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Article ; Online: Inflammatory biomarkers to predict the prognosis of acute bacterial and viral infections.

de Nooijer, Aline H / Pickkers, Peter / Netea, Mihai G / Kox, Matthijs

2023 Volume 78, Page(s) 154360

Abstract: Mortality in acute infections is mostly associated with sepsis, defined as 'life-threatening organ dysfunction caused by a dysregulated host response to infection'. It remains challenging to identify the patients with increased mortality risk due to the ... ...

Abstract	Mortality in acute infections is mostly associated with sepsis, defined as 'life-threatening organ dysfunction caused by a dysregulated host response to infection'. It remains challenging to identify the patients with increased mortality risk due to the high heterogeneity in the dysregulated host immune response and disease progression. Biomarkers reflecting different pathways involved in the inflammatory response might improve prediction of mortality risk (prognostic enrichment) among patients with acute infections by reducing heterogeneity of the host response, as well as suggest novel strategies for patient stratification and treatment (predictive enrichment) through precision medicine approaches. The predictive value of inflammatory biomarkers has been extensively investigated in bacterial infections and the recent COVID-19 pandemic caused an increased interest in inflammatory biomarkers in this viral infection. However, limited research investigated whether the prognostic potential of these biomarkers differs between bacterial and viral infections. In this narrative review, we provide an overview of the value of various inflammatory biomarkers for the prediction of mortality in bacterial and viral infections.
MeSH term(s)	Humans ; Pandemics ; COVID-19 ; Biomarkers/metabolism ; Prognosis ; Sepsis/diagnosis ; Infections ; Bacterial Infections/diagnosis
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632818-0
ISSN	1557-8615 ; 0883-9441
ISSN (online)	1557-8615
ISSN	0883-9441
DOI	10.1016/j.jcrc.2023.154360
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Article ; Online: Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity.

de Nooijer, Aline H / Kotsaki, Antigone / Kranidioti, Eleftheria / Kox, Matthijs / Pickkers, Peter / Toonen, Erik J M / Giamarellos-Bourboulis, Evangelos J / Netea, Mihai G

Critical care (London, England)

2023 Volume 27, Issue 1, Page(s) 63

Abstract: ... terminal complement complex were assessed in ethylenediaminetetraacetic acid plasma samples collected within 24 h after sepsis ...

Abstract	Background: Sepsis is characterized by a dysregulated immune response to infection. The complement system plays an important role in the host defence to pathogens. However, exaggerated complement activation might contribute to a hyperinflammatory state. The interplay between complement activation and inflammation in relationship with adverse outcomes in sepsis patients is unclear. Methods: Secondary analysis of complement factors in a prospective study in 209 hospitalized sepsis patients, of whom the majority presented with shock. Concentrations of complement factors C3, C3a, C3c, C5, C5a, and soluble terminal complement complex were assessed in ethylenediaminetetraacetic acid plasma samples collected within 24 h after sepsis diagnosis using enzyme-linked immunosorbent assays. Results: The concentration of complement factors in plasma of severely ill sepsis patients indicated profound activation of the complement system (all P < 0.01 compared to healthy controls). Spearman rank correlation tests indicated consistent relationships between the different complement factors measured, but no significant correlations were observed between the complement factors and other inflammatory biomarkers such as leukocyte numbers, C-reactive protein and ferritin concentrations, or HLA-DR expression on monocytes. The concentration of complement factors was not associated with Sequential Organ Failure Assessment score, the incidence of septic shock, and mortality rates (all P > 0.05) in this cohort of patients with high disease severity. Conclusions: Once an infection progresses to severe sepsis or septic shock, the complement pathway is already profoundly activated and is no longer related to a dysregulated inflammatory response, nor to clinical outcome. This implies that in this patient category with severe disease, the complement system is activated to such an extent that it no longer has predictive value for clinical outcome.
MeSH term(s)	Humans ; Shock, Septic ; Prospective Studies ; Sepsis ; Complement Activation/physiology ; Inflammation ; Patient Acuity
Language	English
Publishing date	2023-02-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2041406-7
ISSN	1466-609X ; 1364-8535
ISSN (online)	1466-609X
ISSN	1364-8535
DOI	10.1186/s13054-023-04344-6
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Article ; Online: THE ROLE OF OBESITY AND PLASMA ADIPOCYTOKINES IN IMMUNE DYSREGULATION IN SEPSIS PATIENTS.

de Nooijer, Aline H / Antonakos, Nikolaos / Markopoulou, Dimitra / Grondman, Inge / Kox, Matthijs / Pickkers, Peter / Giamarellos-Bourboulis, Evangelos J / Netea, Mihai G

Shock (Augusta, Ga.)

