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Thorsted, A., Bouchene, S., Tano, E., Castegren, M., Lipcsey, M., Sjölin, J., . . . Nielsen, E. I. (2019). A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6. PLoS ONE, 14(2), Article ID e0211981.
Open this publication in new window or tab >>A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211981Article in journal (Refereed) Published
Abstract [en]

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-379038 (URN)10.1371/journal.pone.0211981 (DOI)000459330800014 ()30789941 (PubMedID)
Funder
Swedish Foundation for Strategic Research
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2019). The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis. Intensive Care Medicine Experimental, 7(1), Article ID 52.
Open this publication in new window or tab >>The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 2197-425X, Vol. 7, no 1, article id 52Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bacterial translocation from the gut has been suggested to induce a systemic inflammatory response syndrome (SIRS) and organ dysfunction. The liver has a pivotal role in eliminating circulating bacteria entering from the gut. We investigated whether pre-existing inflammation affects hepatic bacterial elimination.

METHODS: Fifteen anaesthetised piglets were infused with E. coli in the portal vein for 3 h. The naive group (n = 6) received the bacterial infusion without endotoxin exposure. SIRS (SIRS group, n = 6) was induced by endotoxin infusion 24 h before the bacterial infusion. For effects of anaesthesia, controls (n = 3) received saline instead of endotoxin for 24 h. Bacterial counts and endotoxin levels in the portal and hepatic veins were analysed during bacterial infusion.

RESULTS: The bacterial killing rate was higher in the naive group compared with the SIRS group (p = 0.001). The ratio of hepatic to portal venous bacterial counts, i.e. the median bacterial influx from the splanchnic circulation, was 0.06 (IQR 0.01-0.11) in the naive group and 0.71 (0.03-1.77) in the SIRS group at 3 h, and a magnitude lower in the naive group during bacteraemia (p = 0.03). Similar results were seen for hepatic endotoxin elimination. Peak log tumour necrosis factor alpha was higher in the naive 4.84 (4.77-4.89) vs. the SIRS group 3.27 (3.26-3.32) mg/L (p < 0.001).

CONCLUSIONS: Our results suggest that hepatic bacterial and endotoxin elimination is impaired in pigs with pre-existing SIRS while the inflammatory response to bacterial infusion is diminished. If similar mechanisms operate in human critical illness, the hepatic elimination of bacteria from the gut could be impaired by SIRS.

Keywords
Animal models, Bacterial translocation, Endotoxins, Escherichia coli, Mononuclear phagocyte system, Sepsis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-392098 (URN)10.1186/s40635-019-0266-x (DOI)000483360800001 ()31456116 (PubMedID)
Funder
Swedish Society of Medicine, SLS-409831
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-10-18Bibliographically approved
Skorup, P., Maudsdotter, L., Tano, E., Lipcsey, M., Castegren, M., Larsson, A. & Sjölin, J. (2018). Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model. Critical Care Medicine, 46(7), e634-e641
Open this publication in new window or tab >>Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model
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2018 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 46, no 7, p. e634-e641Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses.

DESIGN: Prospective, placebo-controlled interventional experimental study.

SETTING: University research unit.

SUBJECTS: Thirty-six healthy pigs administered Escherichia coli as a 3-hour infusion.

INTERVENTIONS: After 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline.

MEASUREMENTS AND MAIN RESULTS: Plasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation.

CONCLUSIONS: Treatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-349226 (URN)10.1097/CCM.0000000000003139 (DOI)000435290400002 ()29595561 (PubMedID)
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-12-12Bibliographically approved
Sperber, J., Nyberg, A., Lipcsey, M., Melhus, Å., Larsson, A., Sjölin, J. & Castegren, M. (2017). Protective ventilation reduces Pseudomonas aeruginosa growth in lung tissue in a porcine pneumonia model. Intensive & Critical Care Nursing, 5, Article ID 40.
Open this publication in new window or tab >>Protective ventilation reduces Pseudomonas aeruginosa growth in lung tissue in a porcine pneumonia model
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2017 (English)In: Intensive & Critical Care Nursing, ISSN 0964-3397, E-ISSN 1532-4036, Vol. 5, article id 40Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Mechanical ventilation with positive end expiratory pressure and low tidal volume, i.e. protective ventilation, is recommended in patients with acute respiratory distress syndrome. However, the effect of protective ventilation on bacterial growth during early pneumonia in non-injured lungs is not extensively studied. The main objectives were to compare two different ventilator settings on Pseudomonas aeruginosa growth in lung tissue and the development of lung injury.

