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Yang N, Jiang N, Shen C, Gao M, Tong Q, Sun J. Protective effect of exercise on animals with sepsis: a systematic review of the existing literature. BMC Infect Dis 2025; 25:195. [PMID: 39923007 PMCID: PMC11807334 DOI: 10.1186/s12879-025-10557-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/24/2025] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND Sepsis often led to multiple organ dysfunction (MODS) and even death. Although a variety of medicine were used to treat sepsis in clinic, there was still no specific and effective clinical medicine treatment. Exercise had been shown to work on MODS. However, in preclinical studies, there was no systematic evidence to summarize the effects of exercise training on sepsis. OBJECTIVES To investigate the effects of exercise training on sepsis in preclinical studies and explore possible mechanisms to provide reliable preclinical evidence for the use of exercise training in sepsis. METHOD Preclinical studies were retrieved from electronic databases (Pubmed, Embase, Cochrane Library, Scopus, Medline, Web of science) as of June 25, 2024. Our review included in vivo English studies evaluating the radioprotective effects of exercise training on sepsis. The quality of each study was assessed using the Center for Systematic Evaluation of Experimental Animal Studies (SYCLE) Animal Research Bias Risk Tool. All results were described comprehensively. RESULTS 17 in vivo studies were included. Our comprehensive descriptive analysis showed that exercise could improve the general condition, lung injury, liver injury, kidney injury, heart and aortic injury, spleen and thymus injury, and other injuries in animals with sepsis. And its possible mechanisms were involved improving the general condition of sepsis animals, pathological and cell number of organs, anti-inflammation, anti-oxidative stress, anti-DNA damage, and so on. CONCLUSION Exercise training could protect sepsis by anti-inflammatory, anti-oxidative stress, increased antibacterial ability, reduced cell death, improved metabolism, vital signs and MODS.
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Affiliation(s)
- Na Yang
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China
| | - Nan Jiang
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China
| | - Chunming Shen
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China
| | - Ming Gao
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China
| | - Qian Tong
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China
| | - Jian Sun
- Department of Cardiovascular Center, Jilin University First Hospital, Changchun, Jilin Province, 130000, China.
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Bou Chebl R, Haidar S, Kattouf N, Assaf M, Alwan JS, Khamis MM, Abdeldaem K, Makki M, Tamim H, Abou Dagher G. Comparing the Prognostic Value of Lactate to the Neutrophil to Lymphocyte Ratio Among Sepsis Patients: A Prospective Cohort Study. Open Access Emerg Med 2025; 17:3-13. [PMID: 39867261 PMCID: PMC11759577 DOI: 10.2147/oaem.s486966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 12/14/2024] [Indexed: 01/28/2025] Open
Abstract
Background Lactate has long been recognized as a key prognostic biomarker in sepsis. Similarly, the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) has been investigated in various conditions, including sepsis. Previous studies have explored the optimal NLR cutoff to differentiate sepsis survivors from nonsurvivors, predict bacteremia, diagnose sepsis, and assess mortality. This study compares the prognostic value of lactate and NLR in septic patients. Methods This prospective cohort study included 874 adult septic or septic shock patients presenting to a tertiary care center's Emergency Department between September 2018 and February 2021. The primary outcome was to compare the prognostic value of NLR and lactate regarding in-hospital mortality. Secondary outcomes compared their prognostic value in different septic subgroups. Results Stepwise logistic regression showed NLR was not associated with in-hospital mortality (OR=1.003, p=0.544), while lactate was significantly associated with in-hospital mortality (OR=1.188, p<0.0001). There was no significant difference in the AUCs of NLR and lactate (0.552 vs 0.591, p=0.22). Lactate outperformed NLR in patients with albumin <30, those <65 years old, and those with sepsis from a urinary tract infection. No significant differences were found in AUCs between lactate and NLR in patients with septic shock, Lactate<2, Lactate≥2, diabetes, malignancy, chronic kidney diseases, other sources of infection, albumin ≥30 and age ≥ 65. Conclusion In this study, lactate but not NLR was associated with in-hospital mortality. There was no significant difference in the AUCs between lactate and NLR among sepsis patients and among most of the subgroups. However, lactate outperformed NLR in the following subgroups: albumin<30 g/L, patients <65 years old and patients with sepsis due to a urinary tract infection. Our results advocate for the continued use of serum lactate rather than NLR, despite its limitations, as a predictor of mortality among septic patients and the different subgroups in this study.
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Affiliation(s)
- Ralphe Bou Chebl
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | - Saadeddine Haidar
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | - Nadim Kattouf
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | - Mohamad Assaf
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | - Joudie Sahar Alwan
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Karim Abdeldaem
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
| | - Maha Makki
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - Hani Tamim
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - Gilbert Abou Dagher
- Department of Emergency Medicine, American University of Beirut, Beirut, Lebanon
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Sater MS, Almansour N, Malalla ZHA, Fredericks S, Ali ME, Giha HA. Potentials of Presepsin as a Novel Sepsis Biomarker in Critically Ill Adults: Correlation Analysis with the Current Diagnostic Markers. Diagnostics (Basel) 2025; 15:217. [PMID: 39857101 PMCID: PMC11763968 DOI: 10.3390/diagnostics15020217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Sepsis is a major cause of patient death in intensive care units (ICUs). Rapid diagnosis of sepsis assists in optimizing treatments and improves outcomes. Several biomarkers are employed to aid in the diagnosis, prognostication, severity grading, and sub-type discrimination of severe septic infections (SSIs), including current diagnostic parameters, hemostatic measures, and specific organ dysfunction markers. Methods: This study involved 129 critically ill adults categorized into three groups: sepsis (Se = 48), pneumonia (Pn = 48), and Se/Pn (33). Concentrations of five plasma markers (IL-6, IL-8, TREM1, uPAR, and presepsin) were compared with 13 well-established measures of SSI in critically ill patients. These measures were heart rate (HR), white blood count (WBC), C-reactive protein (CRP), procalcitonin (PCT), lactate plasma concentrations, and measures of hemostasis status (platelets count (PLT), fibrinogen, prothrombin time (PT), activated partial thromboplastin time (APTT), international normalization ratio (INR) and D-dimer). Plasma bilirubin and creatinine served as indicators of liver and kidney dysfunction, respectively. Results: Promising roles for these biomarkers were found. The best results were for presepsin, which scored 10/13, followed by IL-6 and IL-8 (each scored 7/13), and the worst were for TREM-1 and uPAR (scored 3/13). Presepsin, IL-6, and IL-8 discriminated between the SSI sub-types, whilst only presepsin correlated with bilirubin and creatinine. uPAR was positive for kidney dysfunction, and TREM-1 was the only indicator of artificial ventilation (AV). Conclusions: Presepsin is an important potential biomarker in SSIs. However, further work is needed to define this marker's diagnostic and prognostic cutoff values.
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Affiliation(s)
- Mai S. Sater
- Department of Medical Biochemistry, College of Medicine and Medical Sciences (CMMS), Arabian Gulf University (AGU), Manama 293, Bahrain; (Z.H.A.M.); (M.E.A.)
| | - Nourah Almansour
- Immunology and Microbiology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Zainab Hasan Abdulla Malalla
- Department of Medical Biochemistry, College of Medicine and Medical Sciences (CMMS), Arabian Gulf University (AGU), Manama 293, Bahrain; (Z.H.A.M.); (M.E.A.)
| | - Salim Fredericks
- Department of Biochemistry, Royal College of Surgeons in Ireland–Medical University of Bahrain (RCSI-MUB), Busaiteen 228, Bahrain;
| | - Muhalab E. Ali
- Department of Medical Biochemistry, College of Medicine and Medical Sciences (CMMS), Arabian Gulf University (AGU), Manama 293, Bahrain; (Z.H.A.M.); (M.E.A.)
| | - Hayder A. Giha
- Medical Biochemistry and Molecular Biology, Khartoum, Sudan;
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Ahmadi S, Sedaghat FR, Memar MY, Yekani M. Metabolomics in the Diagnosis of Bacterial Infections. Clin Chim Acta 2025; 565:120020. [PMID: 39489271 DOI: 10.1016/j.cca.2024.120020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/25/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024]
Abstract
One of the essential factors in the appropriate treatment of infections is accurate and timely laboratory diagnosis. The correct diagnosis of infections plays a vital role in determining desirable therapy and controlling the spread of pathogens. Traditional methods of infection diagnosis are limited by several factors such as insufficient sensitivity and specificity, being time-consuming and laborious, having a low ability to distinguish infection from non-infectious inflammatory conditions and a low potential to predict treatment outcomes. Therefore, it is necessary to find innovative strategies for detecting specific biomarkers in order to diagnose infections. The rapid advancement of metabolomics makes it possible to determine the pattern of metabolite changes in the both of pathogen and the host during an infection. Metabolomics is a method used to assess the levels and type of metabolites in an organism. Metabolites are of low-molecular-weight compounds produced as a result of metabolic processes and pathways within cells. Metabolomics provides valuable data to detect accurate biomarkers of specific biochemical features directly related to certain phenotypes or conditions. This study aimed to review the applications and progress of metabolomics as a biomarker for the diagnosis of bacterial infections.
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Affiliation(s)
- Somayeh Ahmadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Rafie Sedaghat
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Bacteriology and Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mina Yekani
- Department of Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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Reikvam H, Tsykunova G, Sandnes M, Wendelbo Ø. Infectious complications and the utility of serum and cellular markers of infections in the setting of allogeneic hematopoietic stem cell transplantation. Expert Rev Clin Immunol 2025. [PMID: 39760208 DOI: 10.1080/1744666x.2025.2450014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025]
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are severely immunocompromised and susceptible to bacterial, viral, and fungal infections. Despite improved anti-microbial prophylaxis and preemptive strategies, bacterial bloodstream infections (BSIs) occur frequently in allo-HSCT recipients and are associated with increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein Barr virus (EBV) are the most relevant viruses following allo-HSCT and remain major concerns. Fungal infections, including those caused by Candida and Aspergillus species, are persistent and feared complications. AREAS COVERED We aim to provide clinicians caring for allo-HSCT recipients with a comprehensive overview of the risk factors that predispose patients to common bacterial, fungal, and viral infections during the first years post-transplant. The focus is on the value of noninvasive diagnostic biomarkers and serological assays in enhancing the early detection and management of these infections. EXPERT OPINION Effective management of infectious complications following allo-HSCT relies on continuous immune recovery monitoring and the implementation of advanced diagnostic methods. Utilizing noninvasive diagnostic methods is crucial for early detection and different intervention strategies. The development and integration of reliable microbiological markers into clinical practice is essential for enhancing patient outcomes and mitigating infection-related risks. Emphasizing diagnostic innovation will be pivotal in advancing patient care post-allo-HSCT.
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Affiliation(s)
- Håkon Reikvam
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- K.G. Jebsen Center for Myeloid Blood Cancer, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Galina Tsykunova
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Hemato- oncology, Østfold Hospital, Norway
| | - Miriam Sandnes
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Øystein Wendelbo
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Faculty of Health, VID Specialized University, Bergen, Norway
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Van Nynatten LR, Patel MA, Daley M, Miller MR, Cepinskas G, Slessarev M, Russell JA, Fraser DD. Putative biomarkers of hepatic dysfunction in critically ill sepsis patients. Clin Exp Med 2025; 25:28. [PMID: 39751971 PMCID: PMC11698781 DOI: 10.1007/s10238-024-01545-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025]
Abstract
Sepsis is a major cause of morbidity and mortality worldwide. Among the various types of end-organ damage associated with sepsis, hepatic injury is linked to significantly higher mortality rates compared to dysfunction in other organ systems. This study aimed to investigate potential biomarkers of hepatic injury in sepsis patients through a multi-center, case-control approach. We enrolled three matched cohorts: 37 sepsis patients with hepatic dysfunction (S-HD), 37 sepsis patients without hepatic dysfunction (S-CON), and 18 healthy controls (HC). We measured five proposed biomarkers of hepatic dysfunction-ARG1, MDH1, GSTα, 5-NT, and SDH-using multiplex immunoassays. These biomarkers were compared to traditional markers of hepatic dysfunction, including albumin, bilirubin, ALT, AST, and GGT, across the cohorts using both conventional statistical methods and machine learning techniques. The median age of participants was comparable across cohorts: S-HD (65.0 years, IQR 49.5-82.5), S-CON (65.0 years, IQR 48.0-81.5), and HC (62.5 years, IQR 53.0-65.0; P = 0.794). Patients with hepatic dysfunction (S-HD) exhibited higher illness severity scores compared to those without hepatic dysfunction (S-CON): MODS scores were median 7.0 (IQR 4.0-10.0) in S-HD versus median 4.0 (IQR 2.0-7.0) in S-CON (P = 0.005), and SOFA scores were median 7.0 (IQR 4.0-11.0) in S-HD versus median 3.0 (IQR 2.0-6.0) in S-CON (P < 0.001). Hemoglobin and platelet counts were lower, while creatinine levels were higher in S-HD compared to S-CON (P < 0.05). On ICU Day 1, bilirubin, ALT, AST, GGT, and INR were significantly elevated in S-HD relative to S-CON (P ≤ 0.001), and albumin levels were lower (P < 0.05). Additionally, ARG1, GSTα, 5-NT, and SDH were significantly higher in S-HD patients on ICU Day 1 compared to S-CON (P < 0.05). ARG1, MDH1, and SDH showed positive correlations with AST, ALT, and MODS (P < 0.01). From ICU Day 1 to Day 7, ARG1, GSTα, SDH, and AST levels significantly decreased in S-HD patients (P < 0.05), whereas MDH1 and 5-NT levels did not. Among the proposed biomarkers, GSTα and 5-NT did not correlate with traditional hepatic dysfunction markers but were significant in identifying S-HD patients (feature importance 0.131 and 0.097, respectively) in a random forest classification model. This comprehensive model demonstrated excellent performance in distinguishing sepsis patients with hepatic injury, with sensitivity 0.93, specificity 0.94, NPV 0.94, PPV 0.94, and AUC 0.94. The biomarkers ARG1, MDH1, GSTα, 5-NT, and SDH show promise as novel indicators of hepatic dysfunction associated with sepsis. This study provides a foundational basis for subsequent research aimed at characterizing and clinically validating these markers. Future investigations should focus on integrating these potential biomarkers into routine laboratory assessments for sepsis and related hepatic injury.
