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Biomedicines
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Sepsis: Pathophysiology and Early Diagnostics
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Sepsis: Pathophysiology and Early Diagnostics

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 8422

Special Issue Editor

Dr. Alexandros Rovas

E-Mail Website
Guest Editor
Department of Medicine, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
Interests: endothelium; microcirculation; glycocalyx; endothelial dysfunction; intravital microscopy; sepsis

Special Issue Information

Dear Colleagues,

Sepsis, a life-threatening condition triggered by an overwhelming immune response to infection, remains the leading cause of death in hospitalized patients and continues to present a significant global health challenge. Recent advancements have shed light on novel pathophysiological pathways, emphasizing the importance of endotheliopathy and microvascular dysfunction. Furthermore, sepsis and non-infection-induced systemic inflammatory response syndrome have similar clinical symptoms but differ in treatment and prognosis, and the high mortality rate makes early diagnosis especially important. However, there are currently no definitive biomarkers to accurately predict sepsis development or outcome.

The current focus remains on gaining insight into underlying disease mechanisms and providing new diagnostics for early detection of patients with sepsis. In light of these advancements, we are pleased to announce a Special Issue of Biomedicines, inviting authors to submit their original research, communications, and review articles. We encourage contributions on a wide range of topics, including, but not limited to:

  • Immune response dysregulation in sepsis: unraveling the mechanisms;
  • Novel pathophysiological pathways: bridging the gap between bench and bedside;
  • Sepsis biomarkers: advancements and clinical applications;
  • Antibiotic stewardship;
  • Endothelium, endothelial glycocalyx, and microcirculatory dysregulation in sepsis;
  • Distinct subtypes of sepsis: implications for personalized treatment;
  • Clinical trials in sepsis: paving the way for evidence-based interventions.

Dr. Alexandros Rovas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biomarkers
  • infection
  • organ dysfunction
  • endothelial dysfunction
  • organ dysfunction
  • glycocalyx
  • cytokine storm
  • dysregulated immune response

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Published Papers (9 papers)