METHODS: A porcine model of severe pneumonia was used. The protective group (n = 10) had an end expiratory pressure of 10 cm H2O and a tidal volume of 6 ml x kg-1. The control group (n = 10) had an end expiratory pressure of 5 cm H2O and a tidal volume of 10 ml x kg-1. 1011 colony forming units of Pseudomonas aeruginosa were inoculated intra-tracheally at baseline, after which the experiment continued for 6 h. Two animals from each group received only saline, and served as sham animals. Lung tissue samples from each animal were used for bacterial cultures and wet-to-dry weight ratio measurements.

RESULTS: The protective group displayed lower numbers of Pseudomonas aeruginosa (p < 0.05) in the lung tissue, and a lower wet-to-dry ratio (p < 0.01) than the control group. The control group deteriorated in arterial oxygen tension/inspired oxygen fraction, whereas the protective group was unchanged (p < 0.01).

CONCLUSIONS: In early phase pneumonia, protective ventilation with lower tidal volume and higher end expiratory pressure has the potential to reduce the pulmonary bacterial burden and the development of lung injury.

Keywords
Bacterial infections, Critical care, Models, animal, Protective ventilation, Ventilators, mechanical
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-329206 (URN)10.1186/s40635-017-0152-3 (DOI)000446939000001 ()28861863 (PubMedID)
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2019-02-22Bibliographically approved
Mörth, C., Kafantaris, I., Castegren, M. & Valachis, A. (2016). Validation and optimization of a predictive model for radiation pneumonitis in patients with lung cancer. Oncology Letters, 12(2), 1144-1148
Open this publication in new window or tab >>Validation and optimization of a predictive model for radiation pneumonitis in patients with lung cancer
2016 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 12, no 2, p. 1144-1148Article in journal (Refereed) Published
Abstract [en]

The aim of the current retrospective study was to validate a predictive model for radiation pneumonitis (STRIPE) in an independent dataset and to investigate whether the addition of other potential risk factors could strengthen the accuracy of the model. Consecutive patients with non-small cell lung carcinoma (NSCLC; n=71) treated with definitive concurrent chemotherapy and radiotherapy were retrospectively assessed for radiation pneumonitis (RP). The results identified that 16 (23%) patients developed grade >= 2 RP. Furthermore, STRIPE score (intermediate vs. low risk) was independently associated with the development of RP [odds ratio (OR), 3.72; 95% confidence interval (CI), 1.00-13.89], whereas current smoking status was found to be protective against RP (OR, 0.09; 95% CI, 0.01-0.78). Similar discriminatory power of the STRIPE score was observed as in the original study. The addition of smoking status strengthened the model's discriminatory ability to predict RP. Thus, the addition of smoking status as a risk factor may strengthen the accuracy of the model for predicting RP in patients with NSCLC.

Keywords
non-small cell lung cancer, radiation pneumonitis, radiotherapy, concurrent chemoradiation therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-301419 (URN)10.3892/ol.2016.4678 (DOI)000379982500060 ()
Available from: 2016-08-23 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
Sperber, J., Lipcsey, M., Larsson, A., Larsson, A., Sjölin, J. & Castegren, M. (2015). Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis. BMC Pulmonary Medicine, 15, Article ID 60.
Open this publication in new window or tab >>Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis
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2015 (English)In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 15, article id 60Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Protective ventilation with lower tidal volume (VT) and higher positive end-expiratory pressure (PEEP) reduces the negative additive effects of mechanical ventilation during systemic inflammatory response syndrome. We hypothesised that protective ventilation during surgery would affect the organ-specific immune response in an experimental animal model of endotoxin-induced sepsis-like syndrome.

METHODS: 30 pigs were laparotomised for 2 hours (h), after which a continuous endotoxin infusion was started at 0.25 micrograms × kg(-1) × h(-1) for 5 h. Catheters were placed in the carotid artery, hepatic vein, portal vein and jugular bulb. Animals were randomised to two protective ventilation groups (n = 10 each): one group was ventilated with VT 6 mL × kg(-1) during the whole experiment while the other group was ventilated during the surgical phase with VT of 10 mL × kg(-1). In both groups PEEP was 5 cmH2O during surgery and increased to 10 cmH2O at the start of endotoxin infusion. A control group (n = 10) was ventilated with VT of 10 mL × kg(-1) and PEEP 5 cm H20 throughout the experiment. In four sample locations we a) simultaneously compared cytokine levels, b) studied the effect of protective ventilation initiated before and during endotoxemia and c) evaluated protective ventilation on organ-specific cytokine levels.

