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Sökning: WFRF:(Nyman Ulf)

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  • Sennefelt Nyman, Sofi, et al. (författare)
  • Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study : idarubicin dose selection, tissue response and survival
  • 2022
  • Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:11
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance.METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival.ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden.TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31.
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  • Alexandersson, Karin, et al. (författare)
  • Producing and consuming knowledge in social work practice: research and development activities in a Swedish context
  • 2009
  • Ingår i: Evidence & Policy. - : Bristol University Press. - 1744-2648 .- 1744-2656. ; 5:2, s. 127-139
  • Tidskriftsartikel (refereegranskat)abstract
    • This article presents various forms of activities performed by locally based social welfare research and development (R&D) units in Sweden. The authors argue that these units are vital actors in the field of encouraging and strengthening evidence-based social work practice. They are close to social services organisations and have the ability to use flexible methods in order to bridge the gap between research and practice in a local context. The theoretical framework for the article is the organisational excellence model – an archetype for how research can be used in practice.
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  • Ali, Hazrat, et al. (författare)
  • Translation of atherosclerotic disease features onto healthy carotid ultrasound images using domain-to-domain translation
  • 2023
  • Ingår i: Biomedical Signal Processing and Control. - 1746-8094 .- 1746-8108. ; 85
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: In this work, we evaluated a model for the translation of atherosclerotic disease features onto healthy carotid ultrasound images.Methods: An un-paired domain-to-domain translation model – the cycle Generative Adversarial Network (cycleGAN) – was trained to translate between carotid ultrasound images of healthy arteries and images of pronounced disease. Translation performance was evaluated using the measurement of wall thickness in original and generated images. In addition, we explored disease translation in different tissue segments (subcutaneous tissue, muscle, lumen, far wall, and deep tissues), using structural similarity index measure (SSIM) maps.Results: Features of pronounced disease were successfully translated to the healthy images (1.2 (0.33) mm vs 0.43 (0.07) mm, p < 0.001), while overall anatomy was retained as SSIM value was equal to 0.78 (0.02). Exploration of translated features showed that both arterial wall and subcutaneous tissues were modified in the translation, but that the subcutaneous tissue was subject to distortion of the anatomy in some cases. The image quality influenced the disease translation performance.Conclusion: The results show that the model can learn a mapping between healthy and diseased images while retaining the overall anatomical contents. This is the first study on atherosclerosis disease translation in medical images.Significance: The concept of translating disease onto existing healthy images may serve purposes such as education, cardiovascular risk communication in health conversations, or personalized modelling in precision medicine.
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  • Andrä, Heiko, et al. (författare)
  • Micromechanical network model for the evaluation of quality controls of paper
  • 2011
  • Ingår i: Progress in Paper Physics Seminar. - 9783851251630 ; , s. 49-55
  • Konferensbidrag (refereegranskat)abstract
    • In this paper, we discuss the challenges in modelling and simulating infinitesimal and large deformations of cellulose fiber networks, mainly in the context of the prediction of quality controls for paper.Understanding the influence and sensitivity of macroscopic production parameters like grammage and thickness of paperboard and understanding the influence of the fiber suspension on the quality of paper is important for the development of better papers and for preserving raw materials and energy.The new simulation framework consists of the virtual stochastic paper structure generator PaperGeo, that was integrated in the GeoDict 1 software suite, and the finite element solver FeelMath (Finite Elements for Elastic Materials and Homogenization) for solving the equations of elasticity. The fibers and the contacts are modelled by using geometrically exact beams of Simo-type [1].The microstructural model and the fiber network model are validated against standard measurements of existing papers in the following way: At first we perform tensile and bending tests to measure the macroscopic stress-strain relations. In the next step we apply a representative macroscopic stress or strain onto the boundaries of realizations of the stochastic fiber network model and compute by homogenization the effective (stiffness) coefficients. Finally we compare the numerical results with the measurements.This procedure can also be used for an identification of elastic parameters on the microscale and to study the sensitivity of the effective (macroscopic) stiffness with regard to the parameters of the microstructure
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  • Annertz, Mårten, et al. (författare)
  • Ländryggsröntgen ger falsk säkerhet och ringa nytta för patienten : MRT och DT ger bättre och billigare resultat
  • 2017
  • Ingår i: Läkartidningen. - 0023-7205. ; 114:46, s. 1962-1962
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • In 2016 140 000 lumbar spine radiographies were performed in Sweden (14 000 per million inhabitants) to a cost of about 85 million SEK (≈8.5 million Euro) and a negligible value for the patients with low back pain. In the work-up of low back pain, when imaging is indicated, lumbar spine radiography should be replaced by limited magnetic resonance imaging including a whole lower body coronal STIR sequence or computed tomography with radiation dose adapted to indication and patient age. Indication for imaging should be restricted to 1) low back pain with more than 3-4 weeks duration in combination with at least one »red flag«, 2) radicular pain without improvement on conservative treatment, or 3) low back pain with more than 8 weeks duration in combination with »yellow flags«.
