Sepsis Therapy Research Articles

Enriching Data Science and Health Care Education: Application and Impact of Synthetic Data Sets Through the Health Gym Project.

Large-scale medical data sets are vital for hands-on education in health data science but are often inaccessible due to privacy concerns. Addressing this gap, we developed the Health Gym project, a free and open-source platform designed to generate synthetic health data sets applicable to various areas of data science education, including machine learning, data visualization, and traditional statistical models. Initially, we generated 3 synthetic data sets for sepsis, acute hypotension, and antiretroviral therapy for HIV infection. This paper discusses the educational applications of Health Gym's synthetic data sets. We illustrate this through their use in postgraduate health data science courses delivered by the University of New South Wales, Australia, and a Datathon event, involving academics, students, clinicians, and local health district professionals. We also include adaptable worked examples using our synthetic data sets, designed to enrich hands-on tutorial and workshop experiences. Although we highlight the potential of these data sets in advancing data science education and health care artificial intelligence, we also emphasize the need for continued research into the inherent limitations of synthetic data.

Robust and Multifunctional Therapeutic Nanoparticles against Peritonitis-Induced Sepsis.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Methazolamide Reduces the AQP5 mRNA Expression and Immune Cell Migration-A New Potential Drug in Sepsis Therapy?

Sepsis is a life-threatening condition caused by the dysregulated host response to infection. Novel therapeutic options are urgently needed and aquaporin inhibitors could suffice as aquaporin 5 (Aqp5) knockdown provided enhanced sepsis survival in a murine sepsis model. Potential AQP5 inhibitors provide sulfonamides and their derivatives. In this study, we tested the hypothesis that sulfonamides reduce AQP5 expression in different conditions. The impact of sulfonamides on AQP5 expression and immune cell migration was examined in cell lines REH and RAW 264.7 by qPCR, Western blot and migration assay. Subsequently, whether furosemide and methazolamide are capable of reducing AQP5 expression after LPS incubation was investigated in whole blood samples of healthy volunteers. Incubation with methazolamide (10-5 M) and furosemide (10-6 M) reduced AQP5 mRNA and protein expression by about 30% in REH cells. Pre-incubation of the cells with methazolamide reduced cell migration towards SDF1-α compared to non-preincubated cells to control level. Pre-incubation with methazolamide in PBMCs led to a reduction in LPS-induced AQP5 expression compared to control levels, while furosemide failed to reduce it. Methazolamide appears to reduce AQP5 expression and migration of immune cells. However, after LPS administration, the reduction in AQP5 expression by methazolamide is no longer possible. Hence, our study indicates that methazolamide is capable of reducing AQP5 expression and has the potential to be used in sepsis prophylaxis.

Serum Concentration at 24 h With Intensive Beta-Lactam Therapy in Sepsis and Septic Shock: A Prospective Study: Beta-Lactam Blood Levels in Sepsis.

Introduction: Early administration of appropriate antibiotics has been shown to be among the most effective interventions to reduce mortality in septic patients. We evaluated the attainment of efficacy and safety targets at 24 h associated with the use of intensive beta-lactam therapy in patients admitted to the intensive care unit for sepsis. Methods: This was a prospective study with patients who received beta-lactams for sepsis or septic shock between February 2023 and September 2023. The antibiotic dose was unadjusted for renal function and administered by a loading dose followed by extended infusions, according to local practices. Blood samples were taken at the trough 24 h after the start of the beta-lactam to obtain serum levels. These levels were compared to efficacy and innocuity thresholds found in the literature. Results: Among 36 included patients, all of them achieved serum concentrations above the minimum inhibitory concentration (MIC) for 100% of the therapeutic interval and 75% of them achieved serum concentrations above four times the MIC for 100% of the therapeutic interval. The predefined toxicity thresholds were reached by 8.3% of patients. Renal impairment was the factor most associated with the achievement of higher serum levels. Conclusion: Nonrenally adjusted doses of beta-lactams administered by extended infusion showed good attainment of effective concentrations and few toxic concentrations in critically ill patients with sepsis or septic shock. Further studies are needed to better define the association between toxic concentrations and toxicity manifestations.