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Affiliation(s)
| | - Maitray A Patel
- Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Mark Daley
- Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Michael R Miller
- London Health Sciences Centre Research Institute, London, ON, Canada
| | - Gediminas Cepinskas
- London Health Sciences Centre Research Institute, London, ON, Canada
- Medical Biophysics, Western University, London, ON, Canada
- Anatomy and Cell Biology, Western University, London, ON, Canada
| | - Marat Slessarev
- Medicine, Western University, London, ON, Canada
- London Health Sciences Centre Research Institute, London, ON, Canada
| | - James A Russell
- University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
| | - Douglas D Fraser
- Pediatrics, Western University, London, ON, Canada.
- London Health Sciences Centre Research Institute, London, ON, Canada.
- Physiology and Pharmacology, Western University, London, ON, Canada.
- Clinical Neurological Sciences, Western University, London, ON, Canada.
- London Health Sciences Centre, 800 Commissioners Road East, London, ON, N6A 5W9, Canada.
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Griffin K, Miller L, Yang Y, Sharp E, Young L, Garcia L, Griswold J, Pappas D. Affinity-based 3D-printed microfluidic chip for clinical sepsis detection with CD69, CD64, and CD25. J Pharm Biomed Anal 2025; 252:116500. [PMID: 39383543 DOI: 10.1016/j.jpba.2024.116500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/24/2024] [Accepted: 10/02/2024] [Indexed: 10/11/2024]
Abstract
Sepsis is a life-threatening immune response to infection in the body, eventually resulting in fatal organ failure. Current methods utilize blood cultures and quick-Sequential-Organ-Failure-Assessment (qSOFA), but there is a need for more accurate and time-sensitive diagnostic methods to improve survival rates. We present a 3D-printed microfluidic chip that bioconjugates antibodies CD69, CD64, and CD25 to channel surfaces to capture sepsis cells in blood samples and validate it with clinical samples (n = 125 septic, n = 10 healthy). Other variables were taken such as healthy volunteer blood samples and patient demographics to validate and confirm our device's diagnostic ability. Statistical differences were found between healthy volunteer and sepsis patient antigen cell counts (CD69 p-value < 0.001, CD64 p-value < 0.004, CD25 p-value < 0.0009), and were confirmed using principal component analysis. Demographics such as length of stay, age, culture results, and need for surgery also factored into sepsis detection on a smaller scale than the antigen cell counts. The receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.989, 0.988, and 0.992 for CD69, CD64, and CD25, respectively, and a combined biomarker panel of 0.997. Overall, the device performed within a shorter time frame of 4 h compared to standard blood culture tests and was validated for use in detecting sepsis in patients.
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Affiliation(s)
- Kitiara Griffin
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
| | - Lindsee Miller
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
| | - Yijia Yang
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA
| | - Elizabeth Sharp
- Clinical Research Institute, Texas Tech Health Sciences Center, Lubbock, TX, USA
| | - Lane Young
- Clinical Research Institute, Texas Tech Health Sciences Center, Lubbock, TX, USA
| | - Liza Garcia
- Clinical Research Institute, Texas Tech Health Sciences Center, Lubbock, TX, USA
| | - John Griswold
- Department of Surgery, Texas Tech Health Sciences Center, Lubbock, TX, USA
| | - Dimitri Pappas
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
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Fazekas B, Hamon S, De Marco Verissimo C, Cwiklinski K, López Corrales J, Gaughan S, Ryan S, Taggart CC, Weldon S, Griffin MD, Dalton JP, Lalor R. PROTECTION OF MICE AGAINST CECAL LIGATION AND PUNCTURE-INDUCED POLYMICROBIAL SEPSIS BY A FASCIOLA HEPATICA HELMINTH DEFENSE MOLECULE. Shock 2025; 63:132-140. [PMID: 39455069 DOI: 10.1097/shk.0000000000002489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2024]
Abstract
ABSTRACT Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the cecal ligation and puncture model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h. While many typical proinflammatory cytokine/chemokines were systemically elevated, a specific array including IL-10, eotaxin, MIP-1α, MIP-1β, MCP-1, and RANTES noticeably increased just prior to animals reaching the humane endpoint. Treatment of mice with 10 μg of a synthetic 68-amino acid peptide derived from an immunomodulatory molecule secreted by a parasitic worm of humans and livestock, F. hepatica , termed F. hepatica helminth defense molecule, potently suppressed the systemic inflammatory profile, protected mice against acute kidney injury, and improved survival between 48 and 72 h after procedure. These results suggest that the anti-inflammatory parasite-derived F. hepatica helminth defense molecule peptide has potential as a biotherapeutic treatment for sepsis.
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Affiliation(s)
- Barbara Fazekas
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Siobhán Hamon
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Carolina De Marco Verissimo
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Krystyna Cwiklinski
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Jesús López Corrales
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Siobhán Gaughan
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Sinéad Ryan
- Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland
| | - Clifford C Taggart
- Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland
| | - Sinéad Weldon
- Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland
| | - Matthew D Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
| | - John P Dalton
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
| | - Richard Lalor
- Molecular Parasitology Laboratory, Centre of One Health (COH), Ryan Institute, University of Galway, Galway, Ireland
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Chen M, Lei L, Jiang Z, Yang H, Zou J, Song N, Zheng Y. Risk Factors of Mortality and Clinical Characteristics in Descending Necrotizing Mediastinitis: A Retrospective Evaluation of 181 Patients. EAR, NOSE & THROAT JOURNAL 2024:1455613241304277. [PMID: 39614422 DOI: 10.1177/01455613241304277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2024] Open
Abstract
Objectives: Descending necrotizing mediastinitis (DNM) is a serious infection with a high-mortality rate. However, large-scale studies analyzing the clinical characteristics and risk factors of mortality in DNM are rare. This study aimed to clarify the risk factors and some clinical characteristics of mortality of DNM in our hospital. Methods: We retrospectively analyzed the data, including clinical characteristics and mortality, of 181 patients diagnosed with DNM between 2008 and 2022 to clarify the mortality-related risk factors. Results: A total of 181 patients were evaluated, and the mortality rate was 21.55% (39/181 patients). Endo classification type IIB; advanced age; higher white blood cell count, neutrophil percentage, C-reactive protein (CRP) level on admission; and the incidence of septic shock, sepsis, hypoalbuminemia, and electrolyte disorders were significantly related to mortality. Logistic analysis showed that age (≥55 years old), Endo classification type IIB on computed tomography (CT), septic shock, and high CRP level on admission were independent risk factors of mortality. Conclusion: Old age and high CRP levels on admission increase the risk of mortality in DNM patients. Further, Endo classification type IIB on CT and septic shock were associated with poor prognosis.
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Affiliation(s)
- Min Chen
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
- Department of Otorhinolaryngology, Head & Neck Surgery, Chengdu Shang Jin Nan Fu Hospital, West China Hospital, Sichuan Uuniversity, Sichuan, China
| | - Lei Lei
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
| | - Zheng Jiang
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
| | - Hao Yang
- Department of Information Center, West China Hospital, Sichuan University, Sichuan, China
| | - Jian Zou
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
| | - Ningying Song
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
| | - Yongbo Zheng
- Department of Otorhinolaryngology, Head & Neck Surgery, West China Hospital, Sichuan University, Sichuan, China
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10
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Yuan Y, Xiao Y, Zhao J, Zhang L, Li M, Luo L, Jia Y, Wang K, Chen Y, Wang P, Wang Y, Wei J, Shen K, Hu D. Exosomes as novel biomarkers in sepsis and sepsis related organ failure. J Transl Med 2024; 22:1078. [PMID: 39609831 PMCID: PMC11604007 DOI: 10.1186/s12967-024-05817-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/29/2024] [Indexed: 11/30/2024] Open
Abstract
Sepsis, a severe and life-threatening condition arising from a dysfunctional host response to infection, presents considerable challenges to the health care system and is characterized by high mortality rates and substantial economic costs. Exosomes have garnered attention as potential diagnostic markers because of their capacity to mirror the pathophysiological milieu of sepsis. This discourse reviews the progression of sepsis classification from Sepsis 1.0 to Sepsis 3.0, highlighting the imperative for sensitive and specific biomarkers to facilitate timely diagnosis and optimize patient outcomes. Existing biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP), exhibit certain limitations, thereby prompting the quest for more dependable diagnostic indicators. Exosomal cargoes, which encompass proteins and miRNAs, present a trove of biomarker candidates, attributable to their stability, pervasive presence, and indicative nature of the disease status. The potential of exosomal biomarkers in the identification of sepsis-induced organ damage, including cardiomyopathy, acute kidney injury, and acute lung injury, is emphasized, as they provide real-time insights into cardiac and renal impairments. Despite promising prospects, hurdles persist in the standardization of exosome extraction and the need for extensive clinical trials to validate their efficacy. The combination of biomarker development and sophisticated exosome detection techniques represents a pioneering strategy in the realm of sepsis diagnosis and management, underscoring the significance of further research and clinical validation.
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Affiliation(s)
- Yixuan Yuan
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yujie Xiao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Jiazhen Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Lixia Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Mengyang Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Liang Luo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yanhui Jia
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Kejia Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yuxi Chen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Peng Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yuhang Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Jingtao Wei
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China.
- Air Force Hospital of Western Theater Command, Gongnongyuan Street #1, Chengdu, 610065, China.
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China.
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Slek C, Magnin M, Allaouchiche B, Bonnet JM, Junot S, Louzier V, Victoni T. Association between cytokines, nitric oxide, hemodynamic and microcirculation in a porcine model of sepsis. Microvasc Res 2024; 156:104730. [PMID: 39111365 DOI: 10.1016/j.mvr.2024.104730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/07/2024] [Accepted: 08/04/2024] [Indexed: 08/11/2024]
Abstract
Systemic inflammation and hemodynamic or microvascular alterations are a hallmark of sepsis and play a role in organs hypoperfusion and dysfunction. Pimobendan, an inodilator agent, could be an interesting option for inotropic support and microcirculation preservation during shock. The objectives of this study were to evaluate effect of pimobendan on cytokine and nitric oxide (NO) release and investigate whether changes of macro and microcirculation parameters are associated with the release of cytokines and NO in pigs sepsis model. After circulatory failure, induced by intravenous inoculation of live Pseudomonas aeruginosa, eight animals were treated with pimobendan and eight with placebo. Pimobendan did not affect cytokines secretion (TNF-α, IL-6 and IL-10), but decreased time-dependently NO release. Data of macro and microcirculation parameters, NO and TNF- α recorded at the time of circulatory failure (Thypotension) and the time maximum of production cytokines was used for analyses. A positive correlation was observed between TNF-α and cardiac index (r = 0.55, p = 0.03) and a negative with systemic vascular resistance (r = -0.52, p = 0.04). Positive correlations were seen both between IL-10, 30 min after resuscitation (T30min), and systolic arterial pressure (r = 0.57, p = 0.03) and cardiac index (r = 0.67, p = 0.01), and also between IL-6, taken 2 h after resuscitation and systolic arterial pressure (r = 0.53, p = 0.04). Negative correlations were found between IL-10 and lactate, measured resuscitation time (r = -0.58, p = 0.03). Regarding microcirculation parameters, we observed a positive correlation between IL-6 and IL-10 with the microvascular flow index (r = 0.52, p = 0.05; r = 0.84, p = 0.0003) and a negative correlation with the heterogeneity index with TNF-α and IL-10 (r = -0.51, p = 0.05; r = -0.74, p = 0.003) respectively. NO derivatives showed a positive correlation with temperature gradient (r = 0.54, p = 0.04). Pimobendan did not show anti-inflammatory effects in cytokines release. Our results also, suggest changes of macro- and microcirculation are associated mainly with low levels of IL-10 in sepsis.
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Affiliation(s)
- Charlotte Slek
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
| | - Mathieu Magnin
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
| | - Bernard Allaouchiche
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France; Université de Lyon, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Réanimation Médicale, 165 Chemin du Grand Revoyet, 69495 Pierre-Bénite, France
| | - Jeanne Marie Bonnet
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
| | - Stéphane Junot
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
| | - Vanessa Louzier
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
| | - Tatiana Victoni
- Université de Lyon, APCSe Agressions Pulmonaires et Circulatoires dans le Sepsis-, UP 2021.A101, VetAgro Sup, 1 Avenue Bourgelat, 69280 Marcy-l'Étoile, France.