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  • Bengtsson, Anna, 1973-, et al. (författare)
  • Multi-view carotid ultrasound is stronger associated with cardiovascular risk factors than presence of plaque or single carotid intima media thickness measurements in subclinical atherosclerosis
  • 2023
  • Ingår i: The International Journal of Cardiovascular Imaging. - : Springer Nature. - 1569-5794 .- 1875-8312. ; 39:8, s. 1461-1471
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed to explore the prevalence of atherosclerosis by using multi-view ultrasound examination of the carotid arteries and its association with clinical risk factors in a middle-aged population at low to intermediate risk of cardiovascular disease (CVD). Carotid vascular ultrasound was performed in 3532 participants in the VIPVIZA trial. Mean and maximal carotid intima media thickness (cIMT) at prespecified angles and plaque presence were examined on the left and right side. Associations between CVD risk factors and ultrasound variables were quantified by partial least squares (PLS) regression. A combined ultrasound variable was computed using weights of the first PLS component. Associations between CVD risk factors and the combined multi-view ultrasound variable, single cIMT and plaque measurements, respectively, were determined using linear regression modelling. The participants’ mean age was 55.7 years and 52.9% were women. Plaque prevalence was 51.1% in men and 39.0% in women. cIMT was higher in men than in women and in the left compared with the right carotid artery. The strongest association of CVD risk factors was observed with the combined multi-view ultrasound variable (R2 = 24%), compared with single cIMT variables (R2 = 14–18%) and plaque presence (R2 = 15%). The pattern was similar in both sexes. The association with CVD risk factors and the combined ultrasound variable was stronger in 40-year olds (R2 = 22%) compared with 50- or 60-year olds (R = 12%). CVD risk factors are stronger associated with a combined ultrasound variable than plaque presence or single cIMT measures suggesting that carotid multi-view ultrasonography better captures the focality of early atherosclerosis. Clinical Trial Registration: ClinicalTrials.gov, number NCT01849575. May 8, 2013.
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  • Bengtsson, Anna, 1973-, et al. (författare)
  • The beneficial effect over 3 years by pictorial information to patients and their physician about subclinical atherosclerosis and cardiovascular risk : results from the VIPVIZA randomized clinical trial
  • 2021
  • Ingår i: American Journal of Preventive Cardiology. - : Elsevier. - 2666-6677. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Non-adherence to guidelines and preventive measures is a major challenge, particularly so to ob- tain long-term adherence to lifestyle changes and recommended medication. The objective was to investigate if pictorial information regarding subclinical carotid atherosclerosis provided to individuals and physicians gave sustained effects on cardiovascular risk beyond the previously reported effect after 1 year and up to 3 years. Methods: A Prospective Randomized Open Blinded End-point (PROBE) trial. Within a CVD prevention program in Västerbotten County, Sweden, 3532 healthy individuals aged 40, 50 or 60 years were enrolled and 1:1 ran- domized to intervention ( n = 1749; pictorial information with additional prevention materials to participants and physicians) or control group ( n = 1783; no pictorial information to participants and physicians). Preventive measures were managed within primary care. Participants were investigated at baseline during 2013–2016 and at follow-up after 1 and 3 years. Results: A beneficial effect on cardiovascular risk was observed at 3-year follow-up; Framingham Risk Score (FRS) was 13.38 for the intervention group and 14.08 for the control group ( p = 0.047) and SCORE was 1.69 vs. 1.82 ( p = 0.022). The effect observed at 1-year was sustained over 3 years after adjustment for sex and education and more pronounced among participants with a severe atherosclerotic picture at baseline.Conclusions: This study provides evidence of sustained beneficial effects on the adherence to prevention guidelines over 3 years of pictorial information about subclinical carotid atherosclerosis, resulting in lower cardiovascular risk regardless of sex and educational level. Direct visualization of the underlying still subclinical atherosclerotic disease, rather than just indirect information about risk factors and statistical risk of future myocardial infarction, stroke and death, is one way to tackle the problem of non-adherence to prevention of cardiovascular diseases.
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  • Bengtsson, Staffan, et al. (författare)
  • Producing and consuming knowledge in social work practice : Research and development activities in a Swedish context.
  • 2009
  • Ingår i: Evidence and policy. - : Policy Press. - 1744-2648 .- 1744-2656. ; 5:2, s. 127-139
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this article is to describe how experince-based knowledge can be made visible by giving some examples of how this has been done in Swedish social welfare services, in collaborations between social services agencies and research and development (R&D) units. These examples will be linked to theories and discussed in relation to different research utilisation models. By using one of these models, it is argued that R&D activities can broaden the concept of evidence-based practice and help brigde the gap between research and practice.
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  • Berg, Ulla B., et al. (författare)
  • New standardized cystatin C and creatinine GFR equations in children validated with inulin clearance
  • 2015
  • Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 30:8, s. 1317-1326
  • Tidskriftsartikel (refereegranskat)abstract
    • This study compares glomerular filtration rate (GFR) equations in children based on standardized cystatin C (CYSC) and creatinine (CREA) and their combinations with renal clearance of inulin (C-inulin). A total of 220 children with different renal disorders were referred for C-inulin (median 84 ml/min/1.73 m(2)). Bias, precision (interquartile range, IQR), and accuracy (percentage of estimates +/- 30 % of C-inulin; P30) were evaluated for two cystatin C equations, CAPA(CYSC) and Berg(CYSC), for creatinine equations, Schwartz(CREA) and Gao(CREA), the arithmetic mean of CAPA(CYSC) and Schwartz(CREA) (MEAN(CAPA+Schwartz)), Berg(CYSC) and Schwartz(CREA) (MEAN(BERG+SCHWARTZ)) and the composite equation Chehade(CYSC+CREA). Overall results of CAPA(CYSC), Berg(CYSC), Schwartz(CREA), Gao(CREA), MEAN(CAPA+Schwartz,) MEAN(BERG+SCHWARTZ) and Chehade(CYSC+CREA) were: median bias -7.6/-4.9/-3.7/-2.3/-4.6/-4.0/-10.1 %, IQR 20.0/19.9/21.7/22.4/21.0/20.9/23.3 ml/min/1.73 m(2) and P30 86/86/80/83/89/91/83 %. The cystatin C equations, MEAN(CAPA+Schwartz) and MEAN(BERG+SCHWARTZ) had a more stable performance across subgroups compared with Schwartz(CREA), Gao(CREA) and Chehade(CYSC+CREA). Cystatin C was the preferred filtration marker for GFR estimation in children, while the benefit of combining cystatin C and creatinine deserves further investigations.