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Research

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11 pages, 2304 KiB  
Article
Presepsin Does Not Predict Risk of Death in Sepsis Patients Admitted to the Intensive Care Unit: A Prospective Single-Center Study
by Michał P. Pluta, Piotr F. Czempik, Magdalena Kwiatkowska, Katarzyna Marczyk-Bełbot, Sebastian Maślanka, Jolanta Mika and Łukasz J. Krzych
Biomedicines 2024, 12(10), 2313; https://doi.org/10.3390/biomedicines12102313 - 11 Oct 2024
Viewed by 546
Abstract
Background: Sepsis is defined as life-threatening organ dysfunction caused by an abnormal host response to infection. The study aimed to evaluate the utility of presepsin (P-SEP) in predicting the risk of death in patients with sepsis at the time of intensive care [...] Read more.
Background: Sepsis is defined as life-threatening organ dysfunction caused by an abnormal host response to infection. The study aimed to evaluate the utility of presepsin (P-SEP) in predicting the risk of death in patients with sepsis at the time of intensive care unit (ICU) admission. Methods: Adult patients were included in the study if they met SEPSIS-3 criteria at ICU admission. Demographic and clinical data were collected. The following inflammatory parameters were determined: C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and presepsin (P-SEP). Material was collected for microbiological testing depending on the suspected source of infection. The primary endpoint was patient death before ICU discharge. The secondary endpoint was a positive microbiological test result. Results: Eighty-six patients were included in the study. Thirty patients (35%) died before discharge from the ICU. There was no difference in P-SEP, CRP, PCT, and IL-6 values between patients who survived and those who died (p > 0.05 for all). P-SEP, CRP, PCT, and IL-6 were determined at ICU admission and did not accurately predict the risk of death in ROC curve analysis (p > 0.05 for all). Confirmation of the location of the focus of bacterial infection by microbiological testing was obtained in 43 (49%) patients. P-SEP, PCT, CRP, and IL-6 were significantly higher in patients with positive microbiological findings. Conclusions: In patients with suspected sepsis admitted to the Intensive Care Unit, presepsin does not accurately predict the risk of in-hospital death, but it can predict a positive microbiological culture. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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13 pages, 1649 KiB  
Article
MPO-DNA Complexes and cf-DNA in Patients with Sepsis and Their Clinical Value
by Danmei Zhang, Jin Guo, Chunxia Shi, Yukun Wang, Yanqiong Zhang, Xiaoya Zhang and Zuojiong Gong
Biomedicines 2024, 12(10), 2190; https://doi.org/10.3390/biomedicines12102190 - 26 Sep 2024
Viewed by 476
Abstract
Background/Objectives: Neutrophils, as the first line of defense in the immune response, produce neutrophil extracellular traps (NETs) upon activation, which are significant in the pathogenesis and organ damage in sepsis. This study aims to explore the clinical value of myeloperoxidase-DNA (MPO-DNA) and cell-free [...] Read more.
Background/Objectives: Neutrophils, as the first line of defense in the immune response, produce neutrophil extracellular traps (NETs) upon activation, which are significant in the pathogenesis and organ damage in sepsis. This study aims to explore the clinical value of myeloperoxidase-DNA (MPO-DNA) and cell-free DNA (cf-DNA) in sepsis patients. Methods: Clinical data were collected from 106 sepsis patients, 25 non-sepsis patients, and 51 healthy controls. Sequential Organ Failure Assessment (SOFA) scores were calculated, and levels of MPO-DNA) complexes and cf-DNA were measured using specific kits. Correlation analyses assessed relationships between indicators, while logistic regression identified independent risk factors. Receiver operating characteristic (ROC) curves calculated the area under the curve (AUC) to evaluate the diagnostic value of the biomarkers. Results: Sepsis patients exhibited significantly elevated levels of MPO-DNA and cf-DNA compared to non-sepsis patients and healthy controls. In sepsis patients, MPO-DNA and cf-DNA levels correlated with inflammation, coagulation, and organ damage indicators, as well as procalcitonin (PCT) levels and SOFA scores. Both C-reactive protein (CRP) and cf-DNA were identified as independent risk factors for sepsis, demonstrating moderate diagnostic value. ROC analysis showed that the combination of MPO-DNA and CRP (AUC: 0.837) enhances the AUC value of CRP (0.777). Conclusions: In summary, elevated serum levels of MPO-DNA and cf-DNA in sepsis patients correlate with SOFA scores and PCT levels, providing reference value for sepsis diagnosis in clinical settings. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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11 pages, 2095 KiB  
Article
ALCAT1-Mediated Pathological Cardiolipin Remodeling and PLSCR3-Mediated Cardiolipin Transferring Contribute to LPS-Induced Myocardial Injury
by Dong Han, Chenyang Wang, Xiaojing Feng, Li Hu, Beibei Wang, Xinyue Hu and Jing Wu
Biomedicines 2024, 12(9), 2013; https://doi.org/10.3390/biomedicines12092013 - 3 Sep 2024
Viewed by 653
Abstract
Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the [...] Read more.
Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the underlying mechanisms remain incompletely understood. This study highlights a notable increase in the expressions of ALCAT1 and PLSCR3 during the advanced stage of lipopolysaccharide (LPS)-induced SCM. This up-regulation potential contribution to mitochondrial dysfunction and cellular apoptosis—as indicated by the augmented oxidative stress and cytochrome c (Cytc) release—coupled with reduced mitophagy, decreased levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) and lowered cell viability. Additionally, the timing of LPS-induced apoptosis coincides with the decline in both autophagy and mitophagy at the late stages, implying that these processes may serve as protective factors against LPS-induced SCM in HL-1 cells. Together, these findings reveal the mechanism of LPS-induced CL changes in the center of SCM, with a particular emphasis on the importance of pathological remodeling and translocation of CL to mitochondrial function and apoptosis. Additionally, it highlights the protective effect of mitophagy in the early stage of SCM. This study complements previous research on the mechanism of CL changes in mediating SCM. These findings enhance our understanding of the role of CL in cardiac pathology and provide a new direction for future research. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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12 pages, 2755 KiB  