Sepsis epidemiology in Australian and New Zealand children (SENTINEL): protocol for a multicountry prospective observational study

IntroductionSepsis affects 25.2 million children per year globally and causes 3.4 million deaths, with an annual cost of hospitalisation in the USA of US$7.3 billion. Despite being common, severe and...

Comparative evaluation of effectiveness and safety of meropenem in term and preterm neonates with neonatal sepsis

Background: Neonatal sepsis is one of the most common causes of substantial neonatal morbidity and mortality. In India, it is estimated that 7.5 lakh neonates die every year, which is the highest neonatal mortality rate (NMR) in the world. This is despite the fact that NMR declined from 44/1000 lives birth in 2000–28/1000 live births in 2013. The rate of decline has been slow and lags behind that of the infant mortality rate and the under-five mortality rate. Aims and Objectives: To study the effectiveness and safety of meropenem in the treatment of sepsis affecting term and preterm neonates. Materials and Methods: The study was a prospective, observational study conducted at Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi. A total of 76 subjects were enrolled (38 term and 38 preterm neonates). All neonates, preterm or term, admitted to the Neonatal Intensive Care Unit with neonatal sepsis, either clinical or culture-proven sepsis, who had not received meropenem before admission and would be given meropenem as empirical or culture-sensitive were included. All enrolled neonates were evaluated for the effectiveness of meropenem. Pre- and post-meropenem dose clinical and laboratory data were evaluated using the presumptive clinical cure score (PCCS). Results: There was a significant difference between pre- and post-PCCS of all the neonates (P < 0.001) in both groups. There was no significant difference in the effectiveness of meropenem therapy in neonatal sepsis in term and preterm neonates (P = 0.253). There was no significant difference in the adverse reaction profile between preterm and term neonates for skin rash (P = 0.614) and diarrhea (P = 1.00). Conclusion: Meropenem is quite effective and safe for neonatal sepsis in both term and preterm neonates. So, giving meropenem as a second or third line in a dose of 20–40 mg/kg 8 hours a day according to gestation is a good drug for the treatment of neonatal sepsis.

Harnessing Nanomedicine for Targeted Sepsis Therapy

Harnessing Nanomedicine for Targeted Sepsis Therapy

Macrophage-derived exosomal miRNA-141 triggers endothelial cell pyroptosis by targeting NLRP3 to accelerate sepsis progression.

Sepsis, critical condition marked by severe organ dysfunction from uncontrolled infection, involves the endothelium significantly. Macrophages, through paracrine actions, play a vital role in sepsis, but their mechanisms in sepsis pathogenesis remain elusive. Objective: We aimed to explore how macrophage-derived exosomes with low miR-141 expression promote pyroptosis in endothelial cells (ECs). Exosomes from THP-1 cell supernatant were isolated and characterized. The effects of miR-141 mimic/inhibitor on apoptosis, proliferation, and invasion of Human Umbilical Vein Endothelial Cells (HUVECs) were assessed using flow cytometry, CCK-8, and transwell assays. Key pyroptosis-related proteins, including caspase-1, IL-18, IL-1β, NLR Family Pyrin Domain Containing 3 (NLRP3), ASC, and cleaved-GSDMD, were analyzed via Western blot. The interaction between miR-141 and NLRP3 was studied using RNAhybrid v2.2 and dual-Luciferase reporter assays. The mRNA and protein level of NLRP3 after exosomal miR-141 inhibitor treatment was detected by qPCR and Western blot, respectively. Exosomes were successfully isolated. miR-141 mimic reduced cell death and pyroptosis-related protein expression in HUVECs, while the inhibitor had opposite effects, increasing cell death, and enhancing pyroptosis protein expression. Additionally, macrophage-derived exosomal miR-141 inhibitor increased cell death and pyroptosis-related proteins in HUVECs. miR-141 inhibits NLRP3 transcription. Macrophages facilitate sepsis progression by secreting miR-141 decreased exosomes to activate NLRP3-mediated pyroptosis in ECs, which could be a potentially valuable target of sepsis therapy.