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  • Berger, Karin, et al. (författare)
  • Cereal Byproducts Have Prebiotic Potential in Mice Fed a High-Fat Diet
  • 2014
  • Ingår i: Journal of Agricultural and Food Chemistry. - : American Chemical Society (ACS). - 0021-8561 .- 1520-5118. ; 62:32, s. 8169-8178
  • Tidskriftsartikel (refereegranskat)abstract
    • Barley husks, rye bran, and a fiber residue from oat milk production were processed by heat pretreatment, various separation steps, and treatment with an endoxylanase in order to improve the prebiotic potential of these cereal byproducts. Metabolic functions were intended to improve along with improved microbial activity. The products obtained were included in a high-fat mouse diet so that all diets contained 5% dietary fiber. In addition, high-fat and low-fat controls as well as partially hydrolyzed guar gum were included in the study. The soluble fiber product obtained from rye bran caused a significant increase in the bifidobacteria (log copies of 16S rRNA genes; median (25−75 percentile): 6.38 (6.04−6.66) and 7.47 (7.30−7.74), respectively; p < 0.001) in parallel with a tendency of increased production of propionic acid and indications of improved metabolic function compared with high-fat fed control mice. The oat-derived product caused an increase in the pool of cecal propionic (from 0.62 ± 0.12 to 0.94 ± 0.08) and butyric acid (from 0.38 ± 0.04 to 0.60 ± 0.04) compared with the high-fat control, and it caused a significant increase in lactobacilli (log copies of 16S rRNA genes; median (25−75 percentile): 6.83 (6.65−7.53) and 8.04 (7.86−8.33), respectively; p < 0.01) in the cecal mucosa. However, no changes in measured metabolic parameters were observed by either oat or barley products.
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  • Björk, Jonas, et al. (författare)
  • A new tool for predicting the probability of chronic kidney disease from a specific value of estimated GFR.
  • 2010
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; Jul 1, s. 327-333
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Objective. To demonstrate how patients' probability of having chronic kidney disease (CKD) stage 3-5 (measured GFR <60 mL/min/1.73 m(2)) can be predicted from a specific value of estimated glomerular filtration rate (eGFR). Material and methods. The probability of CKD stage 3-5 was predicted from a logistic regression model (n = 850) using three different eGFR prediction equations: Lund-Malmö, MDRD and CKD-EPI. Population weighting was used to illustrate how this probability varies in three different populations: original sample (55% true prevalence of CKD stage 3-5), a screening (6.7% prevalence) and a CKD population (84% prevalence). Results. All three eGFR-equations had high classification ability (area under the receiver-operating-characteristic curve = 97%). The probability of CKD stage 3-5 increased with decreasing eGFR, varied substantially among the populations studied and to some extent between the eGFR-equations. Using the Lund-Malmö equation as illustration, the probability of CKD stage 3-5 is > 90% only when eGFR is <38 mL/min/1.73 m(2) in a screening population, whereas it is > 90% already when eGFR is <51 mL/min/1.73 m(2) in a CKD population. Conversely, the probability of CKD stage 3-5 is <10% if eGFR > 59 mL/min/1.73 m(2) in a screening population, whereas it is <10% only when eGFR is > 88 mL/min/1.73 m(2) in a CKD population. Conclusion. Instead of reporting diagnostic accuracy as sensitivity, specificity, and predictive values, actual eGFR supplemented with the probability that it represents a true GFR <60 mL/min/1.73 m(2) may be more valuable for physicians. Clinical (pre-test) probability in the population must be considered when predicting this probability.
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  • Björk, Jonas, et al. (författare)
  • A novel method for creatinine adjustment makes the revised Lund-Malmö GFR estimating equation applicable in children
  • 2020
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 80:6, s. 456-463
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2-40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund-Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P30) of mGFR. Remarkable improvements in bias and accuracy were observed; P30 increased from 56% to 74% after creatinine adjustments in children with mGFR <75 mL/min/1.73 m2 (n = 932), while P30 was relatively unchanged (89-90%) at mGFR ≥75 mL/min/1.73 m2 (n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.
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  • Björk, Jonas, et al. (författare)
  • Accuracy diagrams : a novel way to illustrate uncertainty of estimated GFR
  • 2017
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 77:3, s. 199-204
  • Tidskriftsartikel (refereegranskat)abstract
    • Most studies that validate GFR equations present accuracy results stratified by measured GFR (mGFR; diagnostic correctness) or by estimated GFR (eGFR; diagnostic predictiveness) only, without a clear distinction in interpretation. The accuracy of a GFR equation is normally reported in percent (e.g. P30), but is often misinterpreted when stratified by eGFR. The aim of the study was to develop new accuracy measures and diagrams that allow straightforward interpretations and illustrations of the uncertainty in eGFR in clinical practice. We applied quantile regression to the distribution of estimation errors for two creatinine-based GFR equations, LM-REV and CKD-EPI, in a clinical cohort (n = 3495) referred for GFR measurement (plasma clearance of iohexol). Measures of bias and precision and accuracy intervals (AIs) were expressed in mL/min/1.73 m2. Diagrams with AIs were chosen as a novel way to present the error margin in eGFR at a pre-specified certainty level. It was shown that creatinine-based equations are still quite inaccurate in that large estimation errors could not be ruled out with satisfactory certainty. As an example, the 75% AI for the most accurate equation, LM-REV, was approximately ±10 mL/min/1.73 m2 at eGFR = 45 mL/min/1.73 m2, whereas it ranged between −13 and +20 mL/min/1.73 m2 at eGFR = 90 mL/min/1.73 m2. Accuracy intervals presented in diagrams can be used to illustrate the uncertainty of eGFR. Future validation studies should assess the variability in the predictiveness of eGFR across populations and clinical settings using tools and performance measures that are easy to interpret.
