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Circulating nucleosome levels are commonly elevated in physiological and pathological conditions. Their potential as biomarkers for diagnosing and prognosticating sepsis remains uncertain due, in part, to technical limitations in existing detection methods. This scoping review explores the possible role of nucleosome concentrations in the diagnosis, prognosis, and therapeutic management of sepsis. A comprehensive literature search of the Cochrane and Medline libraries from 1996 to 1 February 2024 identified 110 potentially eligible studies, of which 19 met the inclusion criteria, encompassing a total of 39 SIRS patients, 893 sepsis patients, 280 septic shock patients, 117 other ICU control patients, and 345 healthy volunteers. The enzyme-linked immunosorbent assay [ELISA] was the primary method of nucleosome measurement. Studies consistently reported significant correlations between nucleosome levels and other NET biomarkers. Nucleosome levels were higher in patients with sepsis than in healthy volunteers and associated with disease severity, as indicated by SOFA and APACHE II scores. Non-survivors had higher nucleosome levels than survivors. Circulating nucleosome levels, therefore, show promise as early markers of NETosis in sepsis, with moderate diagnostic accuracy and strong correlations with disease severity and prognosis. However, the available evidence is drawn mainly from single-center, observational studies with small sample sizes and varied detection methods, warranting further investigation. [ABSTRACT FROM AUTHOR]

Abstract Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management. Graphical Abstract

Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management. Highlights: • Due to their unique characteristics, Peptides hold significant promise as part of nanotechnology approaches for diagnosing and treating sepsis, a current leading global killer. • Various diagnostic nanotools utilizing peptides as pathogen recognition moieties can improve the pathogen capturing efficiency for sepsis diagnosis. • Nano-delivery can overcome the limitations of bioactive peptides and enhance their antibacterial and anti-inflammatory efficacy in sepsis management. • Peptides offer significant capabilities as targeting moieties and nanocarriers to augment the effectiveness of antisepsis agents. • Future research identified can potentiate the applications of peptides for the diagnosis and treatment of sepsis. [ABSTRACT FROM AUTHOR]

Circulating nucleosome levels are commonly elevated in physiological and pathological conditions. Their potential as biomarkers for diagnosing and prognosticating sepsis remains uncertain due, in part, to technical limitations in existing detection methods. This scoping review explores the possible role of nucleosome concentrations in the diagnosis, prognosis, and therapeutic management of sepsis. A comprehensive literature search of the Cochrane and Medline libraries from 1996 to 1 February 2024 identified 110 potentially eligible studies, of which 19 met the inclusion criteria, encompassing a total of 39 SIRS patients, 893 sepsis patients, 280 septic shock patients, 117 other ICU control patients, and 345 healthy volunteers. The enzyme-linked immunosorbent assay [ELISA] was the primary method of nucleosome measurement. Studies consistently reported significant correlations between nucleosome levels and other NET biomarkers. Nucleosome levels were higher in patients with sepsis than in healthy volunteers and associated with disease severity, as indicated by SOFA and APACHE II scores. Non-survivors had higher nucleosome levels than survivors. Circulating nucleosome levels, therefore, show promise as early markers of NETosis in sepsis, with moderate diagnostic accuracy and strong correlations with disease severity and prognosis. However, the available evidence is drawn mainly from single-center, observational studies with small sample sizes and varied detection methods, warranting further investigation.

Sepsis is an immune response to a microbial invasion that causes organ injury and dysfunction due to a systemic inflammatory response. Sepsis is a serious, life-threatening condition and a widely recognized global health challenge. Given its high death rate, it is critical to diagnose sepsis and start treatment as early as possible. There is an urgent need for a sensitive and rapid screening method for detecting sepsis. In this study, we investigated the use of MMP-9 as a biomarker for sepsis. A colorimetric paper-based biosensor was used for the detection of MMP-9 utilizing peptide-magnetic nanoparticle conjugates. The method is based on the cleavage of the MMP-9-specific peptide by the protease leading to the detaching of the magnetic beads from the sensor surface and changing of color. A fecal intraperitoneal (FIP) challenge was used to induce sepsis in mice, and an MMP-9 secretion was measured by taking blood and Bronchoalveolar Lavage (BAL) fluid samples at 1 h, 2 h, 4 h, and 20 h (early sepsis) post-challenge intervals. The results of the paper-based sensor for the detection of MMP-9 levels in blood samples and BAL samples were compared with ELISA and Western Blot. We found that both blood and BAL levels of MMP-9 increased immediately and could be detected as early as 1 h in FIP mice post-challenge. Our work adds evidence to the assertion that MMP-9 is a reliable biomarker for the detection of sepsis at early stages. [ABSTRACT FROM AUTHOR]

Blood stream infections (BSIs) cause high mortality, and their rapid detection remains a significant diagnostic challenge. Timely and informed administration of antibiotics can significantly improve patient outcomes. However, blood culture, which takes up to 5 d for a negative result, followed by PCR remains the gold standard in diagnosing BSI. Here, we introduce a new approach to blood-based diagnostics where large blood volumes can be rapidly dried, resulting in inactivation of the inhibitory components in blood. Further thermal treatments then generate a physical microscale and nanoscale fluidic network inside the dried matrix to allow access to target nucleic acid. The amplification enzymes and primers initiate the reaction within the dried blood matrix through these networks, precluding any need for conventional nucleic acid purification. High heme background is confined to the solid phase, while amplicons are enriched in the clear supernatant (liquid phase), giving fluorescence change comparable to purified DNA reactions. We demonstrate single-molecule sensitivity using a loop-mediated isothermal amplification reaction in our platform and detect a broad spectrum of pathogens, including gram-positive methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteria, gram-negative Escherichia coli bacteria, and Candida albicans (fungus) from whole blood with a limit of detection (LOD) of 1.2 colony-forming units (CFU)/mL from 0.8 to 1 mL of starting blood volume. We validated our assay using 63 clinical samples (100% sensitivity and specificity) and significantly reduced sample-to-result time from over 20 h to <2.5 h. The reduction in instrumentation complexity and costs compared to blood culture and alternate molecular diagnostic platforms can have broad applications in healthcare systems in developed world and resource-limited settings. [ABSTRACT FROM AUTHOR]

Sepsis is an immune response to a microbial invasion that causes organ injury and dysfunction due to a systemic inflammatory response. Sepsis is a serious, life-threatening condition and a widely recognized global health challenge. Given its high death rate, it is critical to diagnose sepsis and start treatment as early as possible. There is an urgent need for a sensitive and rapid screening method for detecting sepsis. In this study, we investigated the use of MMP-9 as a biomarker for sepsis. A colorimetric paper-based biosensor was used for the detection of MMP-9 utilizing peptide-magnetic nanoparticle conjugates. The method is based on the cleavage of the MMP-9-specific peptide by the protease leading to the detaching of the magnetic beads from the sensor surface and changing of color. A fecal intraperitoneal (FIP) challenge was used to induce sepsis in mice, and an MMP-9 secretion was measured by taking blood and Bronchoalveolar Lavage (BAL) fluid samples at 1 h, 2 h, 4 h, and 20 h (early sepsis) post-challenge intervals. The results of the paper-based sensor for the detection of MMP-9 levels in blood samples and BAL samples were compared with ELISA and Western Blot. We found that both blood and BAL levels of MMP-9 increased immediately and could be detected as early as 1 h in FIP mice post-challenge. Our work adds evidence to the assertion that MMP-9 is a reliable biomarker for the detection of sepsis at early stages.