Identification and experimental validation of cuproptosis regulatory program in a sepsis immune microenvironment through a combination of single-cell and bulk RNA sequencing.

In spite of its high mortality rate and poor prognosis, the pathogenesis of sepsis is still incompletely understood. This study established a cuproptosis-based risk model to diagnose and predict the risk of sepsis. In addition, the cuproptosis-related genes were identified for targeted therapy. Single-cell sequencing analyses were used to characterize the cuproptosis activity score (CuAS) and intercellular communications in sepsis. Differential cuproptosis-related genes (CRGs) were identified in conjunction with single-cell and bulk RNA sequencing. LASSO and Cox regression analyses were employed to develop a risk model. Three external cohorts were conducted to assess the model's accuracy. Differences in immune infiltration, immune cell subtypes, pathway enrichment, and the expression of immunomodulators were further evaluated in distinct groups. Finally, various in-vitro experiments, such as flow cytometry, Western blot, and ELISA, were used to explore the role of LST1 in sepsis. ScRNA-seq analysis demonstrated that CuAS was highly enriched in monocytes and was closely related to the poor prognosis of sepsis patients. Patients with higher CuAS exhibited prominent strength and numbers of cell-cell interactions. A total of five CRGs were identified based on the LASSO and Cox regression analyses, and a CRG-based risk model was established. The lower riskScore cohort exhibited enhanced immune cell infiltration, elevated immune scores, and increased expression of immune modulators, indicating the activation of an antibacterial response. Ultimately, in-vitro experiments demonstrated that LST1, a key gene in the risk model, was enhanced in the macrophage in response to LPS, which was closely related to the decrease of macrophage survival rate, the enhancement of apoptosis and oxidative stress injury, and the imbalance of the M1/M2 phenotype. This study constructed a cuproptosis-related risk model to accurately predict the prognosis of sepsis. We further characterized the cuproptosis-related gene LST1 to provide a theoretical framework for sepsis therapy.

Extracorporeal Blood Treatment Using Functional Magnetic Nanoclusters Mitigates Organ Dysfunction of Sepsis in Swine.

Mitigating sepsis-induced severe organ dysfunction with magnetic nanoparticles has shown remarkable advances in extracorporeal blood treatment. Nevertheless, treating large septic animals remains challenging due to insufficient magnetic separation at rapid blood flow rates (>6 L h-1) and limited incubation time in an extracorporeal circuit. Herein, superparamagnetic nanoclusters (SPNCs) coated with red blood cell (RBC) membranes are developed, which promptly capture and magnetically separate a wide range of pathogens at high blood flow rates in a swine sepsis model. The SPNCs exhibited an ultranarrow size distribution of clustered iron oxide nanocrystals and exceptionally high saturation magnetization (≈ 90 emu g-1) close to that of bulk magnetite. It is also revealed that CD47 on the RBCs allows the RBC-SPNCs to remain at a consistent concentration in the blood by evading innate immunity. The uniform size distribution of the RBC-SPNCs greatly enhances their effectiveness in eradicating various pathogenic materials in extracorporeal blood. The use of RBC-SPNCs for extracorporeal treatment of swine infected with multidrug-resistant E. coli is validated and found that severe bacteremic sepsis-induced organ dysfunction is significantly mitigated after 12 h. The findings highlight the potential application of RBC-SPNCs for extracorporeal therapy of severe sepsis in large animal models and potentially humans.