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  • Björk, Jonas, et al. (författare)
  • Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays: a cross-sectional study in Sweden
  • 2015
  • Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 53:3, s. 403-414
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The recently established international cystatin C calibrator makes it possible to develop non-laboratory specific glomerular filtration rate (GFR) estimating (eGFR) equations. This study compares the performance of the arithmetic mean of the revised Lund-Malmo creatinine and CAPA cystatin C equations (MEAN(LM-REV+CAPA)), the arithmetic mean of the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) creatinine and cystatin C equations (MEAN(CKD-EPI)), and the composite CKD-EPI equation (CKD-EPICREA+CYSC) with the corresponding single marker equations using internationally standardized calibrators for both cystatin C and creatinine. Methods: The study included 1200 examinations in 1112 adult Swedish patients referred for measurement of GFR (mGFR) 2008-2010 by plasma clearance of iohexol (median 51 mL/min/1.73 m(2)). Bias, precision (interquartile range, IQR) and accuracy (percentage of estimates +/- 30% of mGFR; P-30) were compared. Results: Combined marker equations were unbiased and had higher precision and accuracy than single marker equations. Overall results of MEAN(LM-REV+CAPA)/MEAN(CKD-EPI)/CKD-EPICREA+CYSC were: median bias -2.2%/-0.5%/-1.6%, IQR 9.2/9.2/8.8 mL/min/1.73 m(2), and P-30 91.3%/91.0%/91.1%. The P-30 figures were about 7-14 -percentage points higher than the single marker equations. The combined equations also had a more stable performance across mGFR, age and BMI intervals, generally with P-30 >= 90% and never <80%. Combined equations reached P-30 of 95% when the difference between eGFR(CREA) and eGFR(CYSC) was <10% but decreased to 82% at a difference of >= 40%. Conclusions: Combining cystatin C and creatinine assays improves GFR estimations with P-30 >= 90% in adults. Reporting estimates of both single and combined marker equations in clinical settings makes it possible to assess the validity of the combined equation based on the agreement between the single marker equations.
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  • Björk, Jonas, et al. (författare)
  • Comparison of glomerular filtration rate estimating equations derived from creatinine and cystatin C : Validation in the Age, Gene/Environment Susceptibility-Reykjavik elderly cohort
  • 2018
  • Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 33:8, s. 1380-1388
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Validation studies comparing glomerular filtration rate (GFR) equations based on standardized creatinine and cystatin C assays in the elderly are needed. The Icelandic Age, Gene/Environment Susceptibility-Kidney cohort was used to compare two pairs of recently developed GFR equations, the revised Lund-Malmö creatinine equation (LMRCr) and the arithmetic mean of the LMRCr and Caucasian, Asian, Paediatric and Adult cystatin C equations (MEANLMRþCAPA), as well as the Full Age Spectrum creatinine equation (FASCr) and its combination with cystatin C (FASCrþCys), with the corresponding pair of Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPICr and CKD-EPICrþCys). Methods. A total of 805 individuals, 74-93 years of age, underwent measurement of GFR (mGFR) using plasma clearance of iohexol. Four metrics were used to compare the performance of the GFR equations: bias, precision, accuracy [including the percentage of participants with estimated GFR (eGFR) within 30% of mGFR (P30)] and the ability to detect mGFR <60 mL/min/1.73 m2. Results. All equations had a P30 >90%. LMRCr and FASCr yielded significantly higher precision and P30 than CKD-EPICr, while bias was significantly worse. LMRCr, FASCr and CKD-EPICr showed similar ability to detect mGFR <60 mL/min/1.73 m2 based on the area under the receiver operating characteristic curves. MEANLMRþCAPA, FASCrþCys and CKD-EPICrþCys all exhibited consistent improvements compared with the corresponding creatinine-based equations. Conclusion. None of the creatinine-based equations was clearly superior overall in this community-dwelling elderly cohort. The addition of cystatin C improved all of the creatinine-based equations.
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21.
  • Björk, Jonas, et al. (författare)
  • Diagnostikstudier bör följa internationella riktlinjer : Planering och utvärdering kräver teoretiska och praktiska överväganden.
  • 2013
  • Ingår i: Läkartidningen. - 0023-7205. ; 110:11, s. 562-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Planering, genomförande, rapportering och kritisk granskning av diagnostikstudier bör följa internationella riktlinjer, de sk STARD- och QUADAS-kriterierna, så att resultatens giltighet och generaliserbarhet går att bedöma. Basala kvalitetskriterier omfattar bla adekvat beskrivning av studiedesign, inklusions- och exklusionskriterier, patientkarakteristika, utförande av index- och referenstest inklusive eventuell blindning vid bedömning av testresultaten. Resultatet av indextestet för klassificering av individer som friska eller sjuka ska redovisas i en korstabell, tillsammans med sensitivitet, specificitet och prediktiva värden samt konfidensintervall som beskriver den statistiska osäkerheten. Jämförelser av diagnostisk tillförlitlighet mellan olika indextest ska underbyggas med adekvata statistiska metoder. Utöver diagnostisk tillförlitlighet är det viktigt att också utvärdera patientnyttan, dvs hur förändrad diagnostik påverkar morbiditet och mortalitet, samt hälsoekonomiska aspekter.
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22.
  • Björk, Jonas, et al. (författare)
  • Estimation of the glomerular filtration rate in children and young adults by means of the CKD-EPI equation with age-adjusted creatinine values
  • 2021
  • Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 99:4, s. 940-947
  • Tidskriftsartikel (refereegranskat)abstract
    • The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2–17 years) and 3309 young adults (18–39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P30) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m2, the P30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function.
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23.
  • Björk, Jonas, et al. (författare)
  • Estimation of the glomerular filtration rate in children and young adults using the CKD-EPI equation with age-adjusted creatinine values
  • 2021
  • Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 940-947
  • Tidskriftsartikel (refereegranskat)abstract
    • The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2-17 years) and 3309 young adults (18-39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P30) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m2, the P30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function.
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24.
