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Abujrais, S., Olovsson, M., Ahnoff, M., Rasmusson, A., Larsson, A., Åkerfeldt, T. & Kultima, K. (2019). A sensitive method detecting trace levels of levonorgestrel using LC-HRMS.. Contraception, 100(3), 247-249
Open this publication in new window or tab >>A sensitive method detecting trace levels of levonorgestrel using LC-HRMS.
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2019 (English)In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 100, no 3, p. 247-249Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To develop a high resolution mass spectrometry (HRMS) method to quantify levonorgestrel (LNG) in serum.

STUDY DESIGN: Levonorgestrel was extracted using solid phase extraction and measured using liquid chromatography (LC) HRMS.

RESULTS: Low limit of quantification (LLOQ) was 25pg/mL and low limit of detection (LLOD) was 12.5pg/mL. Precision and accuracy bias were<10%. LNG in serum samples from Mirena® users ranged between 37 to 219pg/mL (n=12). In eight out of 22 patients with suspected intrauterine device (IUD) expulsion LNG was detected (26 to 1272pg/mL).

CONCLUSION: A sensitive, fast and simple LC-HRMS method was developed to detect trace levels of LNG.

Keywords
High resolution mass spectrometry, Intrauterine device, Liquid chromatography, Lower limit of quantification, Solid phase extraction
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-388593 (URN)10.1016/j.contraception.2019.06.001 (DOI)000483452100015 ()31216423 (PubMedID)
Available from: 2019-07-02 Created: 2019-07-02 Last updated: 2019-10-17Bibliographically approved
Nordin, G., Ekvall, S., Kristoffersson, C., Jonsson, A.-S., Bäck, S.-E., Rollborn, N. & Larsson, A. (2019). Accuracy of determination of the glomerular filtration marker iohexol by European laboratories as monitored by external quality assessment. Clinical Chemistry and Laboratory Medicine, 57(7), 1006-1011
Open this publication in new window or tab >>Accuracy of determination of the glomerular filtration marker iohexol by European laboratories as monitored by external quality assessment
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2019 (English)In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 57, no 7, p. 1006-1011Article in journal (Refereed) Published
Abstract [en]

Background Glomerular filtration is the most important kidney function. The most accurate glomerular filtration rate (GFR) estimates are based on the clearance of exogenous filtration markers. Of these, iohexol is the only exogenous marker that is included in an external quality assessment (EQA) scheme. The aim of the present study was to evaluate the performance of the European laboratories participating in Equalis' EQA scheme for iohexol. Methods Weighed amounts of iohexol (Omnipaque) were added to plasma samples and distributed to laboratories participating in the EQA scheme for iohexol. All laboratories performed the assays in a blinded fashion. Results The number of participating laboratories varied between 27 and 34 during the study period. Iohexol was determined by HPLC in 77% of the laboratories and by UPLC/MS/MS methods in 15% of the laboratories. The mean interlaboratory coefficient of variation was 4.7% for the HPLC methods and 6.4% for the UPLC/MS/MS methods. The mean bias between calculated and measured iohexol values was -1.3 mg/L (95% confidence interval ±0.3) during the first part of the study period and 0.1 mg/L (±0.3) during the later part. Conclusions The low interlaboratory variation demonstrates that iohexol can be measured reliably by many laboratories and supports the use of iohexol as a GFR marker when there is a need for high quality GFR measurements.

Place, publisher, year, edition, pages
Walter de Gruyter, 2019
Keywords
GFR, external quality assessment scheme, glomerular filtration rate, iohexol
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-383248 (URN)10.1515/cclm-2018-1175 (DOI)000470676100019 ()31075079 (PubMedID)
Available from: 2019-05-11 Created: 2019-05-11 Last updated: 2019-06-26Bibliographically approved
Chang, A. R., Grams, M. E., Ballew, S. H., Bilo, H., Correa, A., Evans, M., . . . Woodward, M. (2019). Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium. BMJ. British Medical Journal, 364, Article ID k5301.
Open this publication in new window or tab >>Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium
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2019 (English)In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 364, article id k5301Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality.

DESIGN: Individual participant data meta-analysis.

SETTING: Cohorts from 40 countries with data collected between 1970 and 2017.

PARTICIPANTS: Adults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607).

MAIN OUTCOME MEASURES: GFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR <10 mL/min/1.73 m2) and all cause mortality.