Rab26 alleviates sepsis-induced immunosuppression as a master regulator of macrophage ferroptosis and polarization shift

Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1. During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis. Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS, MDA, and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.

Sorbent functionalization with vancomycin enhances bacteria killing in extracorporeal hemoadsorption.

The level of bacteremia in patients with sepsis and septic shock is a predictor of complications and mortality, regardless of the type of bacteria. Devices for bacteria, endotoxin and cytokines removal by adsorption have been recently developed. Thus, extracorporeal blood purification therapies have been proposed as adjunctive therapy in sepsis in combination with drugs. Some potentially useful drugs, however, are precluded due to their organ or metabolic toxicity. The present study represents a preliminary report on the invitro effect of a sorbent device (minimodule with HA380 beads, Jafron medical, Zhuhai, China) in which the particles have been functionalized with vancomycin on the surface. The impact of the surface-modified beads on circulating bacteria (Staphylococcus aureus) has been tested in a simulated invitro circulation. In vitro experiments were carried out with 800 mL of blood enriched with S. aureus species. Blood was circulated in the vancomycin-functionalized and non-functionalized mini-module cartridges in hemoadsorption setup (300 mL each) and the bactericidal effect was assessed. Also, 200 mL of blood was used as a control. A significant increase in the time to positivity of blood cultures was observed after 60 min and also after 120 min of therapy with the mini-module functionalized with vancomycin as opposed to the non-functionalized cartridge. These results suggest a possible way of treating sepsis by using drug- or antibiotic-functionalized cartridges without worrying about pharmacological toxicity. The prolongation of the time to bacterial culture positivity to S. aureus after a passage through a column packed with beads functionalized with vancomycin represents a proof of concept.

Argon inhalation attenuates systemic inflammation and rescues lung architecture during experimental neonatal sepsis.

Neonatal sepsis is a systemic inflammatory infection common in premature infants and a leading cause of mortality. Argon is an emerging interest in the field of noble gas therapy. Neonates with severe sepsis are frequently mechanically ventilated creating an opportunity for inhalation therapy. We aimed to investigate argon inhalation as a novel experimental therapy in neonatal sepsis. Sepsis was established in C57BL/6 neonatal mice by a lipopolysaccharide intraperitoneal injection on postnatal day 9. Septic pup mice were exposed to room air as well as non-septic controls. In the argon group, septic pup mice were exposed to argon (70% Ar, 30% O2) for 6h in a temperature-controlled environment. At 6h, survival was significantly enhanced when septic mice received argon compared to septic controls. Serum profiles of cytokine release were significantly attenuated as well as lung architecture restored. Our findings suggest that argon inhalation as a novel treatment for neonatal sepsis, reducing mortality and counteracting the acute systemic inflammatory response in the blood and preserving the architecture of the lung. This research can contribute to a paradigm shift in the treatment and outcome of neonates with sepsis.

The Role of Probiotics as An Adjuvant Therapy for Sepsis Against Multidrug-Resistant Bacteria

The role of probiotics on sepsis, particularly when induced by multidrug-resistant (MDR) bacteria, is mediated through complex biochemical pathways. Probiotics demonstrate a capacity to effectively combat infections and reduce mortality rates in sepsis cases. A significant contributor to this efficacy is attributed to the short-chain fatty acids (SCFAs) produced by these probiotics. SCFAs play a critical role in modulating the immune system, primarily by influencing the production of inflammatory cytokines, fortifying the integrity of intestinal epithelium, preventing cellular apoptosis, and maintaining the balance of gut microbiota. Moreover, probiotics are instrumental in counteracting the detrimental impacts of excessive antibiotic use, which is a major contributing factor to the emergence of MDR bacterial strains. The integration of probiotics with conventional therapeutic approaches offers a viable and potentially effective strategy in the management of sepsis caused by MDR bacteria, suggesting a promising direction for future clinical interventions.