  • Björk, Jonas, et al. (författare)
  • GFR estimation based on standardized creatinine and cystatin C : A European multicenter analysis in older adults
  • 2018
  • Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1437-4331 .- 1434-6621. ; 56:3, s. 422-435
  • Tidskriftsartikel (refereegranskat)abstract
    • Although recommended by the Kidney Disease Improving Global Outcomes, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICR) creatinine equation was not targeted to estimate glomerular filtration rate (eGFR) among older adults. The Berlin Initiative Study (BIS1CR) equation was specifically developed in older adults, and the Lund-Malmö revised (LMRCR) and the Full Age Spectrum (FASCR) equations have shown promising results in older adults. Our aim was to validate these four creatinine equations, including addition of cystatin C in a large multicenter cohort of Europeans ≥70 years. A total of 3226 individuals (2638 with cystatin C) underwent GFR measurement (mGFR; median, 44 mL/min/1.73 m2) using plasma iohexol clearance. Bias, precision (interquartile range [IQR]), accuracy (percent of estimates ±30% of mGFR, P30), eGFR accuracy diagrams and probability diagrams to classify mGFR<45 mL/min/1.73 m2 were compared. The overall results of BIS1CR/CKD-EPICR/FASCR/LMRCR were as follows: median bias, 1.7/3.6/0.6/-0.7 mL/min/1.73 m2; IQR, 11.6/12.3/11.1/10.5 mL/min/1.73 m2; and P30, 77.5%/76.4%/80.9%/83.5% (significantly higher for LMR, p<0.001). Substandard P30 (<75%) was noted for all equations at mGFR<30 mL/min/1.73 m2, and at body mass index values <20 and ≥35 kg/m2. LMRCR had the most stable performance across mGFR subgroups. Only LMRCR and FASCR had a relatively constant small bias across eGFR levels. Probability diagrams exhibited wide eGFR intervals for all equations where mGFR<45 could not be confidently ruled in or out. Adding cystatin C improved P30 accuracy to 85.7/86.8/85.7/88.7 for BIS2CR+CYS/CKD-EPICR+CYS/FASCR+CYS/MEANLMR+CAPA. LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.
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25.
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26.
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27.
  • Björk, Jonas, et al. (författare)
  • Prospects for improved glomerular filtration rate estimation based on creatinine—results from a transnational multicentre study
  • 2020
  • Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 13:4, s. 674-683
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved.MethodsIn a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation.Results7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%.ConclusionsNone of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.
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28.
  • Björk, Jonas, et al. (författare)
  • Revised equations for estimating glomerular filtration rate based on the Lund-Malmö Study cohort.
  • 2011
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71, s. 232-239
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Objective. To increase the accuracy of estimated GFR (eGFR) from creatinine overall and at measured GFR ≥90 mL/min per 1.73 m(2) by revising the Lund-Malmö (LM) equations, to elaborate on more complex forms to improve the LM and CKD-EPI equations further, and to assess benefits of adding lean body mass (LBM). Material and methods. Swedish Caucasians (n = 850, 376 women; median 60, range 18-95 years) referred for GFR measurement (plasma iohexol-clearance: median 55, range 5-173 mL/min/1.73 m(2)) constituted the Lund-Malmö Study cohort. Bias, precision, accuracy, expressed as median absolute percentage difference and percentage of estimates ±10% (P(10)) and ±30% (P(30)) of measured GFR, and classification ability with respect to five GFR stages were compared with the original LM, CKD-EPI and MDRD equations. Results. LM Revised overall performed better than LM Original without LBM due to increased accuracy at measured GFR ≥90 mL/min/1.73 m(2). Further extensions of the CKD-EPI or LM equations did not substantially improve overall performance. In particular, the performance of LM Revised at measured GFR ≥90 mL/min/1.73 m(2) could not be improved further without decreasing accuracy and classification ability at lower GFR-levels. Adding LBM to the equations had no strong effect on accuracy. Conclusion. Comparisons with the CKD-EPI and MDRD equations suggest that the LM equations are superior for the present Swedish population, due to markedly higher accuracy of the LM equations at measured GFR <30 mL/min/1.73 m(2). However, the LM equations cannot be recommended for use in general clinical practice until validated in other populations.
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29.
  • Björk, Jonas, et al. (författare)
  • Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children
  • 2019
  • Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 0931-041X .- 1432-198X.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Most validations of paediatric glomerular filtration rate (GFR) estimating equations using standardized creatinine (CR) and cystatin C (CYS) assays have comprised relatively small cohorts, which makes accuracy across subgroups of GFR, age, body mass index (BMI) and gender uncertain. To overcome this, a large cohort of children referred for GFR determination has been established from several European medical centres. Methods: Three thousand four hundred eight measurements of GFR (mGFR) using plasma clearance of exogenous substances were performed in 2218 children aged 2–17 years. Validated equations included Schwartz-2009CR/2012CR/CYS/CR+CYS, FASCR/CYS/CR+CYS, LMRCR, Schwartz-LyonCR, BergCYS, CAPACYS, CKD-EPICYS, AndersenCR+CYS and arithmetic means of the best single-marker equations in explorative analysis. Five metrics were used to compare the performance of the GFR equations: bias, precision and three accuracy measures including the percentage of GFR estimates (eGFR) within ± 10% (P10) and ± 30% (P30) of mGFR. Results: Three of the cystatin C equations, BergCYS, CAPACYS and CKD-EPICYS, exhibited low bias and generally satisfactory accuracy across all levels of mGFR; CKD-EPICYS had more stable performance across gender than the two other equations. Among creatinine equations, Schwartz-LyonCR had the best performance but was inaccurate at mGFR < 30 mL/min/1.73 m2 and in underweight patients. Arithmetic means of the best creatinine and cystatin C equations above improved bias compared to the existing composite creatinine+cystatin C equations. Conclusions: The present study strongly suggests that cystatin C should be the primary biomarker of choice when estimating GFR in children with decreased GFR. Arithmetic means of well-performing single-marker equations improve accuracy further at most mGFR levels and have practical advantages compared to composite equations.