Paediatric sepsis has a significant global impact and highly heterogeneous clinical presentation. The clinical pathway encompasses recognition, escalation and de-escalation. In each aspect, diagnostics have a fundamental influence over outcomes in children. Biomarkers can aid in creating a larger low-risk group of children from those in the clinical grey area who would otherwise receive antibiotics 'just in case'. Current biomarkers include C reactive protein and procalcitonin, which are limited in their clinical use to guide appropriate and rapid treatment. Biomarker discovery has focused on single biomarkers, which, so far, have not outperformed current biomarkers, as they fail to recognise the complexity of sepsis. The identification of multiple host biomarkers that may form a panel in a clinical test has the potential to recognise the complexity of sepsis and provide improved diagnostic performance. In this review, we discuss novel biomarkers and novel ways of using existing biomarkers in the assessment and management of sepsis along with the significant challenges in biomarker discovery at present. Validation of biomarkers is made less meaningful due to methodological heterogeneity, including variations in sepsis diagnosis, biomarker cut-off values and patient populations. Therefore, the utilisation of platform studies is necessary to improve the efficiency of biomarkers in clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Quantitative PCR (qPCR) is the gold standard for detection and quantitation of known DNA targets, but the scarcity of spectrally distinct fluorophores and filter sets limits the number of detectable targets. Here, we introduce color cycle multiplex amplification (CCMA) to significantly increase the number of detectable DNA targets in a single qPCR reaction using standard instrumentation. In CCMA, presence of one DNA target species results in a pre-programmed pattern of fluorescence increases. This pattern is distinguished by cycle thresholds (Cts) through rationally designed delays in amplification. For example, we design an assay wherein Staphylococcus aureus sequentially induces FAM, then Cy5.5, then ROX fluorescence increases with more than 3 cycles between each signal. CCMA offers notably higher potential for multiplexing because it uses fluorescence permutation rather than combination. With 4 distinct fluorescence colors, CCMA theoretically allows the detection of up to 136 distinct DNA target sequences using fluorescence permutation. Experimentally, we demonstrated a single-tube qPCR assay screening 21 sepsis-related bacterial DNA targets in samples of blood, sputum, pleural effusion and bronchoalveolar lavage fluid, with 89% clinical sensitivity and 100% clinical specificity, showing its potential as a powerful tool for advanced quantitative screening in molecular diagnostics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022., Materials and Methods: A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry)., Results: The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction., Conclusions: It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker., (Copyright © 2024 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes., Design: Retrospective analysis of data from prospective clinical studies., Setting: Greek ICUs and Internal Medicine departments., Patients and Interventions: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality., Measurements and Main Results: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, β was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern., Conclusions: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications., Competing Interests: Dr. Karakike has received funding by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129- granted to the National and Kapodistrian University of Athens). Dr. Poulakou reports receiving grant funding and/or speaker’s honoraria from Gilead, Menarini, Merck Sharp & Dohme (MSD), Pfizer, Roche, and Sobi. Dr. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. Dr. Milionis reports receiving honoraria, consulting fees, and nonfinancial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. Dr. Dalekos has acted as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen, Genkyotex, Sobi, and Pfizer; he has received grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie, and Bayer; and he was or is currently principal investigator in national and international protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer, Amyndas Pharamaceuticals, CymaBay Therapeutics, and Roche. Dr. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, Brahms GmbH, GlaxoSmithKline, InflaRx GmbH, Pfizer, and Swedish Orphan BioVitrum; he received independent educational grants from Abbott Products Operations, bioMérieux, Johnson & Johnson, MSD, Union Chimique Belge, and Swedish Orphan BioVitrum; and he received funding from the Horizon 2020 European grants ImmunoSep and Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19 and the Horizon Health grant Equine Polyclonal antibodies Immunotherapy against COVID-19/SARS-CoV2–VOC (granted to the Hellenic Institute for the Study of Sepsis). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves’ disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts (CBC) monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of CBC may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Background: Sepsis-induced cardiomyopathy (SICM) is a common and life-threatening complication of sepsis, significantly contributing to elevated mortality. This study aimed to identify crucial indicators for the prompt and early assessment of SICM., Methods: Patients diagnosed with sepsis or SICM within 24 h of intensive care unit (ICU) admission were enrolled in this prospective observational study. Patients were assigned to the training set, validation set and external test set. The primary endpoint was 7-day ICU mortality, and the secondary endpoint was 28-day ICU mortality. Three machine learning algorithms were utilized to identify relevant indicators for diagnosing SICM, incorporating 64 indicators including serum biomarkers associated with cardiac, renal, and liver function, lipid metabolism, coagulation, and inflammation. Internal and external validations were performed on the screening results. Patients were then stratified based on the cut-off value of the most diagnostically effective biomarker identified, and their prognostic outcomes were observed and analyzed., Results: A total of 270 patients were included in the training and validation set, and 52 patients were included in the external test set. Age, sex, and comorbidities did not significantly differ between the sepsis and SICM groups (P > 0.05). The support vector machine (SVM) algorithm identified six indicators with an accuracy of 84.5%, the random forest (RF) algorithm identified six indicators with an accuracy of 81.9%, and the logistic regression (LR) algorithm screened out seven indicators. Following rigorous selection, a diagnostic model for sepsis-induced cardiomyopathy was established based on heart-type fatty acid binding protein (H-FABP) (OR 1.308, 95% CI 1.170-1.462, P < 0.001) and retinol-binding protein (RBP) (OR 1.020, 95% CI 1.006-1.034, P < 0.05). H-FABP alone exhibited the highest diagnostic performance in both the internal (AUROC 0.689, P < 0.05) and external sets (AUROC 0.845, P < 0.05). Patients with SICM were further stratified based on an H-FABP diagnostic cut-off value of 8.335 ng/mL. Kaplan-Meier curve analysis demonstrated that elevated H-FABP levels at admission were associated with higher 7-day ICU mortality in patients with SICM (P < 0.05)., Conclusions: This study revealed that H-FABP concentrations measured within 24 h of patient admission could serve as a crucial biomarker for the early and rapid diagnosis and short-term prognostic evaluation of SICM., (© 2024. The Author(s).)