Therapeutic effect of adipose-derived mesenchymal stem cells in a porcine model of abdominal sepsis

BackgroundThe term sepsis refers to a complex and heterogeneous syndrome. Although great progress has been made in improving the diagnosis and treatment of this condition, it continues to have a huge impact on morbidity and mortality worldwide. Mesenchymal stem cells are a population of multipotent cells that have immunomodulatory properties, anti-apoptotic effects, and antimicrobial activity. We studied these capacities in a porcine model of peritoneal sepsis.MethodsWe infused human adipose-derived mesenchymal stem cells (ADSCs) into a porcine model of peritoneal sepsis. Twenty piglets were treated with antibiotics alone (control group) or antibiotics plus peritoneal infusion of ADSCs at a concentration of 2 × 106 cells/kg or 4 × 106 cells/kg (low- and high-dose experimental groups, respectively). The animals were evaluated at different time points to determine their clinical status, biochemical and hematologic parameters, presence of inflammatory cytokines and chemokines in blood and peritoneal fluid, and finally by histologic analysis of the organs of the peritoneal cavity.ResultsOne day after sepsis induction, all animals presented peritonitis with bacterial infection as well as elevated C-reactive protein, haptoglobin, IL-1Ra, IL-6, and IL-1b. Xenogeneic ADSC infusion did not elicit an immune response, and peritoneal administration of the treatment was safe and feasible. One day after infusion, the two experimental groups showed a superior physical condition (e.g., mobility, feeding) and a significant increase of IL-10 and TGF-β in blood and a decrease of IL-1Ra, IL-1b, and IL-6. After 7 days, all animals treated with ADSCs had better results concerning blood biomarkers, and histopathological analysis revealed a lower degree of inflammatory cell infiltration of the organs of the peritoneal cavity.ConclusionsIntraperitoneal administration of ADSCs as an adjuvant therapy for sepsis improves the outcome and diminishes the effects of peritonitis and associated organ damage by regulating the immune system and reducing intra-abdominal adhesions in a clinically relevant porcine model of abdominal sepsis.

УСПЕШНОЕ ПРИМЕНЕНИЕ МЕТОДА ПОЛИМИКСИНОВОЙ СОРБЦИИ ЭНДОТОКСИНА В КОМПЛЕКСНОЙ ТЕРАПИИ ПАЦИЕНТКИ С ГРАМОТРИЦАТЕЛЬНЫМ СЕПСИСОМ ПРИ ПОЗДНЕМ ИНФИЦИРОВАННОМ ВЫКИДЫШЕ

Abstract. Introduction. Sepsis is one of the most serious problems of modern obstetrics, accounting for 11% of the overall structure of maternal mortality. One of the main initial causes of sepsis is endotoxin having diverse biological effects. Moreover, during sepsis development, endotoxin directly or indirectly leads to irreversible and often life-incompatible damage to organs. Columns for direct hemoperfusion with polymyxin B are used for extracorporeal endotoxin removal. Aim: Reviewing the literature on using columns with polymyxin B in sepsis treatment and describing our own clinical observation of maternal sepsis. Materials and Methods. Review of publications in electronic resources, such as PubMed, eLibrary, EMBASE, and Google Scholar. This article presents a clinical case of successful sepsis treatment during late infected miscarriage in a young patient. Results and Discussion. Currently published systematic reviews and meta- analyses prove the reduction of mortality in patients with sepsis/septic shock. A 39-year-old patient was admitted with signs of chorioamnionitis and incipient miscarriage at 20-21 weeks of pregnancy. After the delivery of a dead fetus, the picture of sepsis and septic shock developed. Removal of the uterus as the primary source of infection did not improve the woman’s condition. Positive changes were only observed after having applied the polymyxin sorption of endotoxin. This new advanced technology in medicine, thanks to the timely use, correct dose, and duration of hemoperfusion with polymyxin B, made it possible to remove bacterial endotoxins safely and effectively from the blood, which led to the successful sepsis therapy. Conclusions. Thanks to the coordinated actions of a multidisciplinary team of highly qualified specialists and the timely administration of adequate therapy, it was possible to save the patient’s life, thus preventing her from maternal mortality.