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30.
  • Björk, Jonas, et al. (författare)
  • Validation of the Lund-Malmö, Chronic Kidney Disease Epidemiology (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations to estimate glomerular filtration rate in a large Swedish clinical population.
  • 2012
  • Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 46:3, s. 212-222
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Objective. The aim of this study was to validate externally the Swedish Lund-Malmö revised creatinine-based glomerular filtration rate (GFR) equations (LM Revised) in a Swedish cohort in comparison with the North American Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI) equations. Material and methods. The study included 1397 examinations [median age 61 years, median body mass index (BMI) 26 kg/m(2)] in 996 patients referred for iohexol clearance (median 44 ml/min/1.73 m(2)). Bias, precision [interquartile range (IQR)], accuracy expressed as percentage of estimates ± 10% (P (10)) and ± 30% (P (30)) of measured GFR, and classification ability for five GFR stages (<15, 15-29, 30-59, 60-89 and ≥90 ml/min/1.73 m(2)) were compared. Results. Overall, all three equations performed satisfactorily: LM Revised, MDRD, CKD-EPI showed, respectively, a median bias of -5.8%, -2.2% and 1.7%, IQR 11.9, 12.3 and 11.7 ml/min/1.73 m(2), P (10) 35%, 34% and 38%, P (30) 84%, 79% and 79% and correctly classified GFR stages 68%, 65% and 69%. LM Revised was at least as accurate in terms of P (30) as the other equations at GFR intervals <90, while CKD-EPI was the only unbiased and the most accurate equation at ≥90 ml/min/1.73 m(2). LM Revised was more stable in terms of bias and accuracy across age and BMI groups than MDRD and CKD-EPI. Both MDRD and CKD-EPI overestimated measured GFR among elderly patients and in the small group of underweight men. Conclusion. The ideal all-purpose GFR prediction equation does not exist. LM Revised should be preferred in patients with suspected or known renal insufficiency, while CKD-EPI is most useful in settings where patients with no a priori suspicion of renal impairment are evaluated. Differences in creatinine measurements between laboratories may limit the generalizability of the present validation.
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31.
  • Björk, Jonas, et al. (författare)
  • Variability in diagnostic accuracy can be estimated using simple population weighting.
  • 2009
  • Ingår i: Journal of Clinical Epidemiology. - : Elsevier BV. - 1878-5921 .- 0895-4356. ; 62:1, s. 54-57
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Diagnostic accuracy of a quantitative diagnostic test at a given numeric cutoff is dependent on the type of population (e.g., chronic, referrals, or screening) under investigation. Simple weighted averages calculated from a single study sample may be used to assess variability in accuracy in different types of populations. STUDY DESIGN AND SETTING: We evaluated the accuracy of the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation as a diagnostic test to separate stage 1 and 2 chronic kidney disease (>or=60 mL/min per 1.73 m(2)) from stage 3-5 (<60 mL/min per 1.73 m(2) requiring treatment to prevent progression) in a sample of 850 patients referred for determination of glomerular filtration rate (GFR). Using population weighting, we also estimated the accuracy of the MDRD equation when the GFR distribution typically found in screening situations was mimicked. RESULTS: Estimated diagnostic accuracy of the MDRD equation varied substantially for different population types (sensitivity range 82%-97%, specificity 67%-93%; figures include the original MDRD study). CONCLUSIONS: Reports of diagnostic accuracy should include estimates of the variability of diagnostic accuracy, using different real or tentative population distributions. Population weighting is a useful tool for this purpose.
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32.
  • Björkdahl, Peter, et al. (författare)
  • Using 100- instead of 120-kVp computed tomography to diagnose pulmonary embolism almost halves the radiation dose with preserved diagnostic quality.
  • 2010
  • Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 51:3, s. 260-270
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Concern has been raised regarding the mounting collective radiation doses from computed tomography (CT), increasing the risk of radiation-induced cancers in exposed populations. Purpose: To compare radiation dose and image quality in a chest phantom and in patients for the diagnosis of pulmonary embolism (PE) at 100 and 120 peak kilovoltage (kVp) using 16-multichannel detector computed tomography (MDCT). Material and Methods: A 20-ml syringe containing 12 mg I/ml was scanned in a chest phantom at 100/120 kVp and 25 milliampere seconds (mAs). Consecutive patients underwent 100 kVp (n = 50) and 120 kVp (n = 50) 16-MDCT using a "quality reference" effective mAs of 100, 300 mg I/kg, and a 12-s injection duration. Attenuation (CT number), image noise (1 standard deviation), and contrast-to-noise ratio (CNR; fresh clot = 70 HU) of the contrast medium syringe and pulmonary arteries were evaluated on 3-mm-thick slices. Subjective image quality was assessed. Computed tomography dose index (CTDI(vol)) and dose-length product (DLP) were presented by the CT software, and effective dose was estimated. Results: Mean values in the chest phantom and patients changed as follows when X-ray tube potential decreased from 120 to 100 kVp: attenuation +23% and +40%, noise +38% and +48%, CNR -6% and 0%, and CTDI(vol) -38% and -40%, respectively. Mean DLP and effective dose in the patients decreased by 42% and 45%, respectively. Subjective image quality was excellent or adequate in 49/48 patients at 100/120 kVp. No patient with a negative CT had any thromboembolism diagnosed during 3-month follow-up. Conclusion: By reducing X-ray tube potential from 120 to 100 kVp, while keeping all other scanning parameters unchanged, the radiation dose to the patient may be almost halved without deterioration of diagnostic quality, which may be of particular benefit in young individuals.
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33.
