceptible to imipenem. P. aeruginosa isolates showed high susceptibility to all antibiotics. CONCLUSIONS: Our findings emphasize the need of clinicians having access to up-to-date bacterial susceptibility data for routinely prescribed drugs. Continuous monitoring of changes in bacterial resistance will aid in the establishment of national priorities for local intervention initiatives in Iran. The increased risk of BSI caused by antibiotic-resistant organisms, emphasizes the significance of implementing appropriate antibiotic prescribing regulations and developing innovative vaccination techniques in Iran.