2022 Volume 59, Issue 3, Page(s) 344–351

Abstract: Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a ... ...

Abstract	Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5-24.9 kg/m 2 n = 67), overweight (BMI, 25.0-29.9 kg/m 2 n = 56), and obesity (BMI ≥30 kg/m 2 n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight ( P = 0.008) and overweight ( P = 0.02), whereas adiponectin and resistin plasma concentrations were not different ( P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients ( P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.
MeSH term(s)	Humans ; Adipokines ; Leptin ; Resistin ; Adiponectin/metabolism ; Prospective Studies ; Overweight/complications ; Obesity/complications ; Inflammation ; Sepsis/complications
Chemical Substances	Adipokines ; Leptin ; Resistin ; Adiponectin
Language	English
Publishing date	2022-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0000000000002063
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Article ; Online: Adipocytokine plasma concentrations reflect influence of inflammation but not body mass index (BMI) on clinical outcomes of COVID-19 patients: A prospective observational study from the Netherlands.

de Nooijer, Aline H / Kooistra, Emma J / Grondman, Inge / Janssen, Nico A F / Joosten, Leo A B / van de Veerdonk, Frank L / Kox, Matthijs / Pickkers, Peter / Netea, Mihai G

Clinical obesity

2022 Volume 13, Issue 2, Page(s) e12568

Abstract: Obesity is recognized as a risk factor for adverse outcome in COVID-19, but the molecular mechanisms underlying this relationship remain unknown. Adipose tissue functions as an endocrine organ by secreting multiple pro-inflammatory and anti-inflammatory ... ...

Abstract	Obesity is recognized as a risk factor for adverse outcome in COVID-19, but the molecular mechanisms underlying this relationship remain unknown. Adipose tissue functions as an endocrine organ by secreting multiple pro-inflammatory and anti-inflammatory factors, known as adipocytokines, which could be involved in COVID-19 severity. We explored the role of adipocytokines in COVID-19 and its association with BMI, clinical outcome, and inflammation. This is an observational study in 195 hospitalized COVID-19 patients. Serial plasma concentrations of the adipocytokines leptin, adiponectin, resistin, and various inflammatory cytokines were assessed. Adipocytokines were compared between patients with normal weight (BMI: 18.5-24.9 kg/m
MeSH term(s)	Humans ; Adipokines ; Leptin ; Resistin ; Adiponectin ; Body Mass Index ; Overweight ; Netherlands ; COVID-19 ; Obesity ; Inflammation
Chemical Substances	Adipokines ; Leptin ; Resistin ; Adiponectin
Language	English
Publishing date	2022-11-25
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	2625816-X
ISSN	1758-8111 ; 1758-8103
ISSN (online)	1758-8111
ISSN	1758-8103
DOI	10.1111/cob.12568
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Article ; Online: Pitfalls in complement analysis: A systematic literature review of assessing complement activation.

Brandwijk, Ricardo J M G E / Michels, Marloes A H M / van Rossum, Mara / de Nooijer, Aline H / Nilsson, Per H / de Bruin, Wieke C C / Toonen, Erik J M

Frontiers in immunology

2022 Volume 13, Page(s) 1007102

Abstract: Background: The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. ...

Abstract	Background: The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging. Objective: We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components. Methods: A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses. Results: A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used. Conclusion: A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis.
MeSH term(s)	Humans ; Complement C5 ; Complement Activation ; Complement C3 ; Complement Membrane Attack Complex ; Biomarkers
Chemical Substances	Complement C5 ; Complement C3 ; Complement Membrane Attack Complex ; Biomarkers
Language	English
Publishing date	2022-10-18
Publishing country	Switzerland
Document type	Systematic Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1007102
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Article ; Online: Characterization of sepsis inflammatory endotypes using circulatory proteins in patients with severe infection: a prospective cohort study.

Ricaño-Ponce, Isis / Riza, Anca-Lelia / de Nooijer, Aline H / Pirvu, Andrei / Dorobantu, Stefania / Dragos, Adina / Streata, Ioana / Roskanovic, Mihaela / Grondman, Inge / Dumitrescu, Florentina / Kumar, Vinod / Netea, Mihai G / Ioana, Mihai

BMC infectious diseases

2022 Volume 22, Issue 1, Page(s) 778

Abstract: Background: Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene ... ...