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Ma C, Jiang W, Li J, Sun W, Zhang J, Xu P, Guo Y, Ning N, Li J, Zhao B, Mao E, Gao C. Association of Stress Hyperglycemia Ratio and in-Hospital Mortality in Patients with Sepsis: A Two Center Retrospective Cohort Study. J Inflamm Res 2024; 17:7939-7950. [PMID: 39494208 PMCID: PMC11531714 DOI: 10.2147/jir.s476898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024] Open
Abstract
Introduction In critically ill patients, the stress hyperglycemia ratio (SHR) was significantly associated with mortality. However, the relationship between SHR and mortality in septic patients is still unclear.In this study, patients with sepsis from two Chinese academic centers were identified and divided into quartiles based on SHR levels. Methods Multivariable regression analysis will be used to determine associations between SHR and clinical outcomes in sepsis patients.The Kaplan-Meier curve was used to predict mortality in various groups of septic patients. Results A total of 1835 septic patients were included in the study.The in-hospital, 30-day, and 60-day mortality rates for all septic patients were 22.8%, 18.7%, and 21.7%, respectively. Increased SHR was significantly associated with hospital mortality in multivariate regression analysis.These results were further confirmed in the adjusted analysis, where the hospital mortality and the 60-day mortality of the highest SHR quartile were significantly increased compared to the lowest SHR quartile. However, the highest SHR quartile was not associated with 30-day mortality.In addition, the risk of in-hospital mortality, 30-day mortality and 60-day mortality showed a consistent upward trend with increasing SHR quartile. The survival curve showed that the worst prognosis was in the fourth SHR quartile. Discussion In conclusion, SHR was significantly associated with hospital mortality in patients with sepsis. This finding indicates that the SHR may be useful in identifying septic patients at higher risk of hospital mortality.
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Affiliation(s)
- Chaoping Ma
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
| | - Weisong Jiang
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Juan Li
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
| | - Wenwu Sun
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Jiyuan Zhang
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
| | - Peixian Xu
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
| | - Yiran Guo
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
| | - Ning Ning
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Jiaoyan Li
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Bing Zhao
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Enqiang Mao
- Departments of Emergency, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, People’s Republic of China
| | - Chengjin Gao
- Departments of Emergency, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China
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Zhang T, Shi Y, Li J, Huang P, Chen K, Yao J. Utilize proteomic analysis to identify potential therapeutic targets for combating sepsis and sepsis-related death. Front Endocrinol (Lausanne) 2024; 15:1448314. [PMID: 39387050 PMCID: PMC11463698 DOI: 10.3389/fendo.2024.1448314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/28/2024] [Indexed: 10/12/2024] Open
Abstract
Background Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death. Methods Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank. Results After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant. Conclusions The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field.
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Affiliation(s)
- Tianlong Zhang
- Department of Critical Care Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Yin Shi
- Department of Internal Medicine, Yiwu Maternity And Children Hospital, Yiwu, Zhejiang, China
| | - Jiayue Li
- Department of Anesthesiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Peiyao Huang
- Department of Gastroenterology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Kun Chen
- Department of Critical Care Medicine, Jinhua Hospital Affiliated to Zhejiang University, Jinhua, Zhejiang, China
| | - Jiali Yao
- Department of Critical Care Medicine, Jinhua Hospital Affiliated to Zhejiang University, Jinhua, Zhejiang, China
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Getsina M, Chernevskaya E, Beloborodova N, Golovnya E, Polyakov P, Kushlinskii N. Features of Metabolites and Biomarkers in Inflammatory and Infectious Complications of Childhood Cancers. Biomedicines 2024; 12:2101. [PMID: 39335614 PMCID: PMC11429149 DOI: 10.3390/biomedicines12092101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/06/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Background: In the treatment of oncological diseases in children, the search for opportunities for the earlier detection of complications to improve treatment results is very important. Metabolomic studies are actively conducted to stratify different groups of patients in order to identify the most promising markers. Methods: Three groups of patients participated in this study: healthy children as a control group (n = 18), children with various malignant oncological diseases (leukemia, lymphoma, nephroblastoma, ependymoma, etc.) as patients (n = 40) without complications, and patients (n = 31) with complications (inflammatory and infectious). The mitochondrial metabolites (succinic and fumaric acids); biomarkers related to inflammation such as C-reactive protein (CRP), procalcitonin (PCT), and presepsin (PSP); and sepsis-associated aromatic metabolites, such as phenyllactic (PhLA), hydroxyphenyllactic (p-HPhLA), and hydroxyphenylacetic acids (p-HPhAA), were identified. Results: It was found that children with malignant oncological diseases had profound metabolic dysfunction compared to healthy children, regardless of the presence of systemic inflammatory response syndrome (SIRS) or sepsis. The prognostic ability of procalcitonin and presepsin for detecting sepsis was high: AUROC = 0.875, cut-off value (Youden index) = 0.913 ng/mL, and AUROC = 0.774, with cut-off value (Youden index) of 526 pg/mL, respectively. Conclusions: A significant increase in aromatic microbial metabolites and biomarkers in non-survivor patients that is registered already in the first days of the development of complications indicates the appropriateness of assessing metabolic dysfunction for its timely targeted correction.
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Affiliation(s)
- Maria Getsina
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Str., 25-2, 107031 Moscow, Russia; (E.C.)
| | - Ekaterina Chernevskaya
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Str., 25-2, 107031 Moscow, Russia; (E.C.)
| | - Natalia Beloborodova
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Str., 25-2, 107031 Moscow, Russia; (E.C.)
| | - Evgeniy Golovnya
- Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia
| | - Petr Polyakov
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Petrovka Str., 25-2, 107031 Moscow, Russia; (E.C.)
| | - Nicolai Kushlinskii
- Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 115522 Moscow, Russia
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15
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Zhang X, Zhang Y, Liu Q, Zeng A, Song L. Glycolysis-associated lncRNAs in cancer energy metabolism and immune microenvironment: a magic key. Front Immunol 2024; 15:1456636. [PMID: 39346921 PMCID: PMC11437524 DOI: 10.3389/fimmu.2024.1456636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
The dependence of tumor cells on glycolysis provides essential energy and raw materials for their survival and growth. Recent research findings have indicated that long chain non-coding RNAs (LncRNAs) have a key regulatory function in the tumor glycolytic pathway and offer new opportunities for cancer therapy. LncRNAs are analogous to a regulatory key during glycolysis. In this paper, we review the mechanisms of LncRNA in the tumor glycolytic pathway and their potential therapeutic strategies, including current alterations in cancer-related energy metabolism with lncRNA mediating the expression of key enzymes, lactate production and transport, and the mechanism of interaction with transcription factors, miRNAs, and other molecules. Studies targeting LncRNA-regulated tumor glycolytic pathways also offer the possibility of developing new therapeutic strategies. By regulating LncRNA expression, the metabolic pathways of tumor cells can be interfered with to inhibit tumor growth and metastasis, thus affecting the immune and drug resistance mechanisms of tumor cells. In addition, lncRNAs have the capacity to function as molecular markers and target therapies, thereby contributing novel strategies and approaches to the field of personalized cancer therapy and prognosis evaluation. In conclusion, LncRNA, as key molecules regulating the tumor glycolysis pathway, reveals a new mechanism of abnormal metabolism in cancer cells. Future research will more thoroughly investigate the specific mechanisms of LncRNA glycolysis regulation and develop corresponding therapeutic strategies, thereby fostering new optimism for the realization of precision medicine.
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Affiliation(s)
- Xi Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yunchao Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qiong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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16
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Loaiza R, Fattahi F, Kalbitz M, Grailer JJ, Russell MW, Jalife J, Valdivia HH, Zetoune FS, Ward PA. The Impact of Extracellular Histones and Absence of Toll-like Receptors on Cardiac Functional and Electrical Disturbances in Mouse Hearts. Int J Mol Sci 2024; 25:8653. [PMID: 39201339 PMCID: PMC11354419 DOI: 10.3390/ijms25168653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 08/02/2024] [Accepted: 08/04/2024] [Indexed: 09/02/2024] Open
Abstract
In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone-TLR interactions and their mechanisms.
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Affiliation(s)
- Randall Loaiza
- Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA; (R.L.); (J.J.); (H.H.V.)
- CENIBiot Laboratory, The National Center of High Technology (CeNAT-CONARE), San José 10109, Costa Rica
| | - Fatemeh Fattahi
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.K.); (J.J.G.); (F.S.Z.)
| | - Miriam Kalbitz
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.K.); (J.J.G.); (F.S.Z.)
- Department of Orthopaedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, 89081 Ulm, Germany
- Military Medical City Hospital, Doha 486441, Qatar
| | - Jamison J. Grailer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.K.); (J.J.G.); (F.S.Z.)
- Integrated Biology R&D, Bioassay Development, Promega Corporation, Madison, WI 53711, USA
| | - Mark W. Russell
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Jose Jalife
- Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA; (R.L.); (J.J.); (H.H.V.)
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Hector H. Valdivia
- Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48109, USA; (R.L.); (J.J.); (H.H.V.)
- Department of Medicine, Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Firas S. Zetoune
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.K.); (J.J.G.); (F.S.Z.)
| | - Peter A. Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (M.K.); (J.J.G.); (F.S.Z.)
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Patnaik R, Azim A, Singh K, Agarwal V, Mishra P, Poddar B, Gurjar M, Mishra SB. Serial Trend of Neutrophil CD64, C-reactive Protein, and Procalcitonin as a Prognostic Marker in Critically Ill Patients with Sepsis/Septic Shock: A Prospective Observational Study from a Tertiary Care ICU. Indian J Crit Care Med 2024; 28:777-784. [PMID: 39239184 PMCID: PMC11372664 DOI: 10.5005/jp-journals-10071-24777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/19/2024] [Indexed: 09/07/2024] Open
Abstract
Aim and background Neutrophil CD64 (nCD64) is evolving as a prognostic biomarker in sepsis. The primary objective of this study was to evaluate whether serial trend of nCD64, procalcitonin (PCT), and C-reactive protein (CRP) predict 28-day mortality in patients with sepsis/septic shock, as per Sepsis-3 criteria. Materials and methods This prospective, observational single-center cohort study included 60 adult patients (age ≥18 years) with sepsis. Serial biomarker levels with SOFA score were measured at admission (day 0), on day 4, and on day 8. Results Of the 60 patients, 42 (70%) had septic shock. Biomarker levels at admission did not differ between patients with sepsis and septic shock. Thirty-seven patients survived and 23 were non-survivors by day 28. There was a significant fall in serial trend of all three biomarkers from admission till day 8 (Friedman p < 0.001) in survivors compared to a non-significant change in non-survivors. On multivariate analysis, SOFA score at admission (OR 1.731), more days with vasopressor support (OR 1.077), rise in CD64 from day 0 to day 8 (OR 1.074), and rise in CRP from day 0 to 8 (OR 1.245) were the significant predictors of 28-day mortality (p < 0.05). The highest area under the ROC curve was obtained for more days of vasopressor therapy (0.857), followed by a rise in CD64 from day 0 to day 8 (0.798). Conclusion Serial trend of biomarkers has prognostic utility. The rise in CD64 from day 0 to day 8 was a good predictor of mortality compared to the trend of other biomarkers. How to cite this article Patnaik R, Azim A, Singh K, Agarwal V, Mishra P, Poddar B, et al. Serial Trend of Neutrophil CD64, C-reactive Protein, and Procalcitonin as a Prognostic Marker in Critically Ill Patients with Sepsis/Septic Shock: A Prospective Observational Study from a Tertiary Care ICU. Indian J Crit Care Med 2024;28(8):777-784.
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Affiliation(s)
- Rupali Patnaik
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
| | - Afzal Azim
- Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Kritika Singh
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Vikas Agarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Prabhaker Mishra
- Department of Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Banani Poddar
- Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mohan Gurjar
- Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Shakti B Mishra
- Department of Critical Care Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha, India
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Xie L, Chen Y. The protagonist of contemporary and emerging nanotechnology-based theranostics and therapeutic approaches in reshaping intensive care unit. Saudi Med J 2024; 45:759-770. [PMID: 39074899 PMCID: PMC11288488 DOI: 10.15537/smj.2024.45.8.20240069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2024] Open
Abstract
To maintain a clean and hygienic environment in the intensive care unit (ICU) is crucial for ensuring patient safety, preventing infections, and reducing healthcare-associated complications. With the increasing prevalence of infections and the emergence of viral and bacterial resistance to standard antiseptics, there is a pressing need for innovative antiseptic solutions. Nanotechnology is increasingly being employed in medicine, particularly focusing on mitigating the activities of various pathogens, including those associated with hospital-acquired infections. This paper explores the current impact of nanotechnology, with a particular focus on bacterial infections and SARS-CoV-2, which significantly strain healthcare systems, and then discusses how nanotechnology can enhance existing treatment methodologies. We highlight the effectiveness of the nanotechnology-based bactericide Bio-Kil in reducing bacterial counts in an ICU. The aim is to educate healthcare professionals on the existing role and prospects of nanotechnology in addressing prevalent infectious diseases.