Background: Sepsis remains a leading cause of mortality in intensive care units, and rapid and accurate pathogen detection is crucial for effective treatment. This study evaluated the clinical application of multi-site metagenomic next-generation sequencing (mNGS) for the diagnosis of sepsis, comparing its performance against conventional methods., Methods: A retrospective analysis was conducted on 69 patients with sepsis consecutively admitted to the Department of Intensive Care Medicine, Meizhou People's Hospital. Samples of peripheral blood and infection sites were collected for mNGS and conventional method tests to compare the positive rate of mNGS and traditional pathogen detection methods and the distribution of pathogens. The methods used in this study included a comprehensive analysis of pathogen consistency between peripheral blood and infection site samples. Additionally, the correlation between the pathogens detected and clinical outcomes was investigated., Results: Of the patients with sepsis, 57.97% experienced dyspnea, and 65.2% had underlying diseases, with hypertension being the most common. mNGS demonstrated a significantly higher pathogen detection rate (88%) compared to the conventional method tests (26%). The pathogen consistency rate was 60% between plasma and bronchoalveolar lavage fluid samples, and that of plasma and local body fluid samples was 63%. The most frequently detected pathogens were gram-negative bacteria, and Klebsiella pneumonia. There were no significant differences in the clinical features between the pathogens., Conclusion: mNGS is significantly superior to conventional methods in pathogen detection. There was a notable high pathogen consistency detection between blood and local body fluid samples, supporting the clinical relevance of mNGS. This study highlights the superiority of mNGS in detecting a broad spectrum of pathogens quickly and accurately., Trial Registration: Not applicable., (© 2024. The Author(s).)

Objective: The prediction of sepsis, especially early diagnosis, has received a significant attention in biomedical research. In order to improve current medical scoring system and overcome the limitations of class imbalance and sample size of local EHR (electronic health records), we propose a novel knowledge-transfer-based approach, which combines a medical scoring system and an ordinal logistic regression model., Materials and Methods: Medical scoring systems (i.e. NEWS, SIRS and QSOFA) are generally robust and useful for sepsis diagnosis. With local EHR, machine-learning-based methods have been widely used for building prediction models/methods, but they are often impacted by class imbalance and sample size. Knowledge distillation and knowledge transfer have recently been proposed as a combination approach for improving the prediction performance and model generalization. In this study, we developed a novel knowledge-transfer-based method for combining a medical scoring system (after a proposed score transformation) and an ordinal logistic regression model. We mathematically confirmed that it was equivalent to a specific form of the weighted regression. Furthermore, we theoretically explored its effectiveness in the scenario of class imbalance., Results: For the local dataset and the MIMIC-IV dataset, the VUS (the volume under the multi-dimensional ROC surface, a generalization measure of AUC-ROC for ordinal categories) of the knowledge-transfer-based model (ORNEWS) based on the NEWS scoring system were 0.384 and 0.339, respectively, while the VUS of the traditional ordinal regression model (OR) were 0.352 and 0.322, respectively. Consistent analysis results were also observed for the knowledge-transfer-based models based on the SIRS/QSOFA scoring systems in the ordinal scenarios. Additionally, the predicted probabilities and the binary classification ROC curves of the knowledge-transfer-based models indicated that this approach enhanced the predicted probabilities for the minority classes while reducing the predicted probabilities for the majority classes, which improved AUCs/VUSs on imbalanced data., Discussion: Knowledge transfer, which combines a medical scoring system and a machine-learning-based model, improves the prediction performance for early diagnosis of sepsis, especially in the scenarios of class imbalance and limited sample size., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Determining which patients who meet systemic inflammatory response syndrome (SIRS) criteria have bacterial sepsis is a difficult challenge for emergency physicians. We sought to determine whether the neutrophil-to-lymphocyte ratio (NLR) could be used to exclude bacterial sepsis in adult patients who meet ≥2 SIRS criteria and are being evaluated for sepsis., Methods: Consenting adult patients meeting ≥2 SIRS criteria and undergoing evaluation for sepsis were enrolled. We recorded patient age, gender, vital signs, and laboratory results. We then later reviewed health records for culture results, end organ dysfunction, survival to discharge, and final diagnoses. Patients were classified as having sepsis if they met ≥2 SIRS criteria and were ultimately diagnosed with a bacterial source. We analyzed data using descriptive statistics and sensitivity and specificity analyses. A receiver operating characteristic curve (ROC) was created to determine test characteristics., Results: A total of 231 patients had complete datasets. Patients' median age was 69 (interquartile range [IQR] 54-81), and 49.6% were male. There were 154 patients (66.7%) ultimately diagnosed with sepsis with an identified bacterial source, while 77 patients with ≥2 SIRS criteria had non-infectious reasons for their presentations (33.3%). Septic patients had a median NLR 12.36 (IQR [interquartile range] 7.29-21.69), compared to those without sepsis (median NLR 5.62, IQR 3.89-9.11, P  < 0.001). The NLR value of 3 applied as a cutoff for sepsis had a sensitivity of 96.8 (95% confidence interval [CI] 92.2-98.8), and a specificity of 18.2 (95% CI 10.6-29.0). The ROC for NLR had an area under the curve of 0.74., Conclusion: The neutrophil-to-lymphocyte ratio is a sensitive tool to help determine which patients with abnormal SIRS screens have bacterial sepsis., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Sepsis is a life-threatening condition that has the potential to multiple organ dysfunction and mortality. One of its frequent complications is disseminated intravascular coagulation (DIC), characterized by hyperactive clotting mechanisms that cause widespread clot formation and tissue damage. This study aimed to investigate early diagnostic markers of sepsis-associated DIC by comparing inflammatory factor levels, 28-day survival rates, coagulation function, and markers between patients with sepsis (non-DIC group) and those with sepsis-induced DIC (DIC group). The study analyzed the diagnostic efficacy of coagulation function and markers in predicting the occurrence and prognosis of sepsis-associated DIC, presenting survival curves. Results indicated significantly increased levels of APTT, TAT, tPAIC, PIC, and sTM in the DIC group compared to the non-DIC group. Sequential Organ Failure Assessment (SOFA) scores on days 1, 3, and 7 were notably lower in the non-DIC group. Correlation analysis revealed positive associations between PT, APTT, TAT, tPAIC, PIC, sTM levels, and SOFA scores, as well as negative associations with Fib and SOFA scores. Survival curves showed substantially lower mortality rates in the non-DIC group, highlighting significant survival disparities between groups. Combining all four coagulation indicators (TAT+ tPAIC + PIC + sTM) showed promising diagnostic value in evaluating disease severity, early DIC diagnosis, and sepsis prognosis., Competing Interests: The authors state that there are no conflicts of interest to disclose.