Article
Decreased Protein C Pathway Activity in COVID-19 Compared to Non-COVID Sepsis: An Observational and Comparative Cohort Study
by Heiko Rühl, Christian Bode, Tobias Becher, Sebastian Eckert, Ghaith Mohsen, Hannah L. McRae, Jens Müller, Sara Reda, Dirk Loßnitzer, Johannes Oldenburg, Christian Putensen and Bernd Pötzsch
Biomedicines 2024, 12(9), 1982; https://doi.org/10.3390/biomedicines12091982 - 2 Sep 2024
Viewed by 740
Abstract
Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key [...] Read more.
Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10−6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10−4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364–0.661) and non-COVID sepsis patients (r = 0.535–0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10−7) and 3-fold (p = 8 × 10−4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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11 pages, 471 KiB  
Article
Rotational Thromboelastometric Profile in Early Sepsis: A Prospective Cohort Study
by Piotr F. Czempik and Agnieszka Wiórek
Biomedicines 2024, 12(8), 1880; https://doi.org/10.3390/biomedicines12081880 - 17 Aug 2024
Viewed by 721
Abstract
Background: Coagulation abnormalities are common in sepsis patients and are associated with increased mortality. This study aimed to assess the hemostatic profile of sepsis patients using rotational thromboelastometry (ROTEM) and to find the ROTEM parameters best predicting short-term mortality. Methods: We conducted a [...] Read more.
Background: Coagulation abnormalities are common in sepsis patients and are associated with increased mortality. This study aimed to assess the hemostatic profile of sepsis patients using rotational thromboelastometry (ROTEM) and to find the ROTEM parameters best predicting short-term mortality. Methods: We conducted a prospective analysis of consecutive sepsis patients hospitalized in the intensive care unit. The inclusion criteria were diagnosis of sepsis or septic shock and pro-calcitonin concentration >0.5 ng mL−1. Clinical, standard laboratory, and ROTEM analyses were performed. Results: The study group comprised 38 (49%) males and 40 (51%) females. Median Sequential Organ Failure Assessment (SOFA) score was 8 (interquartile range IQR 5–11) points. The most common primary sites of infection were pneumonia (n = 27/35%), intra-abdominal (n = 27/35%), urinary tract infection (n=20/26%), and others (n = 4/6%). The following parameters evaluating fibrinogen function were outside the reference range: clotting time (CT), clot amplitude (A) at 10 and 20 min, and maximal clot firmness (MCF). Out of 78 patients, 28 (36%) died in the intensive care unit. Significant differences between survivors and non-survivors of sepsis were present for the ROTEM parameters assessing fibrinolytic activity. Conclusions: ROTEM in the early phase of sepsis reveals increased coagulation mediated through the function of fibrinogen. Non-survivors showed slightly lower fibrinolytic activity than survivors; however, it was still within test reference values. The highest predicting value was obtained by a model incorporating, among others, extrinsic coagulation pathway fibrinolytic parameters. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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12 pages, 1649 KiB  
Article
Plasma Insulin-like Growth Factor-Binding Protein-2 of Critically Ill Patients Is Related to Disease Severity and Survival
by Patricia Mester, Ulrich Räth, Luisa Popp, Stephan Schmid, Martina Müller, Christa Buechler and Vlad Pavel
Biomedicines 2023, 11(12), 3285; https://doi.org/10.3390/biomedicines11123285 - 12 Dec 2023
Cited by 1 | Viewed by 1095
Abstract
Insulin-like growth factor-binding protein (IGFBP)-2 regulates the bioactivity of the anabolic hormone’s insulin-like growth factors, which are decreased in sepsis and contribute to the catabolic status of severely ill patients. The circulating levels of IGFBP-2 in critical illness have been rarely studied; therefore, [...] Read more.
Insulin-like growth factor-binding protein (IGFBP)-2 regulates the bioactivity of the anabolic hormone’s insulin-like growth factors, which are decreased in sepsis and contribute to the catabolic status of severely ill patients. The circulating levels of IGFBP-2 in critical illness have been rarely studied; therefore, we evaluated IGFBP-2 plasma levels in patients with systemic inflammatory response syndrome (SIRS) or sepsis as well as healthy controls. Our analysis of 157 SIRS/sepsis patients revealed higher plasma IGFBP-2 levels compared to 22 healthy controls. Plasma IGFBP-2 levels correlated positively with procalcitonin but not with C-reactive protein, interleukin-6, or the leukocyte count. Septic shock patients exhibited higher IGFBP-2 levels than those with SIRS. Bacterial or SARS-CoV-2 infection did not influence plasma IGFBP-2 levels. There was no difference in the IGFBP-2 levels between ventilated and non-ventilated SIRS/sepsis patients, and vasopressor therapy did not alter these levels. Dialysis patients had elevated plasma IGFBP-2 levels. Survivors had lower plasma IGFBP-2 levels than non-survivors. In conclusion, our study indicates that plasma IGFBP-2 levels are associated with disease severity, renal failure, and mortality in SIRS/sepsis patients. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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Review