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Affiliation(s)
- Ling Xie
- From the Department of Critical Medicine, First People’s Hospital of Linping District, Hangzhou, China.
| | - Yun Chen
- From the Department of Critical Medicine, First People’s Hospital of Linping District, Hangzhou, China.
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La Via L, Sangiorgio G, Stefani S, Marino A, Nunnari G, Cocuzza S, La Mantia I, Cacopardo B, Stracquadanio S, Spampinato S, Lavalle S, Maniaci A. The Global Burden of Sepsis and Septic Shock. EPIDEMIOLOGIA 2024; 5:456-478. [PMID: 39189251 PMCID: PMC11348270 DOI: 10.3390/epidemiologia5030032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/07/2024] [Accepted: 07/18/2024] [Indexed: 08/28/2024] Open
Abstract
A dysregulated host response to infection causes organ dysfunction in sepsis and septic shock, two potentially fatal diseases. They continue to be major worldwide health burdens with high rates of morbidity and mortality despite advancements in medical care. The goal of this thorough review was to present a thorough summary of the current body of knowledge about the prevalence of sepsis and septic shock worldwide. Using widely used computerized databases, a comprehensive search of the literature was carried out, and relevant studies were chosen in accordance with predetermined inclusion and exclusion criteria. A narrative technique was used to synthesize the data that were retrieved. The review's conclusions show how widely different locations and nations differ in terms of sepsis and septic shock's incidence, prevalence, and fatality rates. Compared to high-income countries (HICs), low- and middle-income countries (LMICs) are disproportionately burdened more heavily. We talk about risk factors, comorbidities, and difficulties in clinical management and diagnosis in a range of healthcare settings. The review highlights the need for more research, enhanced awareness, and context-specific interventions in order to successfully address the global burden of sepsis and septic shock.
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Affiliation(s)
- Luigi La Via
- Department of Anaesthesia and Intensive Care, University Hospital Policlinico “G. Rodolico-San Marco”, 24046 Catania, Italy
| | - Giuseppe Sangiorgio
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy; (G.S.); (S.S.); (S.S.)
| | - Stefania Stefani
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy; (G.S.); (S.S.); (S.S.)
| | - Andrea Marino
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, 95123 Catania, Italy; (A.M.); (G.N.); (B.C.); (S.S.)
| | - Giuseppe Nunnari
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, 95123 Catania, Italy; (A.M.); (G.N.); (B.C.); (S.S.)
| | - Salvatore Cocuzza
- Department of Medical, Surgical Sciences and Advanced Technologies “GF Ingrassia” ENT Section, University of Catania, 95123 Catania, Italy; (S.C.); (I.L.M.)
| | - Ignazio La Mantia
- Department of Medical, Surgical Sciences and Advanced Technologies “GF Ingrassia” ENT Section, University of Catania, 95123 Catania, Italy; (S.C.); (I.L.M.)
| | - Bruno Cacopardo
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, 95123 Catania, Italy; (A.M.); (G.N.); (B.C.); (S.S.)
| | - Stefano Stracquadanio
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy; (G.S.); (S.S.); (S.S.)
| | - Serena Spampinato
- Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, 95123 Catania, Italy; (A.M.); (G.N.); (B.C.); (S.S.)
| | - Salvatore Lavalle
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (S.L.); (A.M.)
| | - Antonino Maniaci
- Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy; (S.L.); (A.M.)
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20
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Jiang L, Chen S, Li S, Wang J, Chen W, Shi Y, Xiong W, Miao C. Exploring biomarkers for diagnosing and predicting organ dysfunction in patients with perioperative sepsis: a preliminary investigation. Perioper Med (Lond) 2024; 13:81. [PMID: 39049003 PMCID: PMC11267738 DOI: 10.1186/s13741-024-00438-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/16/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVE Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients. METHOD This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models. RESULTS Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843-0.954) and good calibration. CONCLUSION Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction. TRIAL REGISTRATION The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022.
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Affiliation(s)
- Linghui Jiang
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shiyu Chen
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shichao Li
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiaxing Wang
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wannan Chen
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuncen Shi
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wanxia Xiong
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Changhong Miao
- Department of Anaesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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21
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Liufu Q, Niu L, He S, Zhang X, Chen M. Risk factors of bloodstream infection in erythroderma from atopic dermatitis, psoriasis, and drug reactions: a retrospective observational cohort study. PeerJ 2024; 12:e17701. [PMID: 39006018 PMCID: PMC11246620 DOI: 10.7717/peerj.17701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/17/2024] [Indexed: 07/16/2024] Open
Abstract
Background Atopic dermatitis (AD), psoriasis, and drug reactions associated with erythroderma are frequently complicated by infections. However, bloodstream infection (BSI) have received less research attention. Objectives This study aimed to investigate the clinical characteristics and risk factors associated with BSI in patients with erythroderma. Methods A retrospective analysis was conducted on 141 erythroderma cases. Eleven cases were identified as having BSI. Clinical records of both BSI and non-BSI groups were reviewed and compared. Results BSI was diagnosed in 7.80% (11/141) of erythroderma cases, with a breakdown of 7.14% in AD, 2.00% in psoriasis, and 17.14% in drug reactions. Notably, all positive skin cultures (7/7) showed bacterial isolates concordant with blood cultures. Univariate logistic regression analysis revealed several significant associations with BSI, including temperature (≤36.0 or ≥38.5 °C; odds ratio (OR) = 28.06; p < 0.001), chilling (OR = 22.10; p < 0.001), kidney disease (OR = 14.64; p < 0.001), etiology of drug reactions (OR = 4.18; p = 0.03), albumin (ALB) (OR = 0.86; p < 0.01), C-reaction protein (CRP) (OR = 1.01; p = 0.02), interleukin 6 (IL-6) (OR = 1.02; p = 0.02), and procalcitonin (PCT) (OR = 1.07; p = 0.03). Receiver operating characteristic (ROC) curves demonstrated significant associations with ALB (p < 0.001; the area under curve (AUC) = 0.80), PCT (p = 0.009; AUC = 0.74), and CRP (p = 0.02; AUC = 0.71). Conclusions Increased awareness of BSI risk is essential in erythroderma management. Patients with specific risk factors, such as abnormal body temperature (≤36.0 or ≥38.5 °C), chilling sensations, kidney disease, a history of drug reactions, elevated CRP (≥32 mg/L), elevated PCT (≥1.00 ng/ml), and low albumin (≤31.0 g/L), require close monitoring for BSI development.
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Affiliation(s)
- Qian Liufu
- Department of Dermatology, The First Affiliated Hospital of GuangZhou Medical University, Guangzhou, Guangdong, China
| | - Lulu Niu
- Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shimin He
- Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Dermatology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xuejiao Zhang
- Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mukai Chen
- Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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22
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Ma Z, Jiang Z, Li H, Lu A, Wu S, Lu H, Wen W, Wang L, Yuan F. Prevalence, early predictors, and outcomes of sepsis in neurocritical illnesses: A prospective cohort study. Am J Infect Control 2024; 52:827-833. [PMID: 38281685 DOI: 10.1016/j.ajic.2024.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND Patients with neurocritically illness are an under-recognized population at high risk of sepsis. We aimed to investigate the prevalence, early predictors, and outcomes of sepsis in neuro-ICU. METHODS Daily and accumulative incidences of sepsis in neuro-ICU were explored. Demographics, medical history, baseline disease severity scores, and baseline biomarkers regarding inflammation, immunology, organ function, and nutritional status were collected and analyzed as potential predictors of sepsis. Logistic regression analyses were used to determine the independent predictors, and a nomogram was used to estimate the individual probability of sepsis in neuro-ICU. RESULTS 153 patients were included in this study. Fifty-nine (38.6%) patients developed sepsis, and 21 (14%) patients developed septic shock. More than 86% of the septic cases occurred within the first week. Sequential organ failure assessment score ((relative risk) RR 1.334, P = .026), history of diabetes (RR 2.346, P = .049), and transferrin (RR 0.128, P = .042) on admission are independent predictors of sepsis. Septic patients had significantly higher mortality (P = .011), higher medical cost (P = .028), and a lower rate of functional independence (P = .010), compared to patients without sepsis. CONCLUSIONS Sepsis afflicted more than one-third of neurocritically-ill patients and occurred mostly in the first week of admission. History of diabetes, serum transferrin, and sequential organ failure assessment score on admission were early predictors. Sepsis led to significantly worse outcomes and higher medical costs.
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Affiliation(s)
- Zhaohui Ma
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zeping Jiang
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Internal Medicine, Puning Hospital of Chinese Medicine, Puning, Guangdong, China
| | - Huiping Li
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Aili Lu
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shibiao Wu
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongji Lu
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wanxing Wen
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lixin Wang
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, China.
| | - Fang Yuan
- Department of Neurocritical Care, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou, China.
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23
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Li BR, Zhuo Y, Jiang YY, Zhang SY. Random forest differentiation of Escherichia coli in elderly sepsis using biomarkers and infectious sites. Sci Rep 2024; 14:12973. [PMID: 38839818 PMCID: PMC11153632 DOI: 10.1038/s41598-024-63944-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 06/03/2024] [Indexed: 06/07/2024] Open
Abstract
This study addresses the challenge of accurately diagnosing sepsis subtypes in elderly patients, particularly distinguishing between Escherichia coli (E. coli) and non-E. coli infections. Utilizing machine learning, we conducted a retrospective analysis of 119 elderly sepsis patients, employing a random forest model to evaluate clinical biomarkers and infection sites. The model demonstrated high diagnostic accuracy, with an overall accuracy of 87.5%, and impressive precision and recall rates of 93.3% and 87.5%, respectively. It identified infection sites, platelet distribution width, reduced platelet count, and procalcitonin levels as key predictors. The model achieved an F1 Score of 90.3% and an area under the receiver operating characteristic curve of 88.0%, effectively differentiating between sepsis subtypes. Similarly, logistic regression and least absolute shrinkage and selection operator analysis underscored the significance of infectious sites. This methodology shows promise for enhancing elderly sepsis diagnosis and contributing to the advancement of precision medicine in the field of infectious diseases.
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Affiliation(s)
- Bu-Ren Li
- Department of Clinical Laboratory, Fuding Hospital, Fujian University of Traditional Chinese Medicine, 120 South Road of Old City, Fuding, 355200, Fujian, China
| | - Ying Zhuo
- Department of Clinical Laboratory, Fuding Hospital, Fujian University of Traditional Chinese Medicine, 120 South Road of Old City, Fuding, 355200, Fujian, China
| | - Ying-Ying Jiang
- Department of Clinical Laboratory, Fuding Hospital, Fujian University of Traditional Chinese Medicine, 120 South Road of Old City, Fuding, 355200, Fujian, China
| | - Shi-Yan Zhang
- Department of Clinical Laboratory, Fuding Hospital, Fujian University of Traditional Chinese Medicine, 120 South Road of Old City, Fuding, 355200, Fujian, China.
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24
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Bolanaki M, Winning J, Slagman A, Lehmann T, Kiehntopf M, Stacke A, Neumann C, Reinhart K, Möckel M, Bauer M. Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department. Crit Care Med 2024; 52:887-899. [PMID: 38502804 PMCID: PMC11093432 DOI: 10.1097/ccm.0000000000006216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
OBJECTIVES Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. DESIGN In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. SETTING Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). PATIENTS One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. CONCLUSIONS Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.
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Affiliation(s)
- Myrto Bolanaki
- Department of Emergency and Acute Medicine, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johannes Winning
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Anna Slagman
- Department of Emergency and Acute Medicine, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Lehmann
- Center for Clinical Studies, Jena University Hospital, Jena, Germany
| | - Michael Kiehntopf
- Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena (IBBJ), Jena University Hospital, Jena, Germany
| | - Angelika Stacke
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Caroline Neumann
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Konrad Reinhart
- Department of Anesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Möckel
- Department of Emergency and Acute Medicine, Campus Virchow and Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
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25
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Yan Y, Liao L. MicroRNA Expression Profile in Patients Admitted to ICU as Novel and Reliable Approach for Diagnostic and Therapeutic Purposes. Mol Biotechnol 2024; 66:1357-1375. [PMID: 37314613 DOI: 10.1007/s12033-023-00767-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 05/06/2023] [Indexed: 06/15/2023]
Abstract
The ability to detect early metabolic changes in patients who have an increased mortality risk in the intensive care units (ICUs) could increase the likelihood of predicting recovery patterns and assist in disease management. Markers that can predict the disease progression of patients in the ICU might also be beneficial for improving their medical profile. Although biomarkers have been used in the ICU more frequently in recent years, the clinical use of most of them is limited. A wide range of biological processes are influenced by microRNAs (miRNAs) that modulate the translation and stability of specific mRNAs. Studies suggest that miRNAs may serve as a diagnostic and therapeutic biomarker in ICUs by profiling miRNA dysregulation in patient samples. To improve the predictive value of biomarkers for ICU patients, researchers have proposed both investigating miRNAs as novel biomarkers and combining them with other clinical biomarkers. Herein, we discuss recent approaches to the diagnosis and prognosis of patients admitted to an ICU, highlighting the use of miRNAs as novel and robust biomarkers for this purpose. In addition, we discuss emerging approaches to biomarker development and ways to improve the quality of biomarkers so that patients in ICU get the best outcomes possible.