Abstract	Background: Sepsis is a heterogeneous syndrome due to a variable range of dysregulated processes in the host immune response. Efforts are made to stratify patients for personalized immune-based treatments and better prognostic prediction. Using gene expression data, different inflammatory profiles have been identified. However, it remains unknown whether these endotypes mirror inflammatory proteome profiling, which would be more feasible to assess in clinical practice. We aim to identify different inflammatory endotypes based on circulating proteins in a cohort of moderately ill patients with severe infection (Sepsis-2 criteria). Methods: In this prospective study, 92 inflammatory plasma markers were profiled using a targeted proteome platform and compared between patients with severe infection (Sepsis-2 criteria) and healthy controls. To identify endotypes with different inflammatory profiles, we performed hierarchical clustering of patients based on the differentially expressed proteins, followed by clinical and demographic characterization of the observed endotypes. Results: In a cohort of 167 patients with severe infection and 192 healthy individuals, we found 62 differentially expressed proteins. Inflammatory proteins such as TNFSF14, OSM, CCL23, IL-6, and HGF were upregulated, while TRANCE, DNER and SCF were downregulated in patients. Unsupervised clustering identified two different inflammatory profiles. One endotype showed significantly higher inflammatory protein abundance, and patients with this endotype were older and showed lower lymphocyte counts compared to the low inflammatory endotype. Conclusions: By identifying endotypes based on inflammatory proteins in moderately ill patients with severe infection, our study suggests that inflammatory proteome profiling can be useful for patient stratification.
MeSH term(s)	Biomarkers ; Humans ; Interleukin-6 ; Prospective Studies ; Proteome ; Sepsis/genetics
Chemical Substances	Biomarkers ; Interleukin-6 ; Proteome
Language	English
Publishing date	2022-10-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2041550-3
ISSN	1471-2334 ; 1471-2334
ISSN (online)	1471-2334
ISSN	1471-2334
DOI	10.1186/s12879-022-07761-0
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Article ; Online: A higher BMI is not associated with a different immune response and disease course in critically ill COVID-19 patients.

Kooistra, Emma J / de Nooijer, Aline H / Claassen, Wout J / Grondman, Inge / Janssen, Nico A F / Netea, Mihai G / van de Veerdonk, Frank L / van der Hoeven, Johannes G / Kox, Matthijs / Pickkers, Peter

International journal of obesity (2005)

2021 Volume 45, Issue 3, Page(s) 687–694

Abstract: Background/objectives: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. ...

Abstract	Background/objectives: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients. Subjects/methods: Sixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m Results: BMI was 32.6 [31.2-34.5] and 26.0 [24.4-27.7] kg/m Conclusions: In COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.
MeSH term(s)	Aged ; Body Mass Index ; COVID-19/complications ; COVID-19/epidemiology ; COVID-19/immunology ; COVID-19/mortality ; Critical Illness ; Cytokines/blood ; Female ; Humans ; Male ; Middle Aged ; Obesity/complications ; Prospective Studies
Chemical Substances	Cytokines
Language	English
Publishing date	2021-01-25
Publishing country	England
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	752409-2
ISSN	1476-5497 ; 0307-0565
ISSN (online)	1476-5497
ISSN	0307-0565
DOI	10.1038/s41366-021-00747-z
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Article ; Online: Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19.

van de Veerdonk, Frank L / Kouijzer, Ilse J E / de Nooijer, Aline H / van der Hoeven, Hans G / Maas, Coen / Netea, Mihai G / Brüggemann, Roger J M

JAMA network open

2020 Volume 3, Issue 8, Page(s) e2017708

MeSH term(s)	Adult ; Aged ; Betacoronavirus ; Bradykinin/analogs & derivatives ; Bradykinin/metabolism ; Bradykinin/therapeutic use ; Bradykinin B2 Receptor Antagonists/therapeutic use ; Coronavirus Infections/drug therapy ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Female ; Humans ; Male ; Middle Aged ; Oxygen/blood ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/virology ; Receptor, Bradykinin B2/metabolism
Chemical Substances	Bradykinin B2 Receptor Antagonists ; Receptor, Bradykinin B2 ; icatibant (7PG89G35Q7) ; Oxygen (S88TT14065) ; Bradykinin (S8TIM42R2W)
Keywords	covid19
Language	English
Publishing date	2020-08-03
Publishing country	United States
Document type	Journal Article
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2020.17708
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Article ; Online: Exploratory analysis of interleukin-38 in hospitalized COVID-19 patients.

de Graaf, Dennis M / Teufel, Lisa U / de Nooijer, Aline H / van Gammeren, Adriaan J / Ermens, Antonius A M / Gaál, Ildikó O / Crișan, Tania O / van de Veerdonk, Frank L / Netea, Mihai G / Dinarello, Charles A / Joosten, Leo A B / Arts, Rob J W

Immunity, inflammation and disease

2022 Volume 10, Issue 11, Page(s) e712

Abstract: Introduction: A major contributor to coronavirus disease 2019 (COVID-19) progression and severity is a dysregulated innate and adaptive immune response. Interleukin-38 (IL-38) is an IL-1 family member with broad anti-inflammatory properties, but thus ... ...