Background: Little is known about differences in patient characteristics before and after implementation of the new definition of sepsis (Sepsis-3) and whether the new definition is affecting clinical practice in intensive care units., Objective: To examine and compare the clinicoepidemiologic characteristics of patients with sepsis or septic shock before and after implementation of Sepsis-3., Methods: In this population-based cohort study, a nationwide registration database in South Korea was used to identify patients with sepsis or septic shock. Patients admitted to hospitals from 2012 to 2015 constituted the Sepsis-2 group, and patients admitted from 2017 to 2020 constituted the Sepsis-3 group., Results: The study involved 443 217 patients, of whom 170 660 (38.5%) were in the Sepsis-2 group and 272 557 (61.5%) were in the Sepsis-3 group. The mean (SD) age was 73.3 (14.5) years in the Sepsis-2 group and 75.5 (14.5) years in the Sepsis-3 group. The intensive care unit admission rate was higher in the Sepsis-2 group (34.6%, 59 081 of 170 660) than in the Sepsis-3 group (21.3%, 57 997 of 272 557). Multivariable Cox regression analysis showed that 1-year all-cause mortality was 21% lower in the Sepsis-3 group than in the Sepsis-2 group (hazard ratio, 0.79; 95% CI, 0.78-0.79; P < .001)., Conclusions: Implementation of the Sepsis-3 definition was associated with an increased number of patients with sepsis. Other findings suggested that patients in the Sepsis-2 group had more severe illness, with increased 1-year all-cause mortality, compared with those in the Sepsis-3 group., (©2024 American Association of Critical-Care Nurses.)

Liver diseases are a significant global cause of morbidity and mortality. Liver cirrhosis can result in severe complications such as bleeding, hepatic encephalopathy (HE), and infections. Implementing a clear strategy for intensive care unit (ICU) admission management improves patient outcomes. Hemodynamically significant esophageal/gastric variceal bleeding (E/GVB) and grade 4 HE, when accompanied by the need for renal replacement therapy (RRT), are definitive indications for ICU admission. E/GVB, spontaneous bacterial peritonitis (SBP), and infections with multidrug-resistant organisms (MDRO) require close and stringent critical assessment. Patients with severe hepatorenal syndrome (HRS) or respiratory failure have increased baseline mortality and most likely benefit from early ICU treatment. Rapid identification of sepsis in patients with liver cirrhosis is a crucial criterion for ICU admission. Prioritizing cases based on mortality risk and clinical urgency enables efficient resource utilization and optimizes patient management. In addition, "Liver Units" provide an intermediate care (IMC) level for patients with liver diseases who require close monitoring but do not need immediate intensive care., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Rapid and reliable identification of the causal organism in bloodstream infections and sepsis is crucial for both individual patient care and public health. We have implemented a rapid in-house identification protocol (with 10 % Triton) using MALDI-TOF MS for identifying the causative organism in positive blood cultures without prior culture. Our objective was to retrospectively analyze data collected over a four-year period while implementing this rapid in-house identification protocol and to develop a guide for evaluating and reporting the obtained results. Overall, our method utilizing MALDI-TOF MS for rapid in-house identification, demonstrated comparable results to other commercially available and in-house methods reported in the literature. Over the past four years, direct identification has facilitated the distinction between clinically relevant positive blood cultures and irrelevant ones, guiding rapid focus control and appropriate antibiotic treatment. The established guide can serve as a valuable tool in reporting positive blood cultures and associated antibiotic treatments., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To analyze relationships between provider-documented signs prompting sepsis evaluations, assessments of illness severity, and late-onset infection (LOI)., Study Design: Retrospective cohort study of all infants receiving a sepsis huddle in conjunction with a LOI evaluation. Participants were ≥3 days old and admitted to a level IV neonatal intensive care unit (NICU) from September 2018 through May 2021. Data were extracted from standardized sepsis huddle notes in the electronic health record, including clinical signs prompting LOI evaluations, illness severity assessments (from least to most severe: green, yellow, and red), and management plans. To analyze relationships of sepsis huddle characteristics with the detection of culture-confirmed LOI (bacteremia, urinary tract infection, or meningitis), we utilized diagnostic test statistics, area under the receiver-operator characteristic analyses, and multivariable logistic regression., Results: We identified 1209 eligible sepsis huddles among 604 infants. There were 111 culture-confirmed LOI episodes (9% of all huddles). Twelve clinical signs of infection poorly distinguished infants with and without LOI, with sensitivity for each ranging from 2% to 36% and area under the receiver-operator characteristic ranging 0.49-0.53. Multivariable logistic regression identified increasing odds of infection with higher perceived illness severity at the time of sepsis huddle, adjusted for gestational age and receipt of intensive care supports., Conclusions: Clinical signs prompting sepsis huddles were nonspecific and not predictive of concurrent LOI. Higher perceived illness severity was associated with presence of infection, despite some misclassification based on objective criteria. In level IV NICUs, antimicrobial stewardship through development of criteria for antibiotic noninitiation may be challenging, as presenting signs of LOI are similar among infants with and without confirmed infection., Competing Interests: Declaration of Competing Interest LHC is partial owner of 2minutemedicine.com, a medical news and educational website. The authors have no conflicts of interest or financial disclosures relevant to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis is the second leading cause of pregnancy-related mortality in the United States. Early recognition, treatment, and escalation of care for the obstetric patient affected by sepsis mitigate the risk of mortality and improve patient outcomes. In this article, we provide an overview of maternal sepsis and address topics of maternal pathophysiology, early warning signs, diagnostic criteria, early goal-directed therapy, and contemporary critical care practices. We also present an overview of common etiologies of maternal sepsis and suggested treatment approaches., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Bloodstream infection is a major cause of morbidity and death worldwide. Timely and appropriate treatment can reduce mortality among critically ill patients. Current diagnostic methods are too slow to inform precise antibiotic choice, leading to the prescription of empirical antibiotics, which may fail to cover the resistance profile of the pathogen, risking poor patient outcomes. Additionally, overuse of broad-spectrum antibiotics may lead to more resistant organisms, putting further pressure on the dwindling pipeline of antibiotics, and risk transmission of these resistant organisms in the health care environment. Therefore, rapid diagnostics are urgently required to better inform antibiotic choice early in the course of treatment. Sequencing offers great promise in reducing time to microbiological diagnosis; however, the amount of host DNA compared with the pathogen in patient samples presents a significant obstacle. Various host-depletion and bacterial-enrichment strategies have been used in samples, such as saliva, urine, or tissue. However, these methods have yet to be collectively integrated and/or extensively explored for rapid bloodstream infection diagnosis. Although most of these workflows possess individual strengths, their lack of analytical/clinical sensitivity and/or comprehensiveness demands additional improvements or synergistic application. This review provides a distinctive classification system for various methods based on their working principles to guide future research, and discusses their strengths and limitations and explores potential avenues for improvement to assist the reader in workflow selection., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. All rights reserved.)