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Affiliation(s)
- Youqin Yan
- ICU Department, People's Hospital of Changshan, Changshan, China
| | - Linjun Liao
- ICU Department, People's Hospital of Changshan, Changshan, China.
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26
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Spoto S, Basili S, Cangemi R, Yuste JR, Lucena F, Romiti GF, Raparelli V, Argemi J, D’Avanzo G, Locorriere L, Masini F, Calarco R, Testorio G, Spiezia S, Ciccozzi M, Angeletti S. A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections. Cells 2024; 13:892. [PMID: 38891025 PMCID: PMC11172186 DOI: 10.3390/cells13110892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/15/2024] [Indexed: 06/20/2024] Open
Abstract
Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.
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Affiliation(s)
- Silvia Spoto
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Stefania Basili
- Department of Translational and Precision Medicine, Sapienza University, Viale dell’Università, 30, 00185 Rome, Italy; (S.B.); (R.C.); (V.R.)
| | - Roberto Cangemi
- Department of Translational and Precision Medicine, Sapienza University, Viale dell’Università, 30, 00185 Rome, Italy; (S.B.); (R.C.); (V.R.)
| | - José Ramón Yuste
- Division of Infectious Diseases, Faculty of Medicine, Clinica Universidad de Navarra, University of Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain;
- Department of Internal Medicine, Faculty of Medicine, Clinica Universidad de Navarra, University of Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain
| | - Felipe Lucena
- Departamento de Medicina Interna, Clinica Universidad de Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain; (F.L.); (J.A.)
| | - Giulio Francesco Romiti
- Department of Translational and Precision Medicine, Sapienza University, Viale dell’Università, 30, 00185 Rome, Italy; (S.B.); (R.C.); (V.R.)
| | - Valeria Raparelli
- Department of Translational and Precision Medicine, Sapienza University, Viale dell’Università, 30, 00185 Rome, Italy; (S.B.); (R.C.); (V.R.)
| | - Josepmaria Argemi
- Departamento de Medicina Interna, Clinica Universidad de Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain; (F.L.); (J.A.)
| | - Giorgio D’Avanzo
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Luciana Locorriere
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Francesco Masini
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Rodolfo Calarco
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Giulia Testorio
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Serenella Spiezia
- Diagnostic and Therapeutic Medicine Department, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy; (G.D.); (L.L.); (F.M.); (R.C.); (G.T.); (S.S.)
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Silvia Angeletti
- Unit of Laboratory, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Rome, Italy;
- Research Unit of Clinical Laboratory Science, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Rome, Italy
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27
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Choi Y, Lee JH. Clinical usefulness of NT-proBNP as a prognostic factor for septic shock patients presenting to the emergency department. Sci Rep 2024; 14:10999. [PMID: 38744896 PMCID: PMC11094059 DOI: 10.1038/s41598-024-61888-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024] Open
Abstract
Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level is primarily used as a biomarker for left ventricular (LV) dysfunction. It is influenced by various conditions, such as myocardial strain and situations affecting the clearance of NT-proBNP, including sepsis and shock. In this study, we investigated the appropriateness of NT-proBNP as a prognostic factor for septic shock. Patients with septic shock who visited the emergency department of the Ewha Womans' University Mokdong Hospital between January 1, 2018, and December 31, 2020, were classified into the survival group (those who survived in the hospital and were discharged) and the death group (those who died in the hospital). The effectiveness of NT-proBNP, lactate, and blood urea nitrogen as predictive factors of in-hospital mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. The AUROC curve was 0.678 and 0.648 for lactate and NT-proBNP, respectively, with lactate showing the highest value. However, there was no significant difference between lactate and NT-proBNP levels in the comparison of their AUROC curve (p = 0.6278). NT-proBNP could be a useful predictor of in-hospital mortality in patients with septic shock who present to the emergency department.
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Affiliation(s)
- Yunhyung Choi
- Chung-Ang University Gwangmyeong Hospital, Deokan-ro 110, Gwangmyeong-si, Gyeonggi-do, 14353, Republic of Korea
| | - Jae Hee Lee
- Department of Emergency Medicine, College of Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, Republic of Korea.
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28
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Padawer D, Qadan A, Karameh M, Darawshy F, Laor A, Banker S, Fridlender ZG. Breath of Health: spectroscopy-based breath test for the detection of SARS-CoV-2. Infect Dis (Lond) 2024; 56:376-383. [PMID: 38424673 DOI: 10.1080/23744235.2024.2313020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 01/27/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Nucleic acid amplification tests (NAAT) are considered the gold standard for COVID-19 diagnosis. These tests require professional manpower and equipment, long processing and swab sampling which is unpleasant to the patients. Several volatile organic compounds (VOCs) have been identified in the breath of COVID-19 patients. Detection of these VOCs using a breath test could help rapidly identify COVID-19 patients. OBJECTIVE Assess the accuracy of 'Breath of Health' (BOH) COVID-19 Fourier-transform infra-red (FTIR) Spectroscopy-based breath test. METHODS Breath samples from patients with or without symptoms suggestive for COVID-19 who had NAAT results were collected using Tedlar bags and were blindly analysed using BOH FTIR spectroscopy. BOH Measures several VOCs simultaneously and differentiating positive and negative results. BOH results were compared to NAAT results as gold standard. RESULTS Breath samples from 531 patients were analysed. The sensitivity of BOH breath test was found to be 79.5% and specificity was 87.2%. Positive predictive value (PPV) was 74.7% and negative predictive value (NPV) 90.0%. Calculated accuracy rate was 84.8% and area under the curve 0.834. Subgroup analysis revealed that the NPV of patients without respiratory symptoms was superior over the NPV of symptomatic patients (94.7% vs 80.7%, P-value < 0.0001) and PPV of patients with respiratory symptoms outranks the PPV of individuals without symptoms (85.3% vs 69.2%, P-value 0.0196). CONCLUSION We found BOH COVID-19 breath test to be a patient-friendly, rapid, non-invasive diagnostic test with high accuracy rate and NPV that could efficiently rule out COVID-19 especially among individuals with low pre-test probability.
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Affiliation(s)
- Dan Padawer
- Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem, Israel
- Department of Internal Medicine D, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abed Qadan
- Department of Internal Medicine D, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Mutaz Karameh
- Department of Internal Medicine D, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- Heart Institute, Hadassah Medical Center, Jerusalem, Israel
| | - Fares Darawshy
- Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Arie Laor
- Breath of Health Ltd, Rehovot, Israel
| | | | - Zvi G Fridlender
- Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem, Israel
- Department of Internal Medicine D, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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29
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de Miranda FS, Claudio LMAM, de Almeida DSM, Nunes JB, Barauna VG, Luiz WB, Vassallo PF, Campos LCG. Cell-Free Nuclear and Mitochondrial DNA as Potential Biomarkers for Assessing Sepsis Severity. Biomedicines 2024; 12:933. [PMID: 38790895 PMCID: PMC11117867 DOI: 10.3390/biomedicines12050933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/26/2024] [Accepted: 04/19/2024] [Indexed: 05/26/2024] Open
Abstract
Sepsis continues to be a significant public health challenge despite advances in understanding its pathophysiology and management strategies. Therefore, this study evaluated the value of cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) for assessing the severity and prognosis of sepsis. Ninety-four patients were divided into three groups: infection (n = 32), sepsis (n = 30), and septic shock (n = 32). Plasma samples were collected at the time of diagnosis, and cfDNA concentrations were determined by qPCR assay. The results showed that plasma cfDNA levels increased with the severity of the disease. To distinguish between patients with infection and those with sepsis, the biomarker L1PA290 achieved the highest AUC of 0.817 (95% CI: 0.725-0.909), demonstrating a sensitivity of 77.0% and a specificity of 79.3%. When cf-nDNA was combined with the SOFA score, there was a significant improvement in the AUC (0.916 (0.853-0.979)), sensitivity (88.1%), and specificity (80.0%). Moreover, patients admitted to the ICU after being diagnosed with sepsis had significantly higher cf-nDNA concentrations. In patients admitted to the ICU, combining cf-nDNA with the SOFA score yielded an AUC of 0.753 (0.622-0.857), with a sensitivity of 95.2% and a specificity of 50.0%. cfDNA can differentiate between patients with infection and those with sepsis. It can also identify patients who are likely to be admitted to the ICU by predicting those with indications for intensive care, suggesting its potential as a biomarker for sepsis.
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Affiliation(s)
- Felipe Silva de Miranda
- Department of Biological Science State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil; (F.S.d.M.); (D.S.M.d.A.); (J.B.N.); (W.B.L.)
- Postgraduate Program in Biology and Biotechnology of Microorganisms State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
- Laboratory of Applied Pathology and Genetics State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
| | - Livia Maria A. M. Claudio
- Post Graduation Program in Physiological Sciences, Federal University of Espírito Santo, Vitória 29075-910, Espírito Santo, Brazil;
| | - Dayanne Silva M. de Almeida
- Department of Biological Science State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil; (F.S.d.M.); (D.S.M.d.A.); (J.B.N.); (W.B.L.)
- Laboratory of Applied Pathology and Genetics State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
| | - Juliana Braga Nunes
- Department of Biological Science State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil; (F.S.d.M.); (D.S.M.d.A.); (J.B.N.); (W.B.L.)
- Laboratory of Applied Pathology and Genetics State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
| | - Valério Garrone Barauna
- Molecular Physiology Laboratory of Exercise Science, Federal University of Espírito Santo, Vitória 29075-910, Espírito Santo, Brazil;
| | - Wilson Barros Luiz
- Department of Biological Science State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil; (F.S.d.M.); (D.S.M.d.A.); (J.B.N.); (W.B.L.)
- Postgraduate Program in Biology and Biotechnology of Microorganisms State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
- Laboratory of Applied Pathology and Genetics State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
| | - Paula Frizzera Vassallo
- Clinical Hospital, Federal University of Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil;
| | - Luciene Cristina Gastalho Campos
- Department of Biological Science State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil; (F.S.d.M.); (D.S.M.d.A.); (J.B.N.); (W.B.L.)
- Postgraduate Program in Biology and Biotechnology of Microorganisms State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
- Laboratory of Applied Pathology and Genetics State, University of Santa Cruz, Ilhéus 45662-900, Bahia, Brazil
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30
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Duda HC, von Toerne C, Korbonits L, Didier A, Scholz AM, Märtlbauer E, Hauck SM, Deeg CA. Cathepsin S Is More Abundant in Serum of Mycobacterium avium subsp. paratuberculosis-Infected Dairy Cows. Metabolites 2024; 14:215. [PMID: 38668343 PMCID: PMC11051907 DOI: 10.3390/metabo14040215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of bovine paratuberculosis, a chronic granulomatous enteritis leading to economic losses and posing a risk to human health due to its zoonotic potential. The pathogen cannot reliably be detected by standard methods, and immunological procedures during the infection are not well understood. Therefore, the aim of our study was to explore host-pathogen interactions in MAP-infected dairy cows and to improve diagnostic tests. Serum proteomics analysis using quantitative label-free LC-MS/MS revealed 60 differentially abundant proteins in MAP-infected dairy cows compared to healthy controls from the same infected herd and 90 differentially abundant proteins in comparison to another control group from an uninfected herd. Pathway enrichment analysis provided new insights into the immune response to MAP and susceptibility to the infection. Furthermore, we found a higher abundance of Cathepsin S (CTSS) in the serum of MAP-infected dairy cows, which is involved in multiple enriched pathways associated with the immune system. Confirmed with Western blotting, we identified CTSS as a potential biomarker for bovine paratuberculosis. This study enabled a better understanding of procedures in the host-pathogen response to MAP and improved detection of paratuberculosis-diseased cattle.
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Affiliation(s)
- Heidi C. Duda
- Chair of Physiology, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, D-82152 Martinsried, Germany
| | - Christine von Toerne
- Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health, D-85763 Neuherberg, Germany (S.M.H.)
| | - Lucia Korbonits
- Chair of Physiology, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, D-82152 Martinsried, Germany
| | - Andrea Didier
- Chair of Hygiene and Technology of Milk, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, D-85764 Oberschleißheim, Germany; (A.D.)
| | - Armin M. Scholz
- Livestock Center of the Faculty of Veterinary Medicine, Ludwig Maximilian University of Munich, D-85764 Oberschleißheim, Germany;
| | - Erwin Märtlbauer
- Chair of Hygiene and Technology of Milk, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, D-85764 Oberschleißheim, Germany; (A.D.)
| | - Stefanie M. Hauck
- Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health, D-85763 Neuherberg, Germany (S.M.H.)
| | - Cornelia A. Deeg
- Chair of Physiology, Department of Veterinary Sciences, Ludwig Maximilian University of Munich, D-82152 Martinsried, Germany
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31
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Persson I, Macura A, Becedas D, Sjövall F. Early prediction of sepsis in intensive care patients using the machine learning algorithm NAVOY® Sepsis, a prospective randomized clinical validation study. J Crit Care 2024; 80:154400. [PMID: 38245375 DOI: 10.1016/j.jcrc.2023.154400] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/09/2023] [Accepted: 08/11/2023] [Indexed: 01/22/2024]
Abstract
PURPOSE To prospectively validate, in an ICU setting, the prognostic accuracy of the sepsis prediction algorithm NAVOY® Sepsis which uses 4 h of input for routinely collected vital parameters, blood gas values, and lab values. MATERIALS AND METHODS Patients 18 years or older admitted to the ICU at Skåne University Hospital Malmö from December 2020 to September 2021 were recruited in the study. A total of 304 patients were randomized into one of two groups: Algorithm group with active sepsis alerts, or Standard of care. NAVOY® Sepsis made silent predictions in the Standard of care group, in order to evaluate its performance without disturbing the outcome. The study was blinded, i.e., study personnel did not know to which group patients were randomized. The healthcare provider followed standard practices in assessing possible development of sepsis and intervening accordingly. The patients were followed-up in the study until ICU discharge. RESULTS NAVOY® Sepsis could predict the development of sepsis, according to the Sepsis-3 criteria, three hours before sepsis onset with high performance: accuracy 0.79; sensitivity 0.80; and specificity 0.78. CONCLUSIONS The accuracy, sensitivity, and specificity were all high, validating the prognostic accuracy of NAVOY® Sepsis in an ICU setting, including Covid-19 patients.