Abstract	Introduction: A major contributor to coronavirus disease 2019 (COVID-19) progression and severity is a dysregulated innate and adaptive immune response. Interleukin-38 (IL-38) is an IL-1 family member with broad anti-inflammatory properties, but thus far little is known about its role in viral infections. Recent studies have shown inconsistent results, as one study finding an increase in circulating IL-38 in COVID-19 patients in comparison to healthy controls, whereas two other studies report no differences in IL-38 concentrations. Methods: Here, we present an exploratory, retrospective cohort study of circulating IL-38 concentrations in hospitalized COVID-19 patients admitted to two Dutch hospitals (discovery n = 148 and validation n = 184) and age- and sex-matched healthy subjects. Plasma IL-38 concentrations were measured by enzyme-linked immunosorbent assay, disease-related proteins by proximity extension assay, and clinical data were retrieved from hospital records. Results: IL-38 concentrations were stable during hospitalization and similar to those of healthy control subjects. IL-38 was not associated with rates of intensive care unit admission or mortality. Only in men in the discovery cohort, IL-38 concentrations were positively correlated with hospitalization duration. A positive correlation between IL-38 and the inflammatory biomarker d-dimer was observed in men of the validation cohort. In women of the validation cohort, IL-38 concentrations correlated negatively with thrombocyte numbers. Furthermore, plasma IL-38 concentrations in the validation cohort correlated positively with TNF, TNFRSF9, IL-10Ra, neurotrophil 3, polymeric immunoglobulin receptor, CHL1, CD244, superoxide dismutase 2, and fatty acid binding protein 2, and negatively with SERPINA12 and cartilage oligomeric matrix protein. Conclusions: These data indicate that IL-38 is not associated with disease outcomes in hospitalized COVID-19 patients. However, moderate correlations between IL-38 concentrations and biomarkers of disease were identified in one of two cohorts. While we demonstrate that IL-38 concentrations are not indicative of COVID-19 severity, its anti-inflammatory effects may reduce COVID-19 severity and should be experimentally investigated.
MeSH term(s)	Male ; Humans ; Female ; COVID-19 ; SARS-CoV-2 ; Retrospective Studies ; Biomarkers ; Anti-Inflammatory Agents ; Interleukins ; Serpins
Chemical Substances	Biomarkers ; Anti-Inflammatory Agents ; Interleukins ; SERPINA12 protein, human ; Serpins ; IL-38 protein, human
Language	English
Publishing date	2022-10-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2740382-8
ISSN	2050-4527 ; 2050-4527
ISSN (online)	2050-4527
ISSN	2050-4527
DOI	10.1002/iid3.712
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Article ; Online: A limited role of cytokine storm and fibrogenesis in COVID-19 related liver injury.

Westerouen van Meeteren, Menso J / Van den Heuvel, Frederik Ma / Weijers, Gert / Joosten, Leo Ab / De Mast, Quirijn / Van de Veerdonk, Frank L / Pickkers, Peter / De Nooijer, Aline H / Hoefsloot, Wouter / Drenth, Joost Ph / De Korte, Chris L / Nijveldt, Robin / Netea, Mihai G / Tjwa, Eric Ttl

Journal of gastrointestinal and liver diseases : JGLD

2021 Volume 30, Issue 1, Page(s) 166–168

MeSH term(s)	Adult ; Aged ; Biomarkers/blood ; COVID-19/complications ; COVID-19/diagnosis ; COVID-19/immunology ; COVID-19/pathology ; Cytokine Release Syndrome/blood ; Cytokine Release Syndrome/diagnosis ; Cytokine Release Syndrome/pathology ; Cytokine Release Syndrome/virology ; Elasticity Imaging Techniques ; Female ; Humans ; Liver Cirrhosis/diagnosis ; Liver Cirrhosis/immunology ; Liver Cirrhosis/pathology ; Liver Cirrhosis/virology ; Male ; Middle Aged
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-03-13
Publishing country	Romania
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2427021-0
ISSN	1842-1121 ; 1841-8724
ISSN (online)	1842-1121
ISSN	1841-8724
DOI	10.15403/jgld-3262
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