Markers of NETosis and DAMPs are altered in critically ill COVID-19 patients

Background Coronavirus disease 19 (COVID-19) is known to present with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels of extracellular histone H3 (H3), neutrophil elastase (NE) and cfDNA in relation to other plasma parameters, including the immune modulators GAS6 and AXL, ICU scoring systems and mortality in patients with severe COVID-19. Methods We measured plasma H3, NE, cfDNA, GAS6 and AXL concentration in plasma of 83 COVID-19-positive and 11 COVID-19-negative patients at admission to the Intensive Care Unit (ICU) at the Uppsala University hospital, a tertiary hospital in Sweden and a total of 333 samples obtained from these patients during the ICU-stay. We determined their correlation with disease severity, organ failure, mortality and other blood parameters. Results H3, NE, cfDNA, GAS6 and AXL were increased in plasma of COVID-19 patients compared to controls. cfDNA and GAS6 decreased in time in in patients surviving to 30 days post ICU admission. Plasma H3 was a common feature of COVID-19 patients, detected in 40% of the patients at ICU admission. Although these measures were not predictive of the final outcome of the disease, they correlated well with parameters of tissue damage (H3 and cfDNA) and neutrophil counts (NE). A subset of samples displayed H3 processing, possibly due to proteolysis. Conclusions Elevated H3 and cfDNA levels in COVID-19 patients illustrate the severity of the cellular damage observed in critically ill COVID-19 patients. The increase in NE indicates the important role of neutrophil response and the process of NETosis in the disease. GAS6 appears as part of an early activated mechanism of response in Covid-19.The study was supported through grants from the dedSciLifeLab/KAW national COVID-19 research program project grant (MH), by Scilifelab, the Knut and Alice Wallenberg Foundation and in part by the Swedish Research Council (RF, grant no 2014-02569 and 2014-07606), and the Netherlands Thrombosis Foundation (GN).N

Presence and evolution of NET markers and DAMPS in critically ill COVID-19 patients

Resumen del trabajo presentado en el 4th European Congress on Thrombosis and Haemostasis, celebrado en Gante (Bélgica), los días 14 y 15 de octubre de 2021Background: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection presents with a wide range of disease symptoms. In the more severe patients, COVID-19 is associated with respiratory failure, neutrophil extracellular trap (NET) formation, and multiple organ failure (MOF). Aims: We investigated the presence and evolution of several damage associated molecular patterns (DAMPs) neutrophil markers and immune modulators in a group of 100 COVID-19-positive ICU patients. Methods: Citrated plasma was collected from adult patients with confirmed COVID-19 by PCR detection of SARS-CoV-2 E and N-genes in nasopharyngeal swabs admitted to the intensive care unit (ICU) at Uppsala University hospital, Sweden. Written informed consent was obtained from the patients, or next of kin if the patient was unable to give consent. The Declaration of Helsinki and its subsequent revisions were followed. Plasma concentration of cell free DNA (cfDNA), extracellular histone H3 (H3), neutrophil elastase (NE), myeloperoxidase (MPO) and the cfDNA-MPO complex, and the immune modulators GAS6, and sAXL were measured in all COVID-19-positive and in COVID-19-negative patients and healthy controls. We determined marker levels upon admission, of their evolution, and correlation with disease severity, organ failure, thromboembolic events, mortality, and other blood parameters. Results: The level of cfDNA, H3, NE, MPO, cfDNA-MPO complex, GAS6, and sAXL were all significantly increased in plasma of COVID-19 patients compared to controls. Importantly, a diminution of cfDNA and GAS6 levels over time was observed in patients surviving 30 days after ICU admission. Histone H3 levels were detected in 40% of the COVID-19 patient plasma at ICU admission and the presence of histone H3 during ICU stay was associated with an increased risk of thromboembolic events and secondary infection. Though NET markers were not predictive of 30-day mortality, they correlated with several parameters of tissue damage and neutrophil counts. Summary/Conclusion: The increased presence of cfDNA, H3 and NE, MPO, and MPO-DNA illustrates the severity of cellular damage and indicates activation of NETosis in severe COVID-19 ICU patients. The evolution of cfDNA and Gas6 is able to predict disease prognosis of severely ill COVID-19 patients, where GAS6 appears to be part of an early activated mechanism in response to COVID-19. These data support treatment aimed at the reduction of NET formation in severe COVID-19 patients

Teachers' interpretations of the concept of problem - a link between written and intended reform curriculum

Over the last decades, there has been an on-going international reform for school mathematics, which has, not surprisingly, been difficult to implement. This study focuses on teachers’ interpretation of formal written curriculum documents, especially whether their interpretations align with how a concept (the concept of problem) is conveyed in the documents (in Sweden). The results show that the formal written documents are vague, but that it to some extent conveys the concept of problem as “a task for which the solution method is not known in advance to the solver.” The interviews show that about 53 % of the teachers interpreted problem as “any task,” and that teachers’ interpretationstherefore are not aligned with how the concept is (albeit vaguely) conveyed in the documents

Teachers' interpretations of the concept of problem - a link between written and intended reform curriculum

Over the last decades, there has been an on-going international reform for school mathematics, which has, not surprisingly, been difficult to implement. This study focuses on teachers’ interpretation of formal written curriculum documents, especially whether their interpretations align with how a concept (the concept of problem) is conveyed in the documents (in Sweden). The results show that the formal written documents are vague, but that it to some extent conveys the concept of problem as “a task for which the solution method is not known in advance to the solver.” The interviews show that about 53 % of the teachers interpreted problem as “any task,” and that teachers’ interpretationstherefore are not aligned with how the concept is (albeit vaguely) conveyed in the documents

What is “strong presence” of a message in a steering document?

The aim of this paper is to discuss what a “strong presence” of a message in a syllabuscould be. The discussion takes a starting point in what we call the reformmessage; that what mathematics is can not only be described in terms of content andprocedures, but must also be defined in terms of competencies, e.g. problem solving,reasoning and communication. The analyzed document is the Swedish syllabus forthe first course at upper secondary school. Different ways, both quantitative andqualitative, of determining what a strong presence of a message could be are presentedand discussed

Teachers' interpretations of the concept of problem - a link between written and intended reform curriculum

Over the last decades, there has been an on-going international reform for school mathematics, which has, not surprisingly, been difficult to implement. This study focuses on teachers’ interpretation of formal written curriculum documents, especially whether their interpretations align with how a concept (the concept of problem) is conveyed in the documents (in Sweden). The results show that the formal written documents are vague, but that it to some extent conveys the concept of problem as “a task for which the solution method is not known in advance to the solver.” The interviews show that about 53 % of the teachers interpreted problem as “any task,” and that teachers’ interpretationstherefore are not aligned with how the concept is (albeit vaguely) conveyed in the documents

WHAT MATHEMATICAL COMPETENCES CAN BE LEARNED FROM WEB-BASED LEARNING RESOURCES?

Two web-based learning resoruces were analysed using the MCRF research framework. The aim was to identify opportunities to develop mathematical competencies. The findings indicate that opportunities are few, and that what is offered in web-based learning resources is similar to what is offered in Swedish classrooms