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Affiliation(s)
- Inger Persson
- Department of Statistics, Uppsala University, Uppsala, Sweden, AlgoDx AB, Stockholm, Sweden.
| | | | | | - Fredrik Sjövall
- Department of Intensive- and Perioperative Medicine, Skåne University Hospital, Malmö, Sweden
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32
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Zheng Y, Qin H, Ma X. A novel group decision making method based on CoCoSo and interval-valued Q-rung orthopair fuzzy sets. Sci Rep 2024; 14:6562. [PMID: 38503822 PMCID: PMC10951264 DOI: 10.1038/s41598-024-56922-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/12/2024] [Indexed: 03/21/2024] Open
Abstract
Interval-valued q-rung orthopair fuzzy set (IVq-ROFS) is a powerful tool for dealing with uncertainty. In this paper, we first propose a new method for aggregating multiple IVq-ROFSs, which is easier to understand and implement in the multi-attribute group decision making process compared to current aggregation operators. Secondly, this paper introduces a new fuzzy entropy with parameters based on IVq-ROFS, which is highly flexible due to its adjustable parameters. Based on this, the IVq-ROFS-based attribute weight calculation method is proposed to obtain the objective weights of the attributes, which is more reasonable and objective than the existing methods. Then, for the dimensional differences between the three compromise scores in the original Combined Compromise Solution (CoCoSo) method, the enhanced compromise scores are proposed. These scores are obtained by normalizing the three dependent compromise scores, ensuring that they fall within the same range. Finally, a novel CoCoSo mothed on IVq-ROFS using the proposed fuzzy entropy and enhanced compromise scores is presented. The proposed method is highly adaptable and scalable, not limited to IVq-ROFS. The excellent performance and robustness of the proposed method are verified in sepsis diagnosis applications.
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Affiliation(s)
- Yan Zheng
- College of Computer Science and Engineering, Northwest Normal University, Lanzhou, 730070, Gansu, China
| | - Hongwu Qin
- College of Computer Science and Engineering, Northwest Normal University, Lanzhou, 730070, Gansu, China.
- Institute for Big Data Analytics and Artificial Intelligence (IBDAAI), Universiti Teknologi MARA, 40450, Shah Alam, Selangor, Malaysia.
| | - Xiuqin Ma
- College of Computer Science and Engineering, Northwest Normal University, Lanzhou, 730070, Gansu, China
- Institute for Big Data Analytics and Artificial Intelligence (IBDAAI), Universiti Teknologi MARA, 40450, Shah Alam, Selangor, Malaysia
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Cortellini S, DeClue AE, Giunti M, Goggs R, Hopper K, Menard JM, Rabelo RC, Rozanski EA, Sharp CR, Silverstein DC, Sinnott-Stutzman V, Stanzani G. Defining sepsis in small animals. J Vet Emerg Crit Care (San Antonio) 2024; 34:97-109. [PMID: 38351524 DOI: 10.1111/vec.13359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/22/2023] [Accepted: 01/03/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE To discuss the definitions of sepsis in human and veterinary medicine. DESIGN International, multicenter position statement on the need for consensus definitions of sepsis in veterinary medicine. SETTING Veterinary private practice and university teaching hospitals. ANIMALS Dogs and cats. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Sepsis is a life-threatening condition associated with the body's response to an infection. In human medicine, sepsis has been defined by consensus on 3 occasions, most recently in 2016. In veterinary medicine, there is little uniformity in how sepsis is defined and no consensus on how to identify it clinically. Most publications rely on modified criteria derived from the 1991 and 2001 human consensus definitions. There is a divergence between the human and veterinary descriptions of sepsis and no consensus on how to diagnose the syndrome. This impedes research, hampers the translation of pathophysiology insights to the clinic, and limits our abilities to optimize patient care. It may be time to formally define sepsis in veterinary medicine to help the field move forward. In this narrative review, we present a synopsis of prior attempts to define sepsis in human and veterinary medicine, discuss developments in our understanding, and highlight some criticisms and shortcomings of existing schemes. CONCLUSIONS This review is intended to serve as the foundation of current efforts to establish a consensus definition for sepsis in small animals and ultimately generate evidence-based criteria for its recognition in veterinary clinical practice.
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Affiliation(s)
- Stefano Cortellini
- Department of Clinical Science and Services, The Royal Veterinary College, University of London, Hatfield, UK
| | - Amy E DeClue
- Fetch Specialty and Emergency Veterinary Center, Greenville, South Carolina, USA
| | - Massimo Giunti
- Department of Veterinary Medical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Robert Goggs
- Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York, USA
| | - Kate Hopper
- Department of Veterinary Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California, USA
| | - Julie M Menard
- Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Elizabeth A Rozanski
- Department of Clinical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA
| | - Claire R Sharp
- School of Veterinary Medicine, Murdoch University, Perth, Western Australia, Australia
| | - Deborah C Silverstein
- Department of Clinical Studies and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Barshilia D, Huang JJ, Komaram AC, Chen YC, Chen CD, Syu MY, Chao WC, Chau LK, Chang GE. Ultrasensitive and Rapid Detection of Procalcitonin via Waveguide-Enhanced Nanogold-Linked Immunosorbent Assay for Early Sepsis Diagnosis. NANO LETTERS 2024; 24:2596-2602. [PMID: 38251930 PMCID: PMC10906069 DOI: 10.1021/acs.nanolett.3c04762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
Sepsis, a life-threatening inflammatory response, demands economical, accurate, and rapid detection of biomarkers during the critical "golden hour" to reduce the patient mortality rate. Here, we demonstrate a cost-effective waveguide-enhanced nanogold-linked immunosorbent assay (WENLISA) based on nanoplasmonic waveguide biosensors for the rapid and sensitive detection of procalcitonin (PCT), a sepsis-related inflammatory biomarker. To enhance the limit of detection (LOD), we employed sandwich assays using immobilized capture antibodies and detection antibodies conjugated to gold nanoparticles to bind the target analyte, leading to a significant evanescent wave redistribution and strong nanoplasmonic absorption near the waveguide surface. Experimentally, we detected PCT for a wide linear response range of 0.1 pg/mL to 1 ng/mL with a record-low LOD of 48.7 fg/mL (3.74 fM) in 8 min. Furthermore, WENLISA has successfully identified PCT levels in the blood plasma of patients with sepsis and healthy individuals, offering a promising technology for early sepsis diagnosis.
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Affiliation(s)
- Devesh Barshilia
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan
- Advanced Institute of Manufacturing with High-Tech Innovations (AIM-HI), National Chung Cheng University, Chiayi 621301, Taiwan
| | - Jhen-Jie Huang
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
| | | | - Yi-Che Chen
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
| | - Chun-Da Chen
- Department of Laboratory Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin 640, Taiwan
| | - Min-Yu Syu
- Department of Laboratory Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin 640, Taiwan
| | - Wen-Cheng Chao
- Department of Critical Care Medicine, Taichung Veterans General Hospital, Taichung 402202, Taiwan
| | - Lai-Kwan Chau
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
- Center for Nano Bio-Detection, National Chung Cheng University, Chiayi 621301, Taiwan
| | - Guo-En Chang
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan
- Advanced Institute of Manufacturing with High-Tech Innovations (AIM-HI), National Chung Cheng University, Chiayi 621301, Taiwan
- Center for Nano Bio-Detection, National Chung Cheng University, Chiayi 621301, Taiwan
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35
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Lehnert T, Gijs MAM. Microfluidic systems for infectious disease diagnostics. LAB ON A CHIP 2024; 24:1441-1493. [PMID: 38372324 DOI: 10.1039/d4lc00117f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Microorganisms, encompassing both uni- and multicellular entities, exhibit remarkable diversity as omnipresent life forms in nature. They play a pivotal role by supplying essential components for sustaining biological processes across diverse ecosystems, including higher host organisms. The complex interactions within the human gut microbiota are crucial for metabolic functions, immune responses, and biochemical signalling, particularly through the gut-brain axis. Viruses also play important roles in biological processes, for example by increasing genetic diversity through horizontal gene transfer when replicating inside living cells. On the other hand, infection of the human body by microbiological agents may lead to severe physiological disorders and diseases. Infectious diseases pose a significant burden on global healthcare systems, characterized by substantial variations in the epidemiological landscape. Fast spreading antibiotic resistance or uncontrolled outbreaks of communicable diseases are major challenges at present. Furthermore, delivering field-proven point-of-care diagnostic tools to the most severely affected populations in low-resource settings is particularly important and challenging. New paradigms and technological approaches enabling rapid and informed disease management need to be implemented. In this respect, infectious disease diagnostics taking advantage of microfluidic systems combined with integrated biosensor-based pathogen detection offers a host of innovative and promising solutions. In this review, we aim to outline recent activities and progress in the development of microfluidic diagnostic tools. Our literature research mainly covers the last 5 years. We will follow a classification scheme based on the human body systems primarily involved at the clinical level or on specific pathogen transmission modes. Important diseases, such as tuberculosis and malaria, will be addressed more extensively.
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Affiliation(s)
- Thomas Lehnert
- Laboratory of Microsystems, École Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland.
| | - Martin A M Gijs
- Laboratory of Microsystems, École Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland.
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Shimoyama Y, Kadono N, Umegaki O. Presepsin is a more useful predictor of septic AKI and ARDS for very-old sepsis patients than for young sepsis patients in ICUs: a pilot study. BMC Res Notes 2024; 17:53. [PMID: 38378647 PMCID: PMC10877906 DOI: 10.1186/s13104-024-06719-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 02/14/2024] [Indexed: 02/22/2024] Open
Abstract
OBJECTIVE Sepsis is a syndrome of life-threatening organ dysfunction. This study aimed to determine whether presepsin is a useful predictor of septic acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and shock in very-old sepsis patients aged 75 years in intensive care units (ICUs). RESULTS A total of 83 adult patients diagnosed with sepsis were prospectively examined and divided into two groups: those aged 75 years and older (over 75 group) and those aged younger than 75 years (under 75 group). Presepsin values were measured after ICU admission. Inflammation-based prognostic scores were also examined. For category classification, total scores ("inflammation-presepsin scores [iPS]") were calculated. Presepsin values, inflammation-based prognostic scores, and iPS were compared between patients with septic AKI, ARDS, DIC, or shock and those without these disorders in the over 75 and under 75 groups. Areas under the curve of presepsin for predicting septic AKI and ARDS in the over 75 group were both > 0.7, which were significantly higher than those in the under 75 group. In conclusion, presepsin is a more useful predictor of septic AKI and ARDS for very-old sepsis patients (over 75 years) than for younger sepsis patients (under 75 years).
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Affiliation(s)
- Yuichiro Shimoyama
- Department of Anesthesiology, Intensive Care Unit, Osaka Medical and Pharmaceutical University, Osaka Medical and Pharmaceutical University Hospital, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
| | - Noriko Kadono
- Department of Anesthesiology, Intensive Care Unit, Osaka Medical and Pharmaceutical University, Osaka Medical and Pharmaceutical University Hospital, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
| | - Osamu Umegaki
- Department of Anesthesiology, Intensive Care Unit, Osaka Medical and Pharmaceutical University, Osaka Medical and Pharmaceutical University Hospital, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan
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Sun Z, Zhao Q, Zhang J, Hu Y, Qu J, Gao H, Peng Z. Bioinformatics reveals diagnostic potential of cuproptosis-related genes in the pathogenesis of sepsis. Heliyon 2024; 10:e22664. [PMID: 38163157 PMCID: PMC10754710 DOI: 10.1016/j.heliyon.2023.e22664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 01/03/2024] Open
Abstract
Background Multiple modes of cell death occur during the development of sepsis. Among these patterns, cuproptosis has recently been identified as a regulated form of cell death. However, its impact on the onset and progression of sepsis remains unclear. Method We screened a dataset of gene expression profiles from patients with sepsis using the GEO database. Survival analysis was performed to analyze the relationship between cuproptosis-related genes (CRGs) and prognosis. Hub genes were identified through univariate Cox regression analysis. The diagnostic value of hub genes in sepsis was tested in both training sets (GSE65682) and validation sets (GSE134347). To examine the association between hub genes and immune cells, single-sample gene set enrichment analysis (ssGSEA) and Pearson correlation analysis were employed. Additionally, the CRGs were validated in a septic mouse model using real-time quantitative PCR (qRT-PCR) and immunohistochemistry (IHC). Results In sepsis, most CRGs were upregulated, with only DLD and MTF1 downregulated. High expression of three genes (GLE, LIAS, and PDHB) was associated with better prognosis, but only two hub genes (LIAS, PDHB) reached statistical significance. The receiver operating characteristic (ROC) analysis for diagnosing sepsis showed LIAS had a range of 0.793-0.906, while PDHB achieved values of 0.882 and 0.975 in the training and validation sets, respectively. ssGSEA analysis revealed a lower number of immune cells in the sepsis group, and there was a correlation between immune cell population and CRGs (LIAS, PDHB). Analysis in the septic mouse model demonstrated no significant difference in mRNA expression levels and IHC staining between LIAS and PDHB in heart and liver tissues, but up-regulation was observed in lung tissues. Furthermore, the mRNA expression levels and IHC staining of LIAS and PDHB were down-regulated in renal tissues. Conclusions Cuproptosis is emerging as a significant factor in the development of sepsis. LIAS and PDHB, identified as potential diagnostic biomarkers for cuproptosis-associated sepsis, are believed to play crucial roles in the initiation and progression of cuproptosis-induced sepsis.