  • Carlqvist, Jeanette, et al. (författare)
  • Minimal risk of contrast-induced kidney injury in a randomly selected cohort with mildly reduced GFR
  • 2021
  • Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 31:5, s. 3248-3257
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Previous large studies of contrast-induced or post-contrast acute kidney injury (CI-AKI/PC-AKI) have been observational, and mostly retrospective, often with patients undergoing non-enhanced CT as controls. This carries risk of inclusion bias that makes the true incidence of PC-AKI hard to interpret. Our aim was to determine the incidence of PC-AKI in a large, randomly selected cohort, comparing the serum creatinine (Scr) changes after contrast medium exposure with the normal intraindividual fluctuation in Scr. Methods: In this prospective study of 1009 participants (age 50–65 years, 48% females) in the Swedish CArdioPulmonary bioImage Study (SCAPIS), with estimated glomerular filtration rate (eGFR) ≥ 50 mL/min, all received standard dose intravenous iohexol at coronary CT angiography (CCTA). Two separate pre-CCTA Scr samples and a follow-up sample 2–4 days post-CCTA were obtained. Change in Scr was statistically analyzed and stratification was used in the search of possible risk factors. Results: Median increase of Scr post-CCTA was 0–2 μmol/L. PC-AKI was observed in 12/1009 individuals (1.2%) according to the old ESUR criteria (> 25% or > 44 μmol/L Scr increase) and 2 individuals (0.2%) when using the updated ESUR criteria (≥ 50% or ≥ 27 μmol/L Scr increase). Possible risk factors (e.g., diabetes, age, eGFR, NSAID use) did not show increased risk of developing PC-AKI. The mean effect of contrast media on Scr did not exceed the intraindividual Scr fluctuation. Conclusions: Iohexol administration to a randomly selected cohort with mildly reduced eGFR is safe, and PC-AKI is very rare, occurring in only 0.2% when applying the updated ESUR criteria. Key Points: • Iohexol administration to a randomly selected cohort, 50–65 years old with mildly reduced eGFR, is safe and PC-AKI is very rare. • Applying the updated ESUR PC-AKI criteria resulted in fewer cases, 0.2% compared to 1.2% using the old ESUR criteria in this cohort with predominantly mild reduction of renal function. • The mean effect of CM on Scr did not exceed the intraindividual background fluctuation of Scr, regardless of potential risk factors, such as diabetes or NSAID use in our cohort of 1009 individuals.
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34.
  • Dahlin, Christer, 1959, et al. (författare)
  • Generation of new bone around titanium implants using a membrane technique: an experimental study in rabbits.
  • 1989
  • Ingår i: The International journal of oral & maxillofacial implants. - 0882-2786. ; 4:1, s. 19-25
  • Tidskriftsartikel (refereegranskat)abstract
    • Insufficient bone volume may be a significant problem in connection with dental implants. In this study, a technique based on the principle of guided tissue regeneration was tested for its ability to generate bone tissue around titanium implants. Implants were inserted in tibiae of rabbits. To create a secluded space for osteogenesis and to prevent soft-tissue ingrowth, a porous Teflon membrane was placed around exposed parts of the implant. Where a membrane had been used, the threads of the implant were completely covered with significant amounts of new bone. This study indicates that the membrane technique is a reconstructive surgical method that may be applicable to create new bone around exposed parts of titanium implants in a clinical setting.
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35.
  • Delanaye, Pierre, et al. (författare)
  • Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research : A review. Part 1: How to measure glomerular filtration rate with iohexol?
  • 2016
  • Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 9:5, s. 682-699
  • Forskningsöversikt (refereegranskat)abstract
    • While there is general agreement on the necessity tomeasure glomerular filtration rate (GFR) inmany clinical situations, there is less agreement on the bestmethod to achieve this purpose. As the gold standardmethod for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtrationmarkers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFRmarker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-Toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, butmultiple-sample protocolsmay bemore accurate in specific situations. In lowGFRs one ormore late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method.
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36.
  • Delanaye, Pierre, et al. (författare)
  • Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research : A review. Part 2: Why to measure glomerular filtration rate with iohexol?
  • 2016
  • Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 9:5, s. 700-704
  • Forskningsöversikt (refereegranskat)abstract
    • A reliable assessment of glomerular filtration rate (GFR) is of paramount importance in clinical practice as well as epidemiological and clinical research settings. It is recommended by Kidney Disease: Improving Global Outcomes guidelines in specific populations (anorectic, cirrhotic, obese, renal and non-renal transplant patients) where estimation equations are unreliable. Measured GFR is the only valuable test to confirm or confute the status of chronic kidney disease (CKD), to evaluate the slope of renal function decay over time, to assess the suitability of living kidney donors and for dosing of potentially toxic medication with a narrowtherapeutic index. Abnormally elevated GFR or hyperfiltration in patients with diabetes or obesity can be correctly diagnosed only by measuring GFR. GFR measurement contributes to assessing the true CKD prevalence rate, avoiding discrepancies due to GFR estimation with different equations. Using measured GFR, successfully accomplished in large epidemiological studies, is the onlyway to study the potential link between decreased renal function and cardiovascular or total mortality, being sure that this association is not due to confounders, i.e. non-GFR determinants of biomarkers. In clinical research, it has been shown that measured GFR (or measured GFR slope) as a secondary endpoint as compared with estimated GFR detected subtle treatment effects and obtained these results with a comparatively smaller sample size than trials choosing estimated GFR. Measuring GFR by iohexol has several advantages: simplicity, low cost, stability and low interlaboratory variation. Iohexol plasma clearance represents the best chance for implementing a standardized GFR measurement protocol applicable worldwide both in clinical practice and in research.
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37.
  • Delanaye, Pierre, et al. (författare)
  • Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil, and Africa
  • 2022
  • Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 38:1, s. 106-118
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: A new Chronic Kidney Disease Epidemiology equation without race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared to the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts.METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France, (n = 4429, including 964 Black Europeans), from Brazil (n = 100), and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed.RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73m², and accuracy within 30% of 86.9 and 87.4, respectively versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value ( = concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans, and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males.CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated, population-specific Q-values presents the best performance in the whole age range in the European and African populations included in this study.
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38.