In absence of a "gold standard", a standardized clinical adjudication process was developed for a registrational trial of a transcriptomic host response (HR) test. Two physicians independently reviewed clinical data to adjudicate presence and source of bacterial and viral infections in emergency department patients. Discordant cases were resolved by a third physician. Agreement among 955 cases was 74.1% (708/955) for bacterial, 75.6% (722/955) for viral infections, and 71.2% (680/955) overall. Most discordances were minor (85.2%; 409/480) versus moderate (11.7%; 56/480) or complete (3.3%; 16/480). Concordance levels were lowest for bacterial skin and soft tissue infections (8.2%) and for viral respiratory tract infections (4.5%). This robust adjudication process can be used to evaluate HR tests and other diagnostics by regulatory agencies and for educating clinicians, laboratorians, and clinical researchers. Clinicaltrials.gov NCT04094818. SUMMARY: Without a gold standard for evaluating host response tests, clinical adjudication is a robust reference standard that is essential to determine the true infection status in diagnostic registrational clinical studies., Competing Interests: Declaration of competing interest NNW and OL: The authors are employees and stock option holders of Inflammatix, Inc. CH: The author is a consultant of Inflammatix, Inc. JC: The author has no conflicts of interest to disclose. LM: The author has received honoraria from Inflammatix, Inc. and Thermofisher and was a consultant to Cytovale. She is an advisor for Roche, Biomerieux, and Talis Biomedical. JH: The author has served as a consultant to Beckman Coulter on the use of Artificial Intelligence tools in the practice of emergency medicine. EBH: The author has no conflicts of interest to disclose. EM: The author has no conflicts of interest to disclose. RR: The author has received research funding through his University from Inflammatix, Inc. and has served as a paid scientific expert advisor to Inflammatix, Inc. DS: The author has no conflicts of interest to disclose. RH: The author has no conflicts of interest to disclose. EAM: The author has received research funding from Inflammatix, Inc. WHS: The author has received research funding from Inflammatix, Inc. HAS: The author has no conflicts of interest to disclose. JSS: The author has no conflicts of interest to disclose. HCSK: The author has no conflicts of interest to disclose. AW: The author has served as a consultant to Inflammatix, Inc. DWW: The author has no conflicts of interest to disclose. NIS: The author has received research funding from Inflammatix, Inc, and Luminos; and served as a consultant for Diagnostic Robotics and Prenosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To assess the impact of different methods of calculating Sequential Organ Failure Assessment (SOFA) scores using electronic health record data on the incidence, outcomes, agreement, and predictive validity of Sepsis-3 criteria., Design: Retrospective observational study., Setting: Five Massachusetts hospitals., Patients: Hospitalized adults, 2015 to 2022., Interventions: None., Measurements and Main Results: We defined sepsis as a suspected infection (culture obtained and antibiotic administered) with a concurrent increase in SOFA score by greater than or equal to 2 points (Sepsis-3 criteria). Our reference SOFA implementation strategy imputed normal values for missing data, used Pa o2 /F io2 ratios for respiratory scores, and assumed normal baseline SOFA scores for community-onset sepsis. We then implemented SOFA scores using different missing data imputation strategies (averaging worst values from preceding and following days vs. carrying forward nonmissing values), imputing respiratory scores using Sp o2 /F io2 ratios, and incorporating comorbidities and prehospital laboratory data into baseline SOFA scores. Among 1,064,459 hospitalizations, 297,512 (27.9%) had suspected infection and 141,052 (13.3%) had sepsis with an in-hospital mortality rate of 10.3% using the reference SOFA method. The percentage of patients missing SOFA components for at least 1 day in the infection window was highest for Pa o2 /F io2 ratios (98.6%), followed by Sp o2 /F io2 ratios (73.5%), bilirubin (68.5%), and Glasgow Coma Scale scores (57.2%). Different missing data imputation strategies yielded near-perfect agreement in identifying sepsis (kappa 0.99). However, using Sp o2 /F io2 imputations yielded higher sepsis incidence (18.3%), lower mortality (8.1%), and slightly lower predictive validity for mortality (area under the receiver operating curves [AUROC] 0.76 vs. 0.78). For community-onset sepsis, incorporating comorbidities and historical laboratory data into baseline SOFA score estimates yielded lower sepsis incidence (6.9% vs. 11.6%), higher mortality (13.4% vs. 9.6%), and higher predictive validity (AUROC 0.79 vs. 0.75) relative to the reference SOFA implementation., Conclusions: Common variations in calculating respiratory and baseline SOFA scores, but not in handling missing data, lead to substantial differences in observed incidence, mortality, agreement, and predictive validity of Sepsis-3 criteria., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Study Objective: Compare physician gestalt to existing screening tools for identifying sepsis in the initial minutes of presentation when time-sensitive treatments must be initiated., Methods: This prospective observational study conducted with consecutive encounter sampling took place in the emergency department (ED) of an academic, urban, safety net hospital between September 2020 and May 2022. The study population included ED patients who were critically ill, excluding traumas, transfers, and self-evident diagnoses. Emergency physician gestalt was measured using a visual analog scale (VAS) from 0 to 100 at 15 and 60 minutes after patient arrival. The primary outcome was an explicit sepsis hospital discharge diagnosis. Clinical data were recorded for up to 3 hours to compare Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), quick SOFA (qSOFA), Modified Early Warning Score (MEWS), and a logistic regression machine learning model using Least Absolute Shrinkage and Selection Operator (LASSO) for variable selection. The screening tools were compared using receiver operating characteristic analysis and area under the curve calculation (AUC)., Results: A total of 2,484 patient-physician encounters involving 59 attending physicians were analyzed. Two hundred seventy-five patients (11%) received an explicit sepsis discharge diagnosis. When limited to available data at 15 minutes, initial VAS (AUC 0.90; 95% confidence interval [CI] 0.88, 0.92) outperformed all tools including LASSO (0.84; 95% CI 0.82 to 0.87), qSOFA (0.67; 95% CI 0.64 to 0.71), SIRS (0.67; 95% 0.64 to 0.70), SOFA (0.67; 95% CI 0.63 to 0.70), and MEWS (0.66; 95% CI 0.64 to 0.69). Expanding to data available at 60 minutes did not meaningfully change results., Conclusion: Among adults presenting to an ED with an undifferentiated critical illness, physician gestalt in the first 15 minutes of the encounter outperformed other screening methods in identifying sepsis., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Objective: Pediatric sepsis screening is becoming the standard of care for children presenting to the emergency department (ED) and has been shown to improve recognition of severe sepsis, but it is unknown if these screening tools can predict progression of disease. The objective of this study was to determine if any elements of a sepsis triage trigger tool were predictive of progression to hypotensive shock in children presenting to the ED with fever and tachycardia., Methods: This study is a retrospective case-control study of children ≤18 years presenting to an ED with fever and tachycardia, comparing those who went on to develop hypotensive shock in the subsequent 24 hours (case) to those who did not (control). Primary outcome was the proportion of encounters where the patient had specific abnormal vital signs or clinical signs as components of the sepsis triage score. The secondary outcomes were the proportion of encounters where the patient had a sepsis risk factor., Results: During the study period, there were 94 patients who met case criteria and 186 controls selected. In the adjusted multivariable model, the 2 components of the sepsis triage score that were more common in case patients were the presence of severe cerebral palsy (adjusted odds ratio, 9.4 [3.7, 23.9]) and abnormal capillary refill at triage (adjusted odds ratio, 3.1 [1.4, 6.9])., Conclusions: Among children who present to a pediatric ED with fever and tachycardia, those with prolonged capillary refill at triage or severe cerebral palsy were more likely to progress to decompensated septic shock, despite routine ED care., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Sepsis continues to be a critical issue in intensive care, characterized by significant morbidity and mortality. This study explores the association between Vasoactive Inotrope Score (VIS) trajectories and 28-day mortality in ICU patients with sepsis, employing VIS trajectories as a marker for assessing severity and guiding therapy., Methods: We conducted a retrospective analysis of the MIMIC-IV database, which included sepsis patients admitted to the ICU between 2008 and 2019. VIS calculations were performed bi-hourly during the first 72 hours of ICU admission. Using latent growth mixture modeling, we identified distinct VIS trajectory patterns, and multivariate Cox proportional hazards models were employed to evaluate their association with 28-day mortality., Findings: Among 6,802 sepsis patients who met the inclusion criteria, four distinct VIS trajectory patterns were identified: "Low-Decreasing" (52.1%), "Mild-Ascending" (13.2%), "Moderate-Decreasing" (23.0%), and "High-Stable" (11.6%). The 28-day survival analysis demonstrated that, compared to the "Low-Decreasing" group, the "Mild-Ascending" group had a hazard ratio (HR) for mortality of 2.55 (95% CI: 2.19-2.97, P < 0.001), the "Moderate-Decreasing" group had an HR of 1.20 (95% CI: 1.03-1.41, P = 0.021), and the "High-Stable" group presented the highest risk with an HR of 4.19 (95% CI: 3.43-5.12, P < 0.001)., Implications: This study offers significant insights into the prognostic value of VIS trajectories in sepsis patients. The identification of distinct trajectory patterns not only underscores the heterogeneity in sepsis but also emphasizes the importance of personalized management strategies. The findings underscore the potential of VIS trajectory monitoring in predicting 28-day outcomes and in guiding clinical decision-making in ICU settings., Competing Interests: Declaration of competing interest The author reports no conflicts of interest in this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Sepsis is a heterogeneous syndrome often misdiagnosed. Point-of-care (POC) diagnostic tests are commonly used to guide decision and include host biomarkers and molecular diagnostics., Areas Covered: The diagnostic and prognostic accuracy of established and emerging biomarkers for sepsis, including procalcitonin (PCT) soluble urokinase plasminogen activator receptor (suPAR), presepsin, TRAIL/IP-10/CRP, MxA, and MxA-CRP, are analyzed in this review. The clinical utility of the two prevalent molecular techniques for pathogens identification using polymerase chain reaction (PCR) assays is also presented: FILMARRAY and QIAstat-Dx RP., Expert Opinion: The rising benefits of the combined use of POC biomarkers with molecular diagnostics in daily clinical routine appear to outperform conventional practices in terms of reduced turnaround time, timely diagnosis, and prompt administration of the appropriate treatment. Yet, this must be further demonstrated in future investigations. However, the cost-effectiveness of POC tests and the high rate of false positive and negative results, indicate the need for a comprehensive clinical evaluation.