1656. Evaluation of Using Oxacillin versus Vancomycin for Empiric Therapy of Late-Onset Neonatal Sepsis in NICU

Abstract Background Our Pediatric Antimicrobial Stewardship Program (PedASP) assessed methicillin-sensitive (MSSA) and methicillin-resistant S. aureus (MRSA) infections in neonatal intensive care unit (NICU) and created a NICU-specific antibiogram. Due to a rising trend of NICU MSSA infections seen in our 84-bed NICU, empiric therapy of late-onset neonatal sepsis (LONS) was modified from vancomycin to oxacillin in January 2021. We report the two-year results of using empiric oxacillin for LONS.Figure 1.Summary of S. aureus identified in LONS cases Methods We assessed MSSA versus MRSA isolated from blood and non-blood cultures in NICU between January 2019 and December 2022. Infants with weight less than 750 grams, previous MRSA infections, maternal MRSA colonization, or serious infections based on clinical judgement were advised to use empiric vancomycin. We examined the vancomycin eligibility criteria, antibiotic-pathogen mismatch rate, 30-day mortality, and frequency of peripheral intravenous (PIV) access loss after vancomycin or oxacillin administration. The cost-savings was estimated by comparing drug and lab costs associated with vancomycin and oxacillin use. Results LONS cases are summarized in Figure 1. There was no statistical difference in incidence of S. aureus bacteremia before and after protocol implementation (p=0.45). Antibiotic-pathogen mismatch rate was 0%. Cases of MRSA bacteremia increased from 0 to 3 post protocol initiation; all cases met vancomycin eligibility criteria. The 30-day mortality among MRSA infections increased from 0 to 1 case. Post protocol implementation, the PIV loss rate decreased from 4.7 to 3.3% (p=0.04), and vancomycin use decreased by 1154 doses while oxacillin use increased by 485 doses. Based on antibiotic use and 141 vancomycin levels averted, the estimated cost-savings was $140,229. Conclusion Our PedASP utilized local susceptibility data to change empiric antibiotics for LONS, reinforcing the benefit of using antibiogram to optimize antibiotic use in NICU. Implementing a NICU-specific antibiogram improved the effectiveness of antibiotic treatment and achieved significant cost savings. Disclosures All Authors: No reported disclosures

IFITM3 overexpression reverses insufficient healing benefits of small extracellular vesicles from high-fat-diet BMSCs in sepsis via the HMGB1 pathway

Bone marrow mesenchymal stem cells (BMSCs) are a promising new therapy for sepsis, a common cause of death in hospitals. However, the global epidemic of metabolic syndromes, including obesity and pre-obesity, threatens the health of the human BMSC pool. The therapeutic effects of BMSCs are primarily due to the secretion of the small extracellular vesicles containing lipids, proteins, and RNA. Accordingly, studies on BMSCs, their small extracellular vesicles, and their modifications in obese individuals are becoming increasingly important. In this study, we investigated the therapeutic potential of small extracellular vesicles (sEVs) from high-fat diet BMSCs (sEVsHFD) in sepsis-induced liver-heart axis injury. We found that sEVsHFD yielded diminished therapeutic benefits compared to sEVs from chow diet BMSCs (sEVsCD). We subsequently verified that IFITM3 significantly differed in sEVsCD and sEVsHFD, alternating in septic liver tissue, and indicating its potential as a remodeling target of sEVs. IFITM3-overexpressed high-fat-diet BMSCs (HFD-BMSCs) showed that corresponding sEVs (sEVsHFD-IFITM3) markedly ameliorated liver-heart axis injury during sepsis. Lastly, we identified the protective action mechanisms of sEVsHFD-IFITM3 in sepsis-induced organ failure and HMGB1 expression and secretion was altered in septic liver and serum while HMGB1 has been demonstrated as a critical mediator of multi-organ failure in sepsis. These findings indicate that IFITM3 overexpression regenerates the therapeutic benefit of sEVs from HFD-BMSCs in sepsis via the HMGB1 pathway.

