scholarly journals A New Method for Optimizing Sepsis Therapy by Nivolumab and Meropenem Combination: Importance of Early Intervention and CTL Reinvigoration Rate as a Response Marker

2021 ◽  
Vol 12 ◽  
Author(s):  
Avi Gillis ◽  
Anat Ben Yaacov ◽  
Zvia Agur
Keyword(s):  
Fitness Function ◽  
Bacterial Sepsis ◽  
Personal Benefit ◽  
Pathogen Elimination ◽  
Pathogen Load ◽  
Maximum Benefit ◽  
Antibiotic Drug ◽  
Sepsis Therapy ◽  
Drug Regimens ◽  
Cellular Immune

Background: Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor.Methods: We defined an optimization problem as a concise framework of treatment aims and formulated a fitness function for grading sepsis treatments according to their success in accomplishing the pre-defined aims. We developed a mathematical model for the interactions between the pathogen, the cellular immune system and the drugs, whose simulations under diverse combined meropenem and nivolumab schedules, and calculation of the fitness function for each schedule served to plot the fitness landscapes for each set of treatments and personal patient parameters.Results: Results show that treatment by meropenem and nivolumab has maximum benefit if the interval between the onset of the two drugs does not exceed a dose-dependent threshold, beyond which the benefit drops sharply. However, a second nivolumab application, within 7–10 days after the first, can extinguish a pathogen which the first nivolumab application failed to remove. The utility of increasing nivolumab total dose above 6 mg/kg is contingent on the patient's personal immune attributes, notably, the reinvigoration rate of exhausted CTLs and the overall suppression rates of functional CTLs. A baseline pathogen load, higher than 5,000 CFU/μL, precludes successful nivolumab and meropenem combination therapy, whereas when the initial load is lower than 3,000 CFU/μL, meropenem monotherapy suffices for removing the pathogen.Discussion: Our study shows that early administration of nivolumab, 6 mg/kg, in combination with antibiotics, can alleviate bacterial sepsis in cases where antibiotics alone are insufficient and the initial pathogen load is not too high. The study pinpoints the role of precision medicine in sepsis, suggesting that personalized therapy by ICBs can improve pathogen elimination and dampen immunosuppression. Our results highlight the importance in using reliable markers for classifying patients according to their predicted response and provides a valuable tool in personalizing the drug regimens for patients with sepsis.

An Unusual Case of Progressive Shock and Highly Elevated Procalcitonin Level

2010 ◽  
Vol 19 (1) ◽  
pp. 96-93 ◽  
Author(s):  
Julia Schumm ◽  
Rüdiger Pfeifer ◽  
Markus Ferrari ◽  
Friedhelm Kuethe ◽  
Hans R. Figulla
Keyword(s):  
Inflammatory Markers ◽  
Unusual Case ◽  
Drotrecogin Alfa ◽  
Signs And Symptoms ◽  
Adrenal Failure ◽  
Bacterial Sepsis ◽  
Suspected Sepsis ◽  
Addison Disease ◽  
Sepsis Therapy ◽  
Focus Of Infection

A 21-year-old man with signs and symptoms of rapidly progressive shock was admitted to the intensive care unit for treatment of suspected sepsis. Levels of inflammatory markers (including procalcitonin) were highly elevated, but no obvious focus of infection was apparent. Initial sepsis therapy included administration of broad-spectrum antibiotics, vasoconstrictors, and drotrecogin alfa. Cultures of blood, sputum, and urine showed no growth, and no viruses were detected. The random (no stimulation with corticotropin) cortisol level at admission was less than 25 nmol/L. Assays for autoantibodies to the adrenal cortex were strongly positive and confirmed the diagnosis of adrenal failure caused by Addison disease. After initiation of steroid therapy, the patient fully recovered. Although increased procalcitonin levels are considered a reliable and specific indicator of severe generalized infections and bacterial sepsis, elevated procalcitonin levels cannot be relied on when trying to differentiate between addisonian crisis and septic shock.

scholarly journals IOX1 activity as sepsis therapy and an antibiotic against multidrug-resistant bacteria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Su Jin Lee ◽  
Jueng Soo You ◽  
Amal Gharbi ◽  
Yong Joo Kim ◽  
Mi Suk Lee ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Bacterial Sepsis ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Carbapenem Resistant ◽  
Sepsis Therapy ◽  
Inflammatory State ◽  
Conventional Antibiotics ◽  
Lysine Demethylase

AbstractSepsis is caused by organ dysfunction initiated by an unrestrained host immune response to infection. The emergence of antibiotic-resistant bacteria has rapidly increased in the last decades and has stimulated a firm research platform to combat infections caused by antibiotic-resistant bacteria that cannot be eradicated with conventional antibiotics. Strategies like epigenetic regulators such as lysine demethylase (Kdm) has received attention as a new target. Thus, we sought to investigate the epigenetic mechanisms in sepsis pathophysiology with the aim of discovering new concepts for treatment. A transcriptome analysis of dendritic cells during their inflammatory state identified Kdm as a critical molecule in sepsis regulation. Next, 8-hydroxyquinoline-5-carboxylic acid (IOX1) ability to control endotoxemia induced by Lipopolysaccharide and bacterial sepsis was demonstrated. IOX1 has been shown to regulate endotoxemia and sepsis caused by Escherichia coli and carbapenem-resistant Acinetobacter baumannii and has also contributed to the suppression of multidrug-resistant bacterial growth through the inhibition of DNA Gyrase. These findings show that IOX1 could be a component agent against bacterial sepsis by functioning as a broad-spectrum antibiotic with dual effects.