Carbapenem-resistant significant members of Acinetobacter calcoaceticus-Acinetobacter baumannii (CR-SM-ACB) complex have emerged as an important cause of sepsis, especially in ICUs. This study demonstrates the application of loop-mediated-isothermal-amplification (LAMP) assay for detection of CR-SM-ACB-complex from patients with sepsis. Whole-blood and culture-broths(CB) collected from patients with culture-positive sepsis were subjected to LAMP and compared with PCR, and RealAmp. Vitek-2 system and conventional PCR results were used as confirmatory references. The sensitivity and specificity of LAMP(97 % & 100 %) and RealAmp(100 % & 100 %) for detection of CR-SM-ACB-complex from CB were better than PCR(87 % & 100 %). Diagnostic accuracy of LAMP, RealAmp, and PCR for detection of SM-ACB-complex from CB was 98.5 %, 100 %, and 88.5 % respectively. Turnaround time of Culture, LAMP, PCR, and RealAmp was 28-53, 6-20, 9-23, and 6-20hours, respectively. LAMP is a simple, inexpensive tool that can be applied directly to positive CB and may be customized to detect emerging pathogens and locally-prevalent resistance genes and to optimize antimicrobial use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Sepsis remains a major cause of mortality in intensive care units (ICUs). Prompt diagnosis and effective management are imperative for better outcomes. In this systematic review and meta-analysis, we explore the potential of circulating cell-free DNA (cfDNA), as a promising tool for early sepsis detection and prognosis assessment, aiming to address limitations associated with traditional diagnostic methods., Methods: Following PRISMA guidelines, we collected relevant literature from thirteen databases. Studies were included if they analyzed quantitative diagnostic or prognostic cfDNA levels in humans in case of sepsis. We collected data on basic study characteristics, baseline patient demographics (e.g. age and sex), and cfDNA levels across different stages of sepsis. Pooled SMD with 95%-CI was calculated, and Comprehensive Meta-Analysis (CMA) software facilitated meta-analysis. Receiver operating characteristic (ROC) curves were generated to assess cfDNA's combined sensitivity and specificity in diagnostics and prognostics., Results: We included a final of 44 studies, of which, only 32 with 2950 participants were included in the meta-analysis. cfDNA levels were higher in septic patients compared to healthy controls (SMD = 3.303; 95%-CI [2.461-4.145], p<0.01). Furthermore, cfDNA levels were higher in non-survivors than survivors (SMD = 1.554; 95%-CI [0.905-2.202], p<0.01). Prognostic studies demonstrated a pooled sensitivity and specificity of 0.78, while diagnostic studies showed a sensitivity of 0.81 and a specificity of 0.87., Conclusion: These findings show that cfDNA levels are significantly higher in sepsis patients compared to control groups and non-survivors in comparison to survivors among both adult and pediatric populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dadam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Explainable artificial intelligence (AI) focuses on developing models and algorithms that provide transparent and interpretable insights into decision-making processes. By elucidating the reasoning behind AI-driven diagnoses and treatment recommendations, explainability can gain the trust of healthcare experts and assist them in difficult diagnostic tasks. Sepsis is characterized as a serious condition that happens when the immune system of the body has an extreme response to an infection, causing tissue and organ damage and leading to death. Physicians face challenges in diagnosing and treating sepsis due to its complex pathogenesis. This work aims to provide an overview of the recent studies that propose explainable AI models in the prediction of sepsis onset and sepsis mortality using intensive care data. The general findings showed that explainable AI can provide the most significant features guiding the decision-making process of the model. Future research will investigate explainability through argumentation theory using intensive care data focused on sepsis patients.

Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven "multidimensional" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis is now defined as a life-threatening syndrome of organ dysfunction triggered by a dysregulated host response to infection, posing significant challenges in critical care. The main objective of this review is to evaluate the potential of emerging biomarkers for early diagnosis and accurate prognosis in sepsis management, which are pivotal for enhancing patient outcomes. Despite advances in supportive care, traditional biomarkers like C-reactive protein and procalcitonin have limitations, and recent studies have identified novel biomarkers with increased sensitivity and specificity, including circular RNAs, HOXA distal transcript antisense RNA, microRNA-486-5p, protein C, triiodothyronine, and prokineticin 2. These emerging biomarkers hold promising potential for the early detection and prognostication of sepsis. They play a crucial role not only in diagnosis but also in guiding antibiotic therapy and evaluating treatment effectiveness. The introduction of point-of-care testing technologies has brought about a paradigm shift in biomarker application, enabling swift and real-time patient evaluation. Despite these advancements, challenges persist, notably concerning biomarker variability and the lack of standardized thresholds. This review summarizes the latest advancements in sepsis biomarker research, spotlighting the progress and clinical implications. It emphasizes the significance of multi-biomarker strategies and the feasibility of personalized medicine in sepsis management. Further verification of biomarkers on a large scale and their integration into clinical practice are advocated to maximize their efficacy in future sepsis treatment.

Aim: To evaluate the urinary biomarkers related to sepsis in preterm newborns (NBs) and to investigate the predictive capacity of these biomarkers for a longer hospital stay. Methods: Serum and urine were collected from 27 healthy NBs, 24 NBs with neonatal infection without sepsis and 11 NBs with sepsis for the measurement of sindecan-1, lipocalin associated with urinary neutrophil gelatinase (uNGAL), urinary cystatin-C (uCysC) and urinary kidney injury molecule-1. Results: Levels of uNGAL and urinary cystatin-C were elevated in NBs with sepsis and neonatal infection, and uNGAL was significant predictor of hospital stay longer than 30 days (odds ratio: 1.052; 95% CI: 1.012-1.093; p  = 0.01). Conclusion: uNGAL was associated with sepsis in preterm NBs and was useful to predict extended hospital stay.

Background: Evidence about the clinical impact of rapid diagnostic tests (RDTs) for the diagnosis of bloodstream infections is limited, and whether RDT are superior to conventional blood cultures (BCs) embedded within antimicrobial stewardship programs (ASPs) is unknown., Methods: We performed network meta-analyses using results from studies of patients with bloodstream infection with the aim of comparing the clinical impact of RDT (applied on positive BC broth or whole blood) to conventional BC, both assessed with and without ASP with respect to mortality, length of stay (LOS), and time to optimal therapy., Results: Eighty-eight papers were selected, including 25 682 patient encounters. There was an appreciable amount of statistical heterogeneity within each meta-analysis. The network meta-analyses showed a significant reduction in mortality associated with the use of RDT + ASP versus BC alone (odds ratio [OR], 0.72; 95% confidence interval [CI], .59-.87) and with the use of RDT + ASP versus BC + ASP (OR, 0.78; 95% CI, .63-.96). No benefit in survival was found associated with the use of RDT alone nor with BC + ASP compared to BC alone. A reduction in LOS was associated with RDT + ASP versus BC alone (OR, 0.91; 95% CI, .84-.98) whereas no difference in LOS was shown between any other groups. A reduced time to optimal therapy was shown when RDT + ASP was compared to BC alone (-29 hours; 95% CI, -35 to -23), BC + ASP (-18 hours; 95% CI, -27 to -10), and to RDT alone (-12 hours; 95% CI, -20 to -3)., Conclusions: The use of RDT + ASP may lead to a survival benefit even when introduced in settings already adopting effective ASP in association with conventional BC., Competing Interests: Potential conflicts of interest . D. L. P. has research funding from Shionogi, Merck, bioMerieux, BioVersys, and Pfizer and has received consulting fees from the AMR Action Fund, CARB-X, Aurobac, Pfizer, Merck, Cepheid, bioMérieux, and Spero. P. N. A. H. reports research grants from Gilead, has served on advisory boards for OpGen, Merck, and Sandoz, and has received honoraria from OpGen, Sandoz, Pfizer, and bioMerieux. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Sepsis is a life-threatening condition characterized by dysregulated host response to infection leading to organ dysfunction. Despite advances in understanding its pathology, sepsis remains a global health concern and remains a major contributor to mortality. Timely identification is crucial for improving clinical outcomes, as delayed treatment significantly impacts survival. Accordingly, biomarkers play a pivotal role in diagnosis, risk stratification, and management. This review comprehensively discusses various biomarkers in sepsis and their potential application in antimicrobial stewardship and risk assessment. Biomarkers such as white blood cell count, neutrophil to lymphocyte ratio, erythrocyte sedimentation rate, C-reactive protein, interleukin-6, presepsin, and procalcitonin have been extensively studied for their diagnostic and prognostic value as well as in guiding antimicrobial therapy. Furthermore, this review explores the role of biomarkers in risk stratification, emphasizing the importance of identifying high-risk patients who may benefit from specific therapeutic interventions. Moreover, the review discusses the emerging field of transcriptional diagnostics and metagenomic sequencing. Advances in sequencing have enabled the identification of host response signatures and microbial genomes, offering insight into disease pathology and aiding species identification. In conclusion, this review provides a comprehensive overview of the current understanding and future directions of biomarker-based approaches in sepsis diagnosis, management, and personalized therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The rapid and sensitive indicator of inflammation in the human body is C-Reactive Protein (CRP). Determination of CRP level is important in medical diagnostics because, depending on that factor, it may indicate, e.g., the occurrence of inflammation of various origins, oncological, cardiovascular, bacterial or viral events. In this study, we describe an interferometric sensor able to detect the CRP level for distinguishing between no-inflammation and inflammation states. The measurement head was made of a single mode optical fiber with a microsphere structure created at the tip. Its surface has been biofunctionalized for specific CRP bonding. Standardized CRP solutions were measured in the range of 1.9 µg/L to 333 mg/L and classified in the initial phase of the study. The real samples obtained from hospitalized patients with diagnosed Urinary Tract Infection or Urosepsis were then investigated. 27 machine learning classifiers were tested for labeling the phantom samples as normal or high CRP levels. With the use of the ExtraTreesClassifier we obtained an accuracy of 95% for the validation dataset. The results of real samples classification showed up to 100% accuracy for the validation dataset using XGB classifier., (© 2024. The Author(s).)