RESULTS: TNF-alpha levels were highest in the hepatic vein, IL-6 levels highest in the artery and jugular bulb and IL-10 levels lowest in the artery. Protective ventilation initiated before and during endotoxemia did not differ in organ-specific cytokine levels. Protective ventilation led to lower levels of TNF-alpha in the hepatic vein compared with the control group, whereas no significant differences were seen in the artery, portal vein or jugular bulb.

CONCLUSIONS: Variation between organs in cytokine output was observed during experimental sepsis. We see no implication from cytokine levels for initiating protective ventilation before endotoxemia. However, during endotoxemia protective ventilation attenuates hepatic inflammatory cytokine output contributing to a reduced total inflammatory burden.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-253174 (URN)10.1186/s12890-015-0052-9 (DOI)000354840700001 ()25958003 (PubMedID)
Available from: 2015-05-23 Created: 2015-05-23 Last updated: 2017-12-04Bibliographically approved
Lipcsey, M., Castegren, M. & Bellomo, R. (2015). Hemodynamic management of septic shock. Minerva Anestesiologica, 81(11), 1262-1272
Open this publication in new window or tab >>Hemodynamic management of septic shock
2015 (English)In: Minerva Anestesiologica, ISSN 0375-9393, E-ISSN 1827-1596, Vol. 81, no 11, p. 1262-1272Article in journal (Refereed) Published
Abstract [en]

We present a review of the hemodynamic management of septic shock. Although substantial amount of evidence is present in this area, most key decisions on the management of these patients remain dependent on physiological reasoning and on pathophysiological principles rather than randomized controlled trials. During primary (early) resuscitation, restoration of adequate arterial pressure and cardiac output using fluids and vasopressor and/or inotropic drugs is guided by basic hemodynamic monitoring and physical examination in the emergency department. When more advanced level of monitoring is present in these patients, i.e. during secondary resuscitation (later phase in the emergency department and in the ICU), hemodynamic management can be guided by more advanced measurements of the macro--circulation. Our understanding of the microcirculation in septic shock is limited and reliable therapeutic modalities to optimize it do not yet exist. No specific hemodynamic treatment strategy, be it medications including fluids, monitoring devices or treatment algorithms has yet been proved to improve outcome. Moreover, there is virtually no data on the optimal management of the resolution phase of septic shock. Despite these gaps in knowledge, the data from observational studies and trials suggests that mortality in septic shock has been generally decreasing during the last decade.

National Category
Medical and Health Sciences Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-265779 (URN)000367565200014 ()25369134 (PubMedID)
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-12-01Bibliographically approved
Castegren, M., Jonasson, M., Castegren, S., Lipcsey, M. & Sjölin, J. (2015). Initial levels of organ failure, microbial findings and mortality in intensive care-treated primary, secondary and tertiary sepsis. CRITICAL CARE AND RESUSCITATION, 17(3), 174-181
Open this publication in new window or tab >>Initial levels of organ failure, microbial findings and mortality in intensive care-treated primary, secondary and tertiary sepsis
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2015 (English)In: CRITICAL CARE AND RESUSCITATION, ISSN 1441-2772, Vol. 17, no 3, p. 174-181Article in journal (Refereed) Published
Abstract [en]

Objective: Analysis of whether patients with primary, secondary and tertiary sepsis, defined by the presence or absence of recent systemic inflammation-inducing events before the onset of sepsis, differ in clinical presentation, microbiological test results, treatment received and outcome. Design, setting and participants: A retrospective observational study in a single, general intensive care unit, of all patients treated for severe sepsis or septic shock from 2006 to 2011. Patients with haematological malignancies, with immunosuppressive diseases or being treated with immunosuppressive drugs were excluded. Interventions: None. Main outcome measures: Sequential Organ Failure Assessment score, incidence of organ failure, microbiological results of blood cultures and mortality. Results: We included 213 patients, who were classified as having primary (n = 121), secondary (n = 65) or tertiary sepsis (n = 27). The groups differed significantly in SOFA score, the incidence of kidney failure and coagulation failure at onset of sepsis in the ICU, as well as in blood culture findings. No differences in 7-day or 28-day mortality were seen, but the time of death occurred earlier among non-survivors in the primary sepsis group. Conclusions: Inflammatory insults before the onset of sepsis affect the clinical picture, blood microbial findings, and in non-survivors, the time of death. These results could, if validated in a prospective study, form a basis for a novel and simple strategy for stratifying patients in clinical studies for immunomodulation therapies in sepsis.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-263441 (URN)000360776400005 ()26282255 (PubMedID)
Available from: 2015-10-07 Created: 2015-09-30 Last updated: 2016-02-29Bibliographically approved
Schell, C. O., Castegren, M., Lugazia, E., Blixt, J., Mulungu, M., Konrad, D. & Baker, T. (2015). Severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a low-income country. BMC Research Notes, 8, Article ID 313.
Open this publication in new window or tab >>Severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a low-income country
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2015 (English)In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 8, article id 313Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Critical care saves lives of the young with reversible disease. Little is known about critical care services in low-income countries. In a setting with a shortage of doctors the actions of the nurse bedside are likely to have a major impact on the outcome of critically ill patients with rapidly changing physiology. Identification of severely deranged vital signs and subsequent treatment modifications are the basis of modern routines in critical care, for example goal directed therapy and rapid response teams. This study assesses how often severely deranged vital signs trigger an acute treatment modification on an Intensive Care Unit (ICU) in Tanzania.