scholarly journals Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Katja Schlatterer ◽  
Christian Beck ◽  
Ulrich Schoppmeier ◽  
Andreas Peschel ◽  
Dorothee Kretschmer
Keyword(s):  
Elevated Serum ◽  
Systemic Infection ◽  
Therapeutic Interventions ◽  
Mouse Serum ◽  
Human Neutrophils ◽  
Wild Type ◽  
Bacterial Sepsis ◽  
Sepsis Therapy ◽  
G Protein Coupled ◽  
Neutrophil Priming

AbstractBacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Effective immunomodulatory approaches are urgently needed but it has remained elusive, which targets might be suitable for intervention. Increased expression of the G-protein-coupled receptor GPR43, which is known to govern intestinal responses to acetate, has been associated with sepsis patient survival but the mechanisms behind this observation have remained unclear. We show that elevated serum acetate concentrations prime neutrophils in a GPR43-dependent fashion, leading to enhanced neutrophil chemotaxis, oxidative burst, cytokine release and upregulation of phagocytic receptors. Consequently, acetate priming improved the capacity of human neutrophils to eliminate methicillin-resistant Staphylococcus aureus. Acetate administration increased mouse serum acetate concentrations and primed neutrophils. Notably, it rescued wild-type mice from severe S. aureus sepsis and reduced bacterial numbers in peripheral organs by several magnitudes. Acetate treatment improved the sepsis course even when applied several hours after onset of the infection, which recommends GPR43 as a potential target for sepsis therapy. Our study indicates that the severity of sepsis depends on transient neutrophil priming by appropriate blood acetate concentrations. Therapeutic interventions based on GPR43 stimulation could become valuable strategies for reducing sepsis-associated morbidity and mortality.

scholarly journals Obesity-induced Hyperleptinemia Improves Survival and Immune Response in a Murine Model of Sepsis

2014 ◽  
Vol 121 (1) ◽  
pp. 98-114 ◽  
Author(s):  
Daniel Siegl ◽  
Thorsten Annecke ◽  
Bobby L. Johnson ◽  
Christian Schlag ◽  
Andre Martignoni ◽  
...  
Keyword(s):  
Immune Response ◽  
Body Temperature ◽  
Cecal Ligation ◽  
Immune Dysfunction ◽  
Normal Weight ◽  
Standard Diet ◽  
Class 1 ◽  
Sepsis Therapy ◽  
Cellular Immune

Abstract Background: Obesity is a growing health problem and associated with immune dysfunction. Sepsis is defined as systemic inflammatory response syndrome that occurs during infection. Excessive inflammation combined with immune dysfunction can lead to multiorgan damage and death. Methods: The authors investigated the influence of a class 1 obesity (body mass index between 30 and 34.9) on immune function and outcome in sepsis and the role of leptin on the immune response. The authors used a long-term high-fat-diet feeding model (12 weeks) on C57Bl/6 mice (n = 100) and controls on standard diet (n = 140) followed by a polymicrobial sepsis induced by cecal ligation and puncture. Results: The authors show that class 1 obesity is connected to significant higher serum leptin levels (data are mean ± SEM) (5.7 ± 1.2 vs. 2.7 ± 0.2 ng/ml; n = 5; P = 0.033) and improved innate immune response followed by significant better survival rate in sepsis (71.4%, n = 10 vs. 10%, n = 14; P < 0.0001). Additional sepsis-induced increases in leptin levels stabilize body temperature and are associated with a controlled immune response in a time-dependent and protective manner. Furthermore, leptin treatment of normal-weight septic mice with relative hypoleptinemia (n = 35) also significantly stabilizes body temperature, improves cellular immune response, and reduces proinflammatory cytokine response resulting in improved survival (30%; n = 10). Conclusions: Relative hyperleptinemia of class 1 obesity or induced by treatment is protective in sepsis. Leptin seems to play a regulatory role in the immune system in sepsis, and treatment of relative hypoleptinemia could offer a new way of an individual sepsis therapy.

Biomimetic Microcavity Interface for Label-free Capture of Pathogens in Fluid Bloodstream by Vortical Crossflow Filtration

Nanoscale ◽  
2021 ◽  
Author(s):  
Liyuan Zheng ◽  
Xiaobo Zheng ◽  
Shanshan Yuan ◽  
Weide Xu ◽  
Changhuan Zhang ◽  
...  
Keyword(s):  
Disease Severity ◽  
Microbial Pathogens ◽  
Major Contributor ◽  
Label Free ◽  
Bacterial Sepsis ◽  
Crossflow Filtration ◽  
Pathogen Load

Bacterial sepsis is a lethal disease triggered by microbial pathogens. The blood pathogen load is a major contributor to both disease severity and mortality in patients with sepsis blood. So...

RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum

2017 ◽  
Vol 1 (6) ◽  
pp. 533-537
Author(s):  
Lorenz von Seidlein ◽  
Borimas Hanboonkunupakarn ◽  
Podjanee Jittmala ◽  
Sasithon Pukrittayakamee
Keyword(s):  
Protective Efficacy ◽  
Age Groups ◽  
Sub Saharan Africa ◽  
Phase Iii ◽  
European Medicines Agency ◽  
Older Children ◽  
Pivotal Phase ◽  
Malaria Epidemiology ◽  
Maximum Benefit ◽  
Sub Saharan

RTS,S/AS01 is the most advanced vaccine to prevent malaria. It is safe and moderately effective. A large pivotal phase III trial in over 15 000 young children in sub-Saharan Africa completed in 2014 showed that the vaccine could protect around one-third of children (aged 5–17 months) and one-fourth of infants (aged 6–12 weeks) from uncomplicated falciparum malaria. The European Medicines Agency approved licensing and programmatic roll-out of the RTSS vaccine in malaria endemic countries in sub-Saharan Africa. WHO is planning further studies in a large Malaria Vaccine Implementation Programme, in more than 400 000 young African children. With the changing malaria epidemiology in Africa resulting in older children at risk, alternative modes of employment are under evaluation, for example the use of RTS,S/AS01 in older children as part of seasonal malaria prophylaxis. Another strategy is combining mass drug administrations with mass vaccine campaigns for all age groups in regional malaria elimination campaigns. A phase II trial is ongoing to evaluate the safety and immunogenicity of the RTSS in combination with antimalarial drugs in Thailand. Such novel approaches aim to extract the maximum benefit from the well-documented, short-lasting protective efficacy of RTS,S/AS01.

Humoral and cellular immune response to a crude exo-antigen and purified keratinase of Microsporum canis in experimentally infected guinea pigs

1999 ◽  
Vol 37 (2) ◽  
pp. 123-129 ◽  
Author(s):  
B. R. Mignon ◽  
T. Leclipteux ◽  
CH. Focant ◽  
A. J. Nikkels ◽  
G. E. PIErard ◽  
...  
Keyword(s):  
Immune Response ◽  
Cellular Immune Response ◽  
Guinea Pigs ◽  
Microsporum Canis ◽  
Cellular Immune

The humoral and cellular immune response of sheep against Borna disease virus in endemic and non-endemic areas

2004 ◽  
Vol 146 (4) ◽  
pp. 159-172 ◽  
Author(s):  
D. Müller-Doblies ◽  
S. Baumann ◽  
P. Grob ◽  
A. Hülsmeier ◽  
U. Müller-Doblies ◽  
...  
Keyword(s):  
Immune Response ◽  
Disease Virus ◽  
Cellular Immune Response ◽  
Borna Disease Virus ◽  
Endemic Areas ◽  
Cellular Immune ◽  
Borna Disease

Academic Course Evaluation

2009 ◽  
Vol 14 (4) ◽  
pp. 297-306 ◽  
Author(s):  
Edith Braun ◽  
Bernhard Leidner
Keyword(s):  
Higher Education ◽  
Education Reform ◽  
Bologna Process ◽  
Course Evaluation ◽  
Higher Education Reform ◽  
Teaching Behavior ◽  
Personal Benefit ◽  
Quality Of Higher Education ◽  
Confirmatory Factor ◽  
The Bologna Process

This article contributes to the conceptual and empirical distinction between (the assessment of) appraisals of teaching behavior and (the assessment of) self-reported competence acquirement within academic course evaluation. The Bologna Process, the current higher-education reform in Europe, emphasizes education aimed toward vocationally oriented competences and demands the certification of acquired competences. Currently available evaluation questionnaires measure the students’ satisfaction with a lecturer’s behavior, whereas the “Evaluation in Higher Education: Self-Assessed Competences” (HEsaCom) measures the students’ personal benefit in terms of competences. In a sample of 1403 German students, we administered a scale of satisfaction with teaching behavior and the German version of the HEsaCom at the same time. Using confirmatory factor analysis, the estimated correlations between the various scales of self-rated competences and teaching behavior appraisals were moderate to strong, yet the constructs were shown to be empirically distinct. We conclude that the self-rated gains in competences are distinct from satisfaction with course and instructor. In line with the higher education reform, self-reported gains in competences are an important aspect of academic course evaluation, which should be taken into account in the future and might be able to restructure the view of “quality of higher education.” The English version of the HEsaCom is presented in the Appendix .

The cognitive reflection test and regional pathogen load

2014 ◽  
Author(s):  
Kilian James Garvey ◽  
Laura Folse ◽  
Crystal Curry
Keyword(s):  
Cognitive Reflection Test ◽  
Cognitive Reflection ◽  
Pathogen Load
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