Background: Owing to a lack of data, this study aimed to explore the effect of cardiac preload on myocardial strain in patients with sepsis., Methods: A total of 70 patients with sepsis in intensive care unit (ICU) of a tertiary teaching hospital in China from January 2018 to July 2019 and underwent transthoracic echocardiography were enrolled. Echocardiographic data were recorded at ICU admission and 24 h later. Patients were assigned to low left ventricular end-diastolic volume index (LVEDVI) and normal LVEDVI groups. We assessed the impact of preload on myocardial strain between the groups and analyzed the correlation of echocardiographic parameters under different preload conditions., Results: Thirty-seven patients (53%) had a low LVEDVI and 33 (47%) a normal LVEDVI. Those in the low LVEDVI group had a faster heart rate (121.7 vs. 95.3, p < 0.001) and required a greater degree of fluid infusion (3.67 L vs. 2.62 L, P = 0.019). The left ventricular global strain (LVGLS) (-8.60% vs. -10.80%, p = 0.001), left ventricular global circumferential strain (LVGCS) (-13.83% vs. -18.26%, p = 0.006), and right ventricular global longitudinal strain (RVGLS) (-6.9% vs. -10.60%, p = 0.001) showed significant improvements in the low LVEDVI group after fluid resuscitation. However, fluid resuscitation resulted in a significantly increased cardiac afterload value (1172.00 vs. 1487.00, p = 0.009) only in the normal LVEDVI group. Multivariate backward linear regression showed that LVEDVI changes were independently associated with myocardial strain-related improvements during fluid resuscitation. The baseline LVEDVI was significantly negatively correlated with the LVGLS and RVGLS (r = -0.44 and - 0.39, respectively) but not LVGCS. LVEDVI increases during fluid resuscitation were associated with improvements in the myocardial strain degree., Conclusions: Myocardial strain alterations were significantly influenced by the cardiac preload during fluid resuscitation in sepsis., (© 2024. The Author(s).)

Introduction: Early identification of patients with sepsis at high risk of death remains a challenge, and whether brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a prognostic effect on patients with sepsis is controversial. Here, we clarified the prognostic value of BNP and NT-proBNP and sought to establish suitable cutoff values and intervals., Methods: We searched five databases to identify studies that met the inclusion criteria. The primary outcomes were the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the curve (AUC), and corresponding 95% credible interval (95% CI) of BNP and NT-proBNP. The secondary outcomes were the sensitivity and specificity of BNP or NT-proBNP in subgroup analyses., Results: Forty-seven studies were included in our meta-analysis. The pooled sensitivity of NT-proBNP (0.77 [0.68, 0.84]) was weaker than that of BNP (0.82 [0.76, 0.87]), the pooled specificity of NT-proBNP (0.70 [0.60, 0.77]) was less than that of BNP (0.77 [0.71, 0.82]), and the AUC of BNP (0.87 [0.83-0.89]) was greater than that of NT-proBNP (0.80 (0.76-0.83]). The results of the subgroup analysis showed that the cutoff range of 400-800 pg/mL for BNP had high sensitivity (0.86 [0.74-0.98]) and specificity (0.87 [0.81-0.93]) and was probably the most appropriate cutoff range., Conclusions: Elevated levels of BNP and NT-proBNP were significantly related to the mortality of patients with sepsis and had a moderate prognostic value in predicting the mortality of patients with sepsis. In addition, our meta-analysis preliminarily established appropriate cutoff values for BNP and NT-proBNP., (© 2024. The Author(s).)

Many methods are being tried for rapid and accurate identification of sepsis-causing microorganisms. We analyzed the performance of three different preparation methods [MBT Sepsityper IVD Kit (Bruker Daltonics GmbH, Germany), sodium dodecyl sulfate (SDS) lysis, and differential centrifugation with protein extraction (Centrifugation +PE)] and compared in standard and Sepsityper modules of the Bruker Biotyper MALDI-TOF MS for direct identification of bacteria from 240 positive blood culture bottles of BACTEC FX (Becton Dickinson, USA). By using the standard module, correct identification at species level (score ≥2) was done in 46.7% of the samples with SDS lysis, 44.2% with centrifugation +PE, and 25.4% with the Sepsityper kit. These ratios at the genus level (score range 1.70-1.99) were 34.6%, 31.3%, and 32.5%, respectively. With SDS lysis (195), more bacteria were identified correctly than centrifugation +PE (181) and the Sepsityper kit (139). A statistically significant difference was found between SDS and the Sepsityper kit and Centrifugation +PE and the Sepsityper kit ( P < 0.001, both). By using the Sepsityper module, correct identification at species level (score ≥1.8) was determined in 74.2% of the samples with SDS lysis and centrifugation +PE each and 55% with the Sepsityper kit. These ratios at the genus level (score range 1.60-1.79) were 16.3%, 10%, and 19.2%, respectively. SDS lysis (217) had significantly higher identification rates than centrifugation +PE (202) and the Sepsityper kit (178) ( P = 0.028 and P < 0.001). A statistically significant difference was also observed between centrifugation +PE and the Sepsityper kit ( P < 0.001). Best performance was obtained with SDS lysis among the methods. Although better performance was achieved by using Sepsityper software module, risk of misidentification should not be ignored., Importance: Sepsis is a life-threatening condition, and rapid and accurate identification of the causative microorganisms from blood cultures is crucial for timely and effective treatment. Although there are many studies on direct identification from blood cultures with MALDI-TOF MS, further standardization is still needed. In our study, we analyzed the performance of three different preparation methods and compared by using two analysis modules of the Bruker Biotyper MALDI-TOF MS for direct identification of bacteria from numerous positive blood culture bottles. The literature reports a limited number of studies that compare different preparation methods for direct blood culture identification, processing a large number of blood samples concurrently and evaluating the same samples as in our study. Moreover, although SDS is used very frequently in medical laboratories, there are few studies on direct identification from blood culture bottles. In our study, the highest correct identification rate was observed with the SDS method., Competing Interests: The authors declare no conflict of interest.