RESULTS: Over a mean follow-up of eight years, 246 607 (5.6%) individuals in the general population cohorts had GFR decline (18 118 (0.4%) end stage kidney disease events) and 782 329 (14.7%) died. Adjusting for age, sex, race, and current smoking, the hazard ratios for GFR decline comparing body mass indices 30, 35, and 40 with body mass index 25 were 1.18 (95% confidence interval 1.09 to 1.27), 1.69 (1.51 to 1.89), and 2.02 (1.80 to 2.27), respectively. Results were similar in all subgroups of estimated GFR. Associations weakened after adjustment for additional comorbidities, with respective hazard ratios of 1.03 (0.95 to 1.11), 1.28 (1.14 to 1.44), and 1.46 (1.28 to 1.67). The association between body mass index and death was J shaped, with the lowest risk at body mass index of 25. In the cohorts with high cardiovascular risk and chronic kidney disease (mean follow-up of six and four years, respectively), risk associations between higher body mass index and GFR decline were weaker than in the general population, and the association between body mass index and death was also J shaped, with the lowest risk between body mass index 25 and 30. In all cohort types, associations between higher waist circumference and higher waist-to-height ratio with GFR decline were similar to that of body mass index; however, increased risk of death was not associated with lower waist circumference or waist-to-height ratio, as was seen with body mass index.

CONCLUSIONS: Elevated body mass index, waist circumference, and waist-to-height ratio are independent risk factors for GFR decline and death in individuals who have normal or reduced levels of estimated GFR.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-373654 (URN)10.1136/bmj.k5301 (DOI)000455770800012 ()30630856 (PubMedID)
Note

Anders Larsson, Lars Lannfelt and Johan Ärnlöv are collaborators in the CKD Prognosis Consortium (CKD-PC).

Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-04-02Bibliographically approved
Ridefelt, P., Hagström, E., Svensson, M. K., Åkerfeldt, T. & Larsson, A. (2019). Age- and sex-specific reference values for non-HDL cholesterol and remnant cholesterol derived from the Nordic Reference Interval Project (NORIP).. Scandinavian Journal of Clinical and Laboratory Investigation
Open this publication in new window or tab >>Age- and sex-specific reference values for non-HDL cholesterol and remnant cholesterol derived from the Nordic Reference Interval Project (NORIP).
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2019 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686Article in journal (Refereed) Epub ahead of print
Abstract [en]

OBJECTIVES: Non-HDL-cholesterol (non-HDL-C) has been reported to be a better marker of cardiovascular risk than LDL-cholesterol (LDL-C) especially in individuals with high triglyceride values. Further, levels of remnant cholesterol have been suggested to in part explain residual risk not captured with LDL-C. The aim of the present study was to define reference values for non-HDL-C and remnant cholesterol based on data from the Nordic Reference Interval Project (NORIP).

METHODS: We analyzed the test results for total cholesterol, HDL-cholesterol and triglycerides from 1392 healthy females and 1236 healthy males. Non-HDL-C was calculated as measured total cholesterol minus measured HDL-cholesterol. Remnant cholesterol was calculated using the Friedewald equation for LDL-C: measured total cholesterol minus measured HDL-cholesterol and minus calculated LDL-cholesterol. The 2.5th and 97.5th percentiles for these markers were calculated according to the International Federation of Clinical Chemistry guidelines on the statistical treatment of reference values.

RESULTS: Age (18-<30, 30-49 and ≥50 years) and sex-specific reference intervals were calculated for non-HDL-cholesterol and remnant-cholesterol. Levels of non-HDL-C and remnant cholesterol differed between sex and age strata.

CONCLUSIONS: Age- and sex-specific reference intervals should be used for the triglyceride rich lipid variables non-HDL-C and remnant cholesterol. Since these markers may add information on risk burden beyond LDL-C, our hope is that these reference intervals will aid the introduction of automatic reporting of non-HDL-C by hospital laboratories.

Keywords
HDL-cholesterol, Reference values, non-HDL-cholesterol, remnant cholesterol, triglyceride-rich particles
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-373651 (URN)10.1080/00365513.2018.1550809 (DOI)30638091 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-04-02Bibliographically approved
Govorov, I., Bremme, K., Larsson, A., Holmström, M., Komlichenko, E., Chaireti, R. & Mints, M. (2019). Blood inflammatory and endothelial markers in women with von Willebrand disease. PLoS ONE, 14(1), Article ID e0210544.
Open this publication in new window or tab >>Blood inflammatory and endothelial markers in women with von Willebrand disease
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210544Article in journal (Refereed) Published
Abstract [en]

Introduction: VWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls.

Materials and methods: The study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI.

Results: Within the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle.