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17 pages, 1437 KiB  
Review
Targeting Sepsis: Disease Tolerance, Immune Resilience, and Compartmentalized Immunity
by Alexis Garduno and Ignacio Martín-Loeches
Biomedicines 2024, 12(11), 2420; https://doi.org/10.3390/biomedicines12112420 - 22 Oct 2024
Viewed by 465
Abstract
Introduction: Sepsis remains a major contributor to critical care mortality and morbidity worldwide. Despite advances in understanding its complex immunopathology, the compartmentalized nature of immune responses across different organs has yet to be fully translated into targeted therapies. This review explores the burden [...] Read more.
Introduction: Sepsis remains a major contributor to critical care mortality and morbidity worldwide. Despite advances in understanding its complex immunopathology, the compartmentalized nature of immune responses across different organs has yet to be fully translated into targeted therapies. This review explores the burden of sepsis on organ-specific immune dysregulation, immune resilience, and epigenetic reprogramming, emphasizing translational challenges and opportunities. Methods: We implemented a systematic literature search strategy, incorporating data from studies published between 2010 and 2024, to evaluate the role of molecular profiling techniques, including transcriptomics and epigenetic markers, in assessing the feasibility of targeted therapies. Results: Sepsis-induced immune dysregulation manifests differently in various organs, with lung, heart, liver, and kidney responses driven by unique local immune environments. Organ-specific biomarkers, such as the Spns2/S1P axis in lung macrophages, mitochondrial dysfunction in the heart, proenkephalin for early acute kidney injury (AKI), and adrenomedullin for predicting multi-organ failure, offer promising avenues for timely intervention. Furthermore, immune resilience, particularly through regulatory T-cell modulation and cytokine targeting (e.g., IL-18), is crucial for long-term recovery. Epigenetic mechanisms, including histone modification and trained immunity, present opportunities for reprogramming immune responses but require more precision to avoid unintended inflammatory sequelae. Conclusions: A deeper understanding of compartmentalized immune responses and the dynamic immune landscape in sepsis is critical for developing precision therapies. Real-time immune monitoring and organ-targeted interventions could revolutionize sepsis management, although significant barriers remain in clinical translation. Further research is required to establish biomarkers and treatment timing that optimize therapeutic efficacy while minimizing systemic risks. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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14 pages, 683 KiB  
Review
MicroRNAs in Sepsis
by Asimina Valsamaki, Vasileios Vazgiourakis, Konstantinos Mantzarlis, Rodopi Stamatiou and Demosthenes Makris
Biomedicines 2024, 12(9), 2049; https://doi.org/10.3390/biomedicines12092049 - 9 Sep 2024
Viewed by 636
Abstract
Sepsis is an insidious and frequent condition of severe inflammation due to infections. Several biomarkers have been established for initial screening, but the non-specific nature of the existing biomarkers has led to the investigation of more sensitive and specific tools, such as microRNAs [...] Read more.
Sepsis is an insidious and frequent condition of severe inflammation due to infections. Several biomarkers have been established for initial screening, but the non-specific nature of the existing biomarkers has led to the investigation of more sensitive and specific tools, such as microRNAs (miRs). These non-coding RNAs are involved in several diseases, including sepsis, due to their roles in cellular homeostasis. Herein, a literature overview was attempted to distinguish the most prominent miRs identified in septic conditions and their usefulness in diagnosis, prognosis and even classification of sepsis. miRs implicated in the regulation of pro and anti-inflammatory mechanisms, such as MIR-146a, MIR-155, MIR-181b, MIR-223-5p, MIR-494-3p, MIR-2055b, MIR-150 and MIR-143 have been pinpointed as acceptable testing tools. Furthermore, the use of miRs as screening panels, specific for septic parameters, such as type of causal infection, inflammation immune pathways affected (NF-kB, STAT/JACK), organs inflicted, as well as parallel screening of certain miRs alongside other long non-coding RNAs (LNCs), as co-regulators of sepsis progression. Overall, miRs exhibit benefits in terms of specificity and sensitivity, as well as practical ease of use and test stability. Furthermore, miRs could offer valuable insights into the molecular basis of disease causality and provide valuable therapeutic information. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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15 pages, 710 KiB  
Review
The Role of Biomarkers in Diagnosis of Sepsis and Acute Kidney Injury
by Gillene Santos Ferreira, Melissa Lopes Frota, Maria José Dias Gonzaga, Maria de Fátima Fernandes Vattimo and Camila Lima
Biomedicines 2024, 12(5), 931; https://doi.org/10.3390/biomedicines12050931 - 23 Apr 2024
Viewed by 2329
Abstract
Sepsis and acute kidney injury (AKI) are two major public health concerns that contribute significantly to illness and death worldwide. Early diagnosis and prompt treatment are essential for achieving the best possible outcomes. To date, there are no specific clinical, imaging, or biochemical [...] Read more.
Sepsis and acute kidney injury (AKI) are two major public health concerns that contribute significantly to illness and death worldwide. Early diagnosis and prompt treatment are essential for achieving the best possible outcomes. To date, there are no specific clinical, imaging, or biochemical indicators available to diagnose sepsis, and diagnosis of AKI based on the KDIGO criterion has limitations. To improve the diagnostic process for sepsis and AKI, it is essential to continually evolve our understanding of these conditions. Delays in diagnosis and appropriate treatment can have serious consequences. Sepsis and AKI often occur together, and patients with kidney dysfunction are more prone to developing sepsis. Therefore, identifying potential biomarkers for both conditions is crucial. In this review, we talk about the main biomarkers that evolve the diagnostic of sepsis and AKI, namely neutrophil gelatinase-associated lipocalin (NGAL), proenkephalin (PENK), and cell-free DNA. Full article
(This article belongs to the Special Issue Sepsis: Pathophysiology and Early Diagnostics)
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