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Affiliation(s)
- Zhongyi Sun
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
| | - Qiuyue Zhao
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
| | - Jiahao Zhang
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
| | - Yanan Hu
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
| | - Jiachen Qu
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
| | - Han Gao
- Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
| | - Zhiyong Peng
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, 430071, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, Hubei, China
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Li N, Ren P, Wang J, Zhu X, Qiao X, Zeng Z, Ye T, Wang S, Meng Z, Gan H, Liu S, Sun Y, Zhu X, Dou G, Gu R. Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis. Int J Mol Sci 2024; 25:749. [PMID: 38255822 PMCID: PMC10815248 DOI: 10.3390/ijms25020749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/23/2023] [Accepted: 12/31/2023] [Indexed: 01/24/2024] Open
Abstract
Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein-protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1β and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.
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Affiliation(s)
- Nanxi Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Peng Ren
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Jingya Wang
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Xiaohui Zhu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Xuan Qiao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zhirui Zeng
- Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550000, China
| | - Tong Ye
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Shanshan Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Zhiyun Meng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Hui Gan
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Shuchen Liu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yunbo Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Xiaoxia Zhu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Guifang Dou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Ruolan Gu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
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Hemmann P, Kloppenburg L, Breinbauer R, Ehnert S, Blumenstock G, Reumann MK, Erne F, Jazewitsch J, Schwarz T, Baumgartner H, Histing T, Rollmann M, Nüssler AK. AZU1: a new promising marker for infection in orthopedic and trauma patients? EXCLI JOURNAL 2024; 23:53-61. [PMID: 38357095 PMCID: PMC10864703 DOI: 10.17179/excli2023-6705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/06/2023] [Indexed: 02/16/2024]
Abstract
Early and reliable detection of infection is vital for successful treatment. Serum markers such as C-reactive protein (CRP) and procalcitonin (PCT) are known to increase with a time lag. Azurocidin 1 (AZU1) has emerged as a promising marker for septic patients, but its diagnostic value in orthopedic and trauma patients remains unexplored. Between July 2020 and August 2023, all patients necessitating inpatient treatment for periprosthetic joint infection (PJI), peri-implant infection (II), soft tissue infection, chronic osteomyelitis, septic arthrodesis, bone non-union with and without infection were enrolled. Patients undergoing elective total joint arthroplasty (TJA) served as the control group. Blood samples were collected and analyzed for CRP, white blood cell count (WBC), PCT, and AZU1. Based on the inclusion and exclusion criteria 222 patients were included in the study (trauma = 38, soft tissue infection = 75, TJA = 33, PJI/II = 39, others = 37). While sensitivity and specificity were comparably high for AZU1 (0.734/0.833), CRP and PCT had higher specificity (0.542/1 and 0.431/1, respectively), and WBC a slightly higher sensitivity (0.814/0.455) for septic conditions. Taken together, the area under the curve (AUC) showed the highest accuracy for AZU1 (0.790), followed by CRP (0.776), WBC (0.641), and PCT (0.656). The Youden-Index was 0.57 for AZU1, 0.54 for CRP, 0.27 for WBC, and 0.43 for PCT. Elevated AZU1 levels effectively distinguished patients with a healthy condition from those suffering from infection. However, there is evidence suggesting that trauma may influence the release of AZU1. Additional research is needed to validate the diagnostic value of this new biomarker and further explore its potential clinical applications.
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Affiliation(s)
- Philipp Hemmann
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
| | - Lisa Kloppenburg
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Regina Breinbauer
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Sabrina Ehnert
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology and Applied Biometry, University of Tuebingen, Tuebingen, Germany
| | - Marie K. Reumann
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Felix Erne
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Johann Jazewitsch
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Tobias Schwarz
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
| | - Heiko Baumgartner
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
| | - Tina Histing
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
| | - Mika Rollmann
- Department of Traumatology and Reconstructive Surgery, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, Schnarrenbergstr. 95, 72076 Tuebingen, Germany
| | - Andreas K. Nüssler
- Siegfried Weller Institute for Trauma Research, BG Unfallklinik Tuebingen, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany
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Zhu Y, Cai W, Zheng Y, Zhang W, Wang B, Kang Y. BIOINFORMATICS APPLICATIONS UNDER CONDITION CONTROL: HIGH DIAGNOSTIC VALUE OF DDX47 IN REAL MEDICAL SETTINGS. Shock 2024; 61:97-104. [PMID: 37553903 DOI: 10.1097/shk.0000000000002199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
ABSTRACT Sepsis is an organ dysfunction caused by a dysregulated host response to infection and remains an ongoing threat to human health worldwide. Septic shock is the most severe subset of sepsis as characterized by abnormalities in cells, circulation, and metabolism. As a time-dependent condition, early recognition allowing appropriate therapeutic measures to be started in a timely manner becomes the most effective way to improve prognosis. However, because of the lack of a criterion standard, most diagnoses merely rely on medical history, empirical diagnosis, and blood culture results. Gene expression profiles have specific diagnostic value, as they reflect a subjective host response to pathogens. We propose a method, Condition Control based on Real-life Medical Scenarios, to control for factors in realistic medical scenarios. Restricted variables are used as much as possible to identify unique differential genes and progressively test their diagnostic value by relaxing restrictions. In total, three data sets were included in the study; the first two data sets were from the Gene Expression Omnibus database, and the third involved patients who were diagnosed with sepsis or septic shock within 7 days of admission to the intensive care unit at West China Hospital of Sichuan University from 2020 to 2021. DDX47 showed preferable diagnostic value in various scenarios, especially in patients with common infections or sepsis and septic shock. Here we also show that hub genes may regulate immune function and immune cell counts through the interaction of different apoptotic pathways and immune checkpoints based on the high correlation. DDX47 is closely associated with B cells according to single-cell sequencing results.
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Affiliation(s)
- Yukun Zhu
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Wei Cai
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ying Zheng
- Abdominal Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Bo Wang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
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Zhao JO, Patel BK, Krishack P, Stutz MR, Pearson SD, Lin J, Lecompte-Osorio PA, Dugan KC, Kim S, Gras N, Pohlman A, Kress JP, Hall JB, Sperling AI, Adegunsoye A, Verhoef PA, Wolfe KS. Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock. Crit Care Med 2023; 51:e253-e263. [PMID: 37678209 PMCID: PMC10840934 DOI: 10.1097/ccm.0000000000006032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
OBJECTIVES To identify cytokine signature clusters in patients with septic shock. DESIGN Prospective observational cohort study. SETTING Single academic center in the United States. PATIENTS Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.
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Affiliation(s)
- Jack O Zhao
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Bhakti K Patel
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Paulette Krishack
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Matthew R Stutz
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Steven D Pearson
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Julie Lin
- Pulmonary Medicine, MD Anderson Cancer Center, The University of Texas, Houston, TX
| | | | | | - Seoyoen Kim
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Nicole Gras
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Anne Pohlman
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - John P Kress
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Jesse B Hall
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Anne I Sperling
- Pulmonary & Critical Care, University of Virginia, Charlottesville, VA
| | - Ayodeji Adegunsoye
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
| | - Philip A Verhoef
- Critical Care Medicine, Hawaii Permanente Medical Group, Honolulu, HI
| | - Krysta S Wolfe
- Pulmonary and Critical Care, University of Chicago Medical Center, Chicago, IL
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Brunialti MKC, Leite GGF, Eburneo GS, de Araujo OR, Peçanha-Pietrobom PM, Ferreira PRA, Bellei NCJ, Arakaki JSO, Medina-Pestana J, Requião-Moura L, Salomao R. Patterns of Circulating Cytokines and Vascular Markers' Response in the Presence of COVID-19 in Kidney Transplant Recipients Compared with Non-Transplanted Patients. Viruses 2023; 15:2166. [PMID: 38005844 PMCID: PMC10675241 DOI: 10.3390/v15112166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
COVID-19's severity has been associated with a possible imbalance in the cross-regulation of cytokines and vascular mediators. Since the beginning of the pandemic, kidney transplant recipients (KTRs) have been identified as patients of high vulnerability to more severe diseases. Thus, aiming to describe the patterns of cytokines and vascular mediators and to trace patients' differences according to their KTR status, this prospective study enrolled 67 COVID-19 patients (20 KTRs) and 29 non-COVID-19 controls before vaccination. A panel comprising 17 circulating cytokines and vascular mediators was run on samples collected at different time points. The cytokine and mediator patterns were investigated via principal component analysis (PCA) and correlation-based network (CBN). In both groups, compared to their respective controls, COVID-19 was associated with higher levels of cytokines and vascular mediators. Differentiating between the KTRs and non-KTRs, the number of correlations was much higher in the non-KTRs (44 vs. 14), and the node analysis showed the highest interactions of NGAL and sVCAM-1 in the non-KTRs and KTRs (9 vs. 4), respectively. In the PCA, while the non-KTRs with COVID-19 were differentiated from their controls in their IL-10, IFN-α, and TNF-α, this pattern was marked in the NGAL, sVCAM-1, and IL-8 of the KTRs.
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Affiliation(s)
- Milena Karina Coló Brunialti
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Giuseppe G. F. Leite
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Gabriela Strafolino Eburneo
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Orlei Ribeiro de Araujo
- Intensive Care Unit, GRAACC, Pediatric Institute of Oncology, Universidade Federal de São Paulo, São Paulo 04039-001, Brazil;
| | - Paula M. Peçanha-Pietrobom
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Paulo Roberto Abrão Ferreira
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Nancy C. Junqueira Bellei
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
| | - Jaquelina Sonoe Ota Arakaki
- Division of Respiratory Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04020-050, Brazil;
| | - José Medina-Pestana
- Division of Nephrology, Universidade Federal de São Paulo, São Paulo 04038-031, Brazil;
- Hospital do Rim, Fundação Oswalado Ramos, São Paulo 04038-002, Brazil
| | - Lúcio Requião-Moura
- Division of Nephrology, Universidade Federal de São Paulo, São Paulo 04038-031, Brazil;
- Hospital do Rim, Fundação Oswalado Ramos, São Paulo 04038-002, Brazil
| | - Reinaldo Salomao
- Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil; (M.K.C.B.); (G.G.F.L.); (G.S.E.); (P.M.P.-P.); (P.R.A.F.); (N.C.J.B.)
- Hospital São Paulo, São Paulo 04024-002, Brazil
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Buys W, Bick A, Madel RJ, Westendorf AM, Buer J, Herbstreit F, Kirschning CJ, Peters J. Substantial heterogeneity of inflammatory cytokine production and its inhibition by a triple cocktail of toll-like receptor blockers in early sepsis. Front Immunol 2023; 14:1277033. [PMID: 37869001 PMCID: PMC10588698 DOI: 10.3389/fimmu.2023.1277033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/20/2023] [Indexed: 10/24/2023] Open
Abstract
Introduction Early sepsis is a life-threatening immune dysregulation believed to feature a "cytokine storm" due to activation of pattern recognition receptors by pathogen and danger associated molecular patterns. However, treatments with single toll-like receptor (TLR) blockers have shown no clinical benefit. We speculated that sepsis patients at the time of diagnosis are heterogeneous in relation to their cytokine production and its potential inhibition by a triple cocktail of TLR blockers. Accordingly, we analyzed inflammatory cytokine production in whole blood assays from early sepsis patients and determined the effects of triple TLR-blockade. Methods Whole blood of 51 intensive care patients sampled within 24h of meeting Sepsis-3 criteria was incubated for 6h without or with specific TLR2, 4, and 7/8 stimuli or suspensions of heat-killed S. aureus or E. coli bacteria as pan-TLR challenges, and also with a combination of monoclonal antibodies against TLR2 and 4 and chloroquine (endosomal TLR inhibition), subsequent to dose optimization. Concentrations of tumor necrosis factor (TNF), Interleukin(IL)-6, IL-8, IL-10, IL-1α and IL-1β were measured (multiplex ELISA) before and after incubation. Samples from 11 sex and age-matched healthy volunteers served as controls and for dose-finding studies. Results Only a fraction of sepsis patient samples revealed ongoing cytokine production ex vivo despite sampling within 24 h of first meeting Sepsis-3 criteria. In dose finding studies, inhibition of TLR2, 4 and endosomal TLRs reliably suppressed cytokine production to specific TLR agonists and added bacteria. However, inflammatory cytokine production ex vivo was only suppressed in the high cytokine producing samples but not in the majority. The suppressive response to TLR-blockade correlated both with intraassay inflammatory cytokine production (r=0.29-0.68; p<0.0001-0.04) and cytokine baseline concentrations (r=0.55; p<0.0001). Discussion Upon meeting Sepsis-3 criteria for less than 24 h, a mere quarter of patient samples exhibits a strong inflammatory phenotype, as characterized by increased baseline inflammatory cytokine concentrations and a stark TLR-dependent increase upon further ex vivo incubation. Thus, early sepsis patient cohorts as defined by Sepsis-3 criteria are very heterogeneous in regard to inflammation. Accordingly, proper ex vivo assays may be useful in septic individuals before embarking on immunomodulatory treatments.