METHODS: A medical records based, observational study. Vital signs (conscious level, respiratory rate, oxygen saturation, heart rate and systolic blood pressure) were collected as repeated point prevalences three times per day in a 1-month period for all adult patients on the ICU. Severely deranged vital signs were identified and treatment modifications within 1 h were noted.

RESULTS: Of 615 vital signs studied, 126 (18%) were severely deranged. An acute treatment modification was in total indicated in 53 situations and was carried out three times (6%) (2/32 for hypotension, 0/8 for tachypnoea, 1/6 for tachycardia, 0/4 for unconsciousness and 0/3 for hypoxia).

CONCLUSIONS: This study suggests that severely deranged vital signs are common and infrequently lead to acute treatment modifications on an ICU in a low-income country. There may be potential to improve outcome if nurses are guided to administer acute treatment modifications by using a vital sign directed approach. A prospective study of a vital sign directed therapy protocol is underway.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-280215 (URN)10.1186/s13104-015-1275-9 (DOI)26205670 (PubMedID)
Available from: 2016-03-09 Created: 2016-03-09 Last updated: 2017-11-30Bibliographically approved
Baker, T., Blixt, J., Lugazia, E., Schell, C. O., Mulungu, M., Milton, A., . . . Konrad, D. (2015). Single Deranged Physiologic Parameters Are Associated With Mortality in a Low-Income Country. Critical Care Medicine, 43(10), 2171-2179
Open this publication in new window or tab >>Single Deranged Physiologic Parameters Are Associated With Mortality in a Low-Income Country
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2015 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 10, p. 2171-2179Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether deranged physiologic parameters at admission to an ICU in Tanzania are associated with in-hospital mortality and compare single deranged physiologic parameters to a more complex scoring system. Design: Prospective, observational cohort study of patient notes and admission records. Data were collected on vital signs at admission to the ICU, patient characteristics, and outcomes. Cutoffs for deranged physiologic parameters were defined a priori and their association with in-hospital mortality was analyzed using multivariable logistic regression. Setting: ICU at Muhimbili National Hospital, Dar es Salaam, Tanzania. Patients: All adults admitted to the ICU in a 15-month period. Measurements and Main Results: Two hundred sixty-nine patients were included: 54% female, median age 35 years. In-hospital mortality was 50%. At admission, 69% of patients had one or more deranged physiologic parameter. Sixty-four percent of the patients with a deranged physiologic parameter died in hospital compared with 18% without (p < 0.001). The presence of a deranged physiologic parameter was associated with mortality (adjusted odds ratio, 4.64; 95% CI, 1.95-11.09). Mortality increased with increasing number of deranged physiologic parameters (odds ratio per deranged physiologic parameter, 2.24 [1.53-3.26]). Every individual deranged physiologic parameter was associated with mortality with unadjusted odds ratios between 1.92 and 16.16. A National Early Warning Score of greater than or equal to 7 had an association with mortality (odds ratio, 2.51 [1.23-5.14]). Conclusion: Single deranged physiologic parameters at admission are associated with mortality in a critically ill population in a low-income country. As a measure of illness severity, single deranged physiologic parameters are as useful as a compound scoring system in this setting and could be termed danger signs. Danger signs may be suitable for the basis of routines to identify and treat critically ill patients.

Keywords
critical care, developing countries, global health, hospital mortality, quality of health care, vital signs
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-264601 (URN)10.1097/CCM.0000000000001194 (DOI)000361358900016 ()26154933 (PubMedID)
Funder
The Karolinska Institutet's Research Foundation
Available from: 2015-10-30 Created: 2015-10-15 Last updated: 2017-12-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9292-0298

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