Conclusions: Higher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia—common complication of VWF deficiency. The latter statement requires confirmation in larger studies.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-373652 (URN)10.1371/journal.pone.0210544 (DOI)000455483000105 ()30629692 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-02-05Bibliographically approved
Larsson, A. & Breimer, L. (2019). Bra att läkare inte stirrar sig blinda på HbA1c. Läkartidningen, 116, FIEW
Open this publication in new window or tab >>Bra att läkare inte stirrar sig blinda på HbA1c
2019 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, p. FIEW-Article in journal (Other academic) Published
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-376653 (URN)
Note

Slutreplik på tidigare publicerad debattartikel i Läkartidningen om hemoglobinopatier.

Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-04-11Bibliographically approved
Frithiof, R., Bandert, A., Larsson, A., Lipcsey, M. & Smekal, D. (2019). Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.. ASAIO journal (1992), 65(4), 408-413
Open this publication in new window or tab >>Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.
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2019 (English)In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 65, no 4, p. 408-413Article in journal (Refereed) Published
Abstract [en]

In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/L [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-353342 (URN)10.1097/MAT.0000000000000839 (DOI)000466791000022 ()29863633 (PubMedID)
Funder
Swedish Research Council, 523-2014-2569
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2019-05-29Bibliographically approved
Ruge, T., Carlsson, A. C., Kjøller, E., Hilden, J., Kolmos, H. J., Sajadieh, A., . . . Ärnlöv, J. (2019). Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study. Atherosclerosis, 284, 202-208
Open this publication in new window or tab >>Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study
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2019 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 284, p. 202-208Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain.

METHODS: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979).

RESULTS: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03-1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00-1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%).

CONCLUSIONS: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

Keywords
Cardiovascular, Endostatin, Epidemiology, Extracellular matrix, Mortality
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-382572 (URN)10.1016/j.atherosclerosis.2019.02.031 (DOI)000466155400027 ()30959314 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung FoundationMarianne and Marcus Wallenberg FoundationThuréus stiftelse för främjande av geriatrisk forskning
Available from: 2019-04-26 Created: 2019-04-26 Last updated: 2019-06-18Bibliographically approved
Idborg, H., Zandian, A., Ossipova, E., Wigren, E., Preger, C., Mobarrez, F., . . . Jakobsson, P.-J. (2019). Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.. Frontiers in Immunology, 10, Article ID 1029.
Open this publication in new window or tab >>Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed) Published
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10-9, 3 × 10-6, and 5 × 10-6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Keywords
Interferon regulating factor 5 (IRF5), SLE - Systemic Lupus Erythematous, antibody suspension bead arrays, biomarker discovery, hierarchical clustering, plasma proteomics, subgroups, unsupervised clustering
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-385062 (URN)10.3389/fimmu.2019.01029 (DOI)000468162000001 ()31156624 (PubMedID)
Funder
Swedish Research Council, 2017-02577Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Research Council, 2018-02000Stockholm County Council, 20160378Stockholm County Council, 20170038Swedish Rheumatism Association, R-748261Swedish Rheumatism Association, R-755861Swedish Rheumatism Association, R-753741Swedish Rheumatism Association, R-850611Swedish Rheumatism Association, R-739631Swedish Society of Medicine
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-11Bibliographically approved
Strandberg, G., Larsson, A., Lipcsey, M. & Eriksson, M. (2019). Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock. Clinical Laboratory, 65(7), 1169-1177
Open this publication in new window or tab >>Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock
2019 (English)In: Clinical Laboratory, ISSN 1433-6510, Vol. 65, no 7, p. 1169-1177Article in journal (Refereed) Published
Abstract [en]

Background: Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding whether and which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited.

Methods: Twelve anesthetized pigs were sampled from IO, venous, and arterial accesses during stable circulation and after hemorrhage corresponding to 20% and 40% of the blood volume. Samples were analyzed for blood gases and acid-base status, electrolytes, hematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), and creatine kinase (CK).

Results: Average differences of blood gases and acid-base parameters, sodium, creatinine, hematocrit, ALT, and γ-GT and between IO and venous samples were small at baseline and after hemorrhage while differences for lactate and glucose increased with hypovolemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolemia. Dispersions of differences were often large.

Conclusions: Average levels of blood gases, acid base parameters, hematocrit, CK, AST, γ-GT, creatinine, and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.

Keywords
analysis, blood drawing, intraosseous sampling, laboratory, precision, shock
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-321402 (URN)10.7754/Clin.Lab.2019.181214 (DOI)000475700400006 ()31307157 (PubMedID)
Note

Title in thesis list of papers: Comparison of Intraosseous, Arterial and Venous Blood Sampling for Laboratory Analysis in Haemorrhagic Shock

Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2019-08-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3161-0402

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