Trueperella pyogenes endocarditis in a Swiss farmer: a case report and review of the literature

BackgroundTrueperella pyogenes (T. pyogenes) is a bacterium that colonizes the skin and mucosal surfaces of various domestic and wild animals. It rarely leads to infections in humans, with only a few descriptions available in the literature.Case presentationA 71-year-old Swiss farmer with a history of recurring basal cell carcinoma and metastasized pancreatic neuroendocrine tumor presented with signs of sepsis after a three-day history of general weakness, malaise and fever. Clinical and echocardiographic findings, as well as persistent bacteremia were consistent with mitral valve endocarditis caused by T. pyogenes. The patient’s condition gradually improved under antibiotic treatment with piperacillin/tazobactam (empiric therapy of sepsis), and later penicillin G based on resistance testing. He was discharged after 13 days and continued outpatient antibiotic therapy with ceftriaxone, resulting in a total antibiotic treatment duration of six weeks. This is the first literature review of T. pyogenes endocarditis in humans. Among nine cases of T. pyogenes endocarditis, three patients had documented contact with farm animals and five had an underlying condition that compromised the immune system. While antibiotic resistance of T. pyogenes is an emerging concern, susceptibility to beta-lactam antibiotics seems to persist. The mortality of T. pyogenes endocarditis described in the literature was high, with 66% of patients not surviving the disease.ConclusionsT. pyogenes is a rare causative organism of infectious endocarditis in humans and descriptions are mainly restricted to case reports. In our review of the literature, we found that both an impaired immune system and contact with farm animals might be risk factors. Growth of T. pyogenes in blood cultures is unlikely to be missed during routine analysis, as it shows marked beta-hemolysis on blood agar culture plates, which generally leads to further characterization of the bacteria. Susceptibility to penicillin, ceftriaxone, and macrolides seems to be retained and the reported mortality in the few patients with T. pyogenes endocarditis is high.

EMERGENCE OF A TECHNOLOGY-DEPENDENT PHENOTYPE OF PEDIATRIC SEPSIS IN A LARGE CHILDREN'S HOSPITAL.

Objective: To investigate whether pediatric sepsis phenotypes are stable in time. Methods: Retrospective cohort study examining children with suspected sepsis admitted to a Pediatric Intensive Care Unit at a large freestanding children's hospital during two distinct periods: 2010-2014 (early cohort) and 2018-2020 (late cohort). K-means consensus clustering was used to derive types separately in the cohorts. Variables included ensured representation of all organ systems. Results: One thousand ninety-one subjects were in the early cohort and 737 subjects in the late cohort. Clustering analysis yielded four phenotypes in the early cohort and five in the late cohort. Four types were in both: type A (34% of early cohort, 25% of late cohort), mild sepsis, with minimal organ dysfunction and low mortality; type B (25%, 22%), primary respiratory failure; type C (25%, 18%), liver dysfunction, coagulopathy, and higher measures of systemic inflammation; type D (16%, 17%), severe multiorgan dysfunction, with high degrees of cardiorespiratory support, renal dysfunction, and highest mortality. Type E was only detected in the late cohort (19%) and was notable for respiratory failure less severe than B or D, mild hypothermia, and high proportion of diagnoses and technological dependence associated with medical complexity. Despite low mortality, this type had the longest PICU length of stay. Conclusions: This single center study identified four pediatric sepsis phenotypes in an earlier epoch but five in a later epoch, with the new type having a large proportion of characteristics associated with medical complexity, particularly technology dependence. Personalized sepsis therapies need to account for this expanding patient population.