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Affiliation(s)
| | - Alexandra Bick
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
| | | | - Astrid M. Westendorf
- Institut für Medizinische Mikrobiologie, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
| | - Jan Buer
- Institut für Medizinische Mikrobiologie, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
| | - Frank Herbstreit
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
| | - Carsten J. Kirschning
- Institut für Medizinische Mikrobiologie, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
| | - Jürgen Peters
- Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg Essen & Universitätsklinikum Essen, Essen, Germany
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Lim SH, Kim MJ, Choi WH, Cheong JC, Kim JW, Lee KJ, Park JH. Explainable machine learning using perioperative serial laboratory results to predict postoperative mortality in patients with peritonitis-induced sepsis. Ann Surg Treat Res 2023; 105:237-244. [PMID: 37908377 PMCID: PMC10613826 DOI: 10.4174/astr.2023.105.4.237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 08/07/2023] [Accepted: 08/28/2023] [Indexed: 11/02/2023] Open
Abstract
Purpose Sepsis is one of the most common causes of death after surgery. Several conventional scoring systems have been developed to predict the outcome of sepsis; however, their predictive power is insufficient. The present study applies explainable machine-learning algorithms to improve the accuracy of predicting postoperative mortality in patients with sepsis caused by peritonitis. Methods We performed a retrospective analysis of data from demographic, clinical, and laboratory analyses, including the delta neutrophil index (DNI), WBC and neutrophil counts, and CRP level. Laboratory data were measured before surgery, 12-36 hours after surgery, and 60-84 hours after surgery. The primary study output was the probability of mortality. The areas under the receiver operating characteristic curves (AUCs) of several machine-learning algorithms using the Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) 3 models were compared. 'SHapley Additive exPlanations' values were used to indicate the direction of the relationship between a variable and mortality. Results The CatBoost model yielded the highest AUC (0.933) for mortality compared to SAPS3 and SOFA (0.860 and 0.867, respectively). Increased DNI on day 3, septic shock, use of norepinephrine therapy, and increased international normalized ratio on day 3 had the greatest impact on the model's prediction of mortality. Conclusion Machine-learning algorithms increase the accuracy of predicting postoperative mortality in patients with sepsis caused by peritonitis.
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Affiliation(s)
- Seung Hee Lim
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Min Jeong Kim
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Won Hyuk Choi
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jin Cheol Cheong
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Jong Wan Kim
- Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Kyung Joo Lee
- Department of Medical Informatics & Statistics, Kangdong Sacred Heart Hospital, Seoul, Korea
| | - Jun Ho Park
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
- Department of Medical Informatics & Statistics, Kangdong Sacred Heart Hospital, Seoul, Korea
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45
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Murakami Y, Tsukano K, Hirata H, Suzuki K. Evaluation of blood serum iron concentration as an alternative biomarker for inflammation in dairy cows. Biol Trace Elem Res 2023; 201:4710-4717. [PMID: 36622523 DOI: 10.1007/s12011-022-03544-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/22/2022] [Indexed: 01/10/2023]
Abstract
This study aimed to clarify the relationship between acute phase protein (APP) concentrations and serum Fe concentrations to determine whether serum iron (Fe) can be clinically applied as a substitute for APPs in cows. One hundred five Holstein-Friesian breed lactating dairy cows were enrolled in this study. Cows with inflammatory diseases were 16 subclinical, and 15 severe mastitis cows, in addition to 15 mild and 16 severe sole ulcer cows. The plasma haptoglobin (HPT), alpha-1 acid glycoprotein (AGP), SAA, serum Fe levels, and other biochemical parameters in the cows were measured. The two-sample t-tests and multiple logistic regression analysis were used to compare the control and inflammatory disease groups. ROC analysis was used to evaluate the ability to diagnose inflammation disease. From the results, the proposed diagnostic cutoff value for plasma SAA and serum Fe concentrations to identify dairy cows with inflammatory diseases based on analyses of ROC curves were set at > 3.65 mg/l and < 120.50 µg/dl, respectively. Therefore, instead of using expensive inflammatory markers to evaluate the inflammatory state at the first treatment day for inflammatory diseases in cow, it shows the useful for screening with serum Fe concentration that can be measured easily and inexpensively as alternative inflammatory biomarkers.
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Affiliation(s)
- Yoshiki Murakami
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido, 069-8501, Japan
| | - Kenji Tsukano
- Hokkaido Agricultual Mutual Releef Association, 74-2 Higashimae, Hokuto, Hokkaido, 041-1214, Japan
| | - Haruyuki Hirata
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido, 069-8501, Japan
| | - Kazuyuki Suzuki
- School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido, 069-8501, Japan.
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46
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Cheng J, Zeng H, Chen H, Fan L, Xu C, Huang H, Tang T, Li M. Current knowledge of thrombocytopenia in sepsis and COVID-19. Front Immunol 2023; 14:1213510. [PMID: 37841241 PMCID: PMC10568455 DOI: 10.3389/fimmu.2023.1213510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/12/2023] [Indexed: 10/17/2023] Open
Abstract
Thrombocytopenia, characterized by a decrease in platelet count, is commonly observed in sepsis and COVID-19. In sepsis, thrombocytopenia can result from various mechanisms, including impaired platelet production in the bone marrow, accelerated platelet destruction due to increased inflammation, sequestration of platelets in the spleen, immune-mediated platelet destruction, or dysregulated host responses. Similarly, thrombocytopenia has been reported in COVID-19 patients, but the immune-related mechanisms underlying this association remain unclear. Notably, interventions targeting thrombocytopenia have shown potential for improving outcomes in both sepsis and COVID-19 patients. Understanding these mechanisms is crucial for developing effective treatments.
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Affiliation(s)
- Junjie Cheng
- Intensive Care Unit, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Hanhai Zeng
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huaijun Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Linfeng Fan
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chaoran Xu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huaping Huang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tianchi Tang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Min Li
- Intensive Care Unit, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
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47
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An AY, Baghela A, Zhang P, Falsafi R, Lee AH, Trahtemberg U, Baker AJ, dos Santos CC, Hancock REW. Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis. Front Immunol 2023; 14:1254873. [PMID: 37822940 PMCID: PMC10562687 DOI: 10.3389/fimmu.2023.1254873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/04/2023] [Indexed: 10/13/2023] Open
Abstract
Introduction Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features, suggesting that severe COVID-19 is a form of viral sepsis. Our objective was to identify shared gene expression trajectories strongly associated with eventual mortality between severe COVID-19 patients and contemporaneous non-COVID-19 sepsis patients in the intensive care unit (ICU) for potential therapeutic implications. Methods Whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Using systems biology methods, drug candidates targeting key genes in the pathophysiology of COVID-19 and sepsis were identified. Results When compared to survivors, non-survivors (irrespective of COVID-19 status) had 3.6-fold more "persistent" genes (genes that stayed up/downregulated at both timepoints) (4,289 vs. 1,186 genes); these included persistently downregulated genes in T-cell signaling and persistently upregulated genes in select innate immune and metabolic pathways, indicating unresolved immune dysfunction in non-survivors, while resolution of these processes occurred in survivors. These findings of persistence were further confirmed using two publicly available datasets of COVID-19 and sepsis patients. Systems biology methods identified multiple immunomodulatory drug candidates that could target this persistent immune dysfunction, which could be repurposed for possible therapeutic use in both COVID-19 and sepsis. Discussion Transcriptional evidence of persistent immune dysfunction was associated with 28-day mortality in both COVID-19 and non-COVID-19 septic patients. These findings highlight the opportunity for mitigating common mechanisms of immune dysfunction with immunomodulatory therapies for both diseases.
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Affiliation(s)
- Andy Y. An
- Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Arjun Baghela
- Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Peter Zhang
- Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Reza Falsafi
- Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
| | - Amy H. Lee
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Uriel Trahtemberg
- Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
- Department of Critical Care, Galilee Medical Center, Nahariya, Israel
| | - Andrew J. Baker
- Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
| | - Claudia C. dos Santos
- Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
| | - Robert E. W. Hancock
- Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada
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Tuerxun K, Eklund D, Wallgren U, Dannenberg K, Repsilber D, Kruse R, Särndahl E, Kurland L. Predicting sepsis using a combination of clinical information and molecular immune markers sampled in the ambulance. Sci Rep 2023; 13:14917. [PMID: 37691028 PMCID: PMC10493220 DOI: 10.1038/s41598-023-42081-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/05/2023] [Indexed: 09/12/2023] Open
Abstract
Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-classified in our prediction models, due to milder symptoms as well as lower expression levels of the investigated immune mediators. This indicates a need of stratifying septic patients with a priori knowledge of certain clinical and molecular parameters in order to improve prediction for early sepsis diagnosis.Trial registration: NCT03249597. Registered 15 August 2017.
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Affiliation(s)
- Kedeye Tuerxun
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
- Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
| | - Daniel Eklund
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | | | - Katharina Dannenberg
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Dirk Repsilber
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Robert Kruse
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Eva Särndahl
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Lisa Kurland
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre, (iRiSC), Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Emergency Medicine, Örebro University Hospital, Örebro, Sweden
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49
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August BA, Kale-Pradhan PB, Giuliano C, Johnson LB. Biomarkers in the intensive care setting: A focus on using procalcitonin and C-reactive protein to optimize antimicrobial duration of therapy. Pharmacotherapy 2023; 43:935-949. [PMID: 37300522 DOI: 10.1002/phar.2834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/11/2023] [Accepted: 04/19/2023] [Indexed: 06/12/2023]
Abstract
Managing the critically ill patient with infection is complex, requiring clinicians to synthesize considerable information relating to antimicrobial efficacy and treatment duration. The use of biomarkers may play an important role in identifying variation in treatment response and providing information about treatment efficacy. Though a vast number of biomarkers for clinical application have been described, procalcitonin and C-reactive protein (CRP) are the most thoroughly investigated in the critically ill. However, the presence of heterogeneous populations, variable end points, and incongruent methodology in the literature complicates the use of such biomarkers to guide antimicrobial therapy. This review focuses on an appraisal of evidence for use of procalcitonin and CRP to optimize antimicrobial duration of therapy (DOT) in critically ill patients. Procalcitonin-guided antimicrobial therapy in mixed critically ill populations with varying degrees of sepsis appears to be safe and might assist in reducing antimicrobial DOT. Compared to procalcitonin, fewer studies exist examining the impact of CRP on antimicrobial DOT and clinical outcomes in the critically ill. Procalcitonin and CRP have been insufficiently studied in many key intensive care unit populations, including surgical patients with concomitant trauma, renally insufficient populations, the immunocompromised, and patients with septic shock. We believe the available evidence is not strong enough to warrant routine use of procalcitonin or CRP to guide antimicrobial DOT in critically ill patients with infection. So long as its limitations are recognized, procalcitonin could be considered to tailor antimicrobial DOT on a case-by-case basis in the critically ill patient.
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Affiliation(s)
- Benjamin A August
- Critical Care, Henry Ford Hospital, Detroit, Michigan, USA
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Science, Wayne State University, Detroit, Michigan, USA
| | - Pramodini B Kale-Pradhan
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Science, Wayne State University, Detroit, Michigan, USA
- Ascension St. John Hospital, Detroit, Michigan, USA
| | - Christopher Giuliano
- Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Science, Wayne State University, Detroit, Michigan, USA
- Ascension St. John Hospital, Detroit, Michigan, USA
| | - Leonard B Johnson
- Division of Infectious Diseases, Department of Internal Medicine, Infection Prevention and Antimicrobial Stewardship, Ascension St. John Hospital, Detroit, Michigan, USA
- Wayne State University School of Medicine, Detroit, Michigan, USA
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50
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Zhang C, Zhang X, Sun Z, Liu X, Shen B. MetaSepsisBase: a biomarker database for systems biological analysis and personalized diagnosis of heterogeneous human sepsis. Intensive Care Med 2023; 49:1015-1017. [PMID: 37329364 DOI: 10.1007/s00134-023-07126-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/01/2023] [Indexed: 06/19/2023]
Affiliation(s)
- Chi Zhang
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xueli Zhang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhandong Sun
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xingyun Liu
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bairong Shen
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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