  • Delanaye, Pierre, et al. (författare)
  • Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment
  • 2022
  • Ingår i: British Journal of Clinical Pharmacology. - : Wiley-Blackwell Publishing Inc.. - 0306-5251 .- 1365-2125. ; 88:5, s. 2118-2127
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing METHODS: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14,804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR), and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision, and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age, and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages.RESULTS: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR<60 mL/min and at BMI [18.5-25[kg/m2 , all equations performed similarly and for BMI<18.5kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI≥25kg/m2 the bias of the CG increased with increasing BMI (+17.2mL/min at BMI≥40kg/m2 ). The four more recent equations also classified mGFR stages better than CG.CONCLUSIONS: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for GFR, age, and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.
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39.
  • Delanaye, Pierre, et al. (författare)
  • Performance of the European Kidney Function Consortium (EKFC) creatinine-based equation in United States cohorts
  • 2024
  • Ingår i: Kidney International. - 0085-2538. ; 105:3, s. 629-637
  • Tidskriftsartikel (refereegranskat)abstract
    • Estimating glomerular filtration rate (GFR) is important in daily practice to assess kidney function and adapting the best clinical care of patients with and without chronic kidney disease. The new creatinine-based European Kidney Function Consortium (EKFC) equation is used to estimate GFR. This equation was developed and validated mainly in European individuals and based on a rescaled creatinine, with the rescaling factor (Q-value) defined as the median normal value of serum creatinine in a given population. The validation was limited in Non-Black Americans and absent in Black Americans. Here, our cross-sectional analysis included 12,854 participants from nine studies encompassing large numbers of both non-Black and Black Americans with measured GFR by clearance of an exogenous marker (reference method), serum creatinine, age, sex, and self-reported race available. Two strategies were considered with population-specific Q-values in Black and non-Black men and women (EKFCPS) or a race-free Q-value (EKFCRF). In the whole population, only the EKFCPS equation showed no statistical median bias (0.14, 95% confidence interval [-0.07; 0.35] mL/min/1.73m2), and the bias for the EKFCRF (0.74, [0.51; 0.94] mL/min/1.73m2) was closer to zero than that for the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI2021) equation (1.22, [0.99; 1.47]) mL/min/1.73m2]. The percentage of estimated GFR within 30% of measured GFR was similar for CKD-EPI2021 (79.2% [78.5%; 79.9%]) and EKFCRF (80.1% [79.4%; 80.7%]), but improved for the EKFCPS equation (81.1% [80.5%; 81.8%]). Thus, our EKFC equations can be used to estimate GFR in the United States incorporating either self-reported race or unknown race at the patient's discretion per hospital registration records.
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40.
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41.
  • Ek, Anna, et al. (författare)
  • A Parent Treatment Program for Preschoolers With Obesity : A Randomized Controlled Trial
  • 2019
  • Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 144:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background And Objectives: Early obesity treatment seems to be the most effective, but few treatments exist. In this study, we examine the effectiveness of a parent-only treatment program with and without booster sessions (Booster or No Booster) focusing on parenting practices and standard treatment (ST).Methods: Families of children 4 to 6 years of age with obesity were recruited from 68 child care centers in Stockholm County and randomly assigned to a parent-only program (10 weeks) with or without boosters (9 months) or to ST. Treatment effects on primary outcomes (BMI z score) and secondary outcomes (BMI and waist circumference) during a 12-month period were examined with linear mixed models. The influence of sociodemographic factors was examined by 3-way interactions. The clinically significant change in BMI z score (−0.5) was assessed with risk ratios.Results: A total of 174 children (mean age: 5.3 years [SD = 0.8]; BMI z score: 3.0 [SD = 0.6], 56% girls) and their parents (60% foreign background; 39% university degree) were included in the analysis (Booster, n = 44; No Booster, n = 43; ST, n = 87). After 12 months, children in the parent-only treatment had a greater reduction in their BMI z score (0.30; 95% confidence interval [CI]: −0.45 to −0.15) compared with ST (0.07; 95% CI: −0.19 to 0.05). Comparing all 3 groups, improvements in weight status were only seen for the Booster group (−0.54; 95% CI: −0.77 to −0.30). The Booster group was 4.8 times (95% CI: 2.4 to 9.6) more likely to reach a clinically significant reduction of ≥0.5 of the BMI z score compared with ST.Conclusion: A parent-only treatment with boosters outperformed standard care for obesity in preschoolers.
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42.
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43.
  • Elmståhl, Barbara, et al. (författare)
  • Gadolinium contrast media are more nephrotoxic than iodine media. The importance of osmolality in direct renal artery injections
  • 2006
  • Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 16:12, s. 2712-2720
  • Tidskriftsartikel (refereegranskat)abstract
    • A study was undertaken of the role of osmotoxicity in gadolinium (Gd) and iodine contrast media (CM) nephrotoxicity in ischemic porcine kidneys. Test solutions: mannitol iso-osmotic to 0.5 M: gadopentetate (1.96 Osm/kg H2O), 0.5 M: gadodiamide (0.78 Osm/kg H2O) and 0.5 M: iohexol (190 mg I/ml, 0.42 Osm/kg H2O). Each solution was injected [3 ml/kg body weight (BW)] into the balloon-occluded (10 min) renal artery of eight left-sided nephrectomized pigs. The plasma half-life of a glomerular filtration rate (GFR) marker was used to compare their effects on GFR 1-3 h post-injection. The median half-lives of the GFR marker after injection of gadopentetate (1,730 min) and mannitol 1.96 Osm/kg H2O (2,782 min) did not differ statistically (P = 0.28), but were significantly longer than after all other solutions (P < 0.001). There was no significant difference (P = 0.06) between gadodiamide (218 min) and mannitol 0.82 Osm/kg H2O (169 min), while there was (P = 0.03) between iohexol (181 min) and mannitol 0.43 Osm/kg H2O (148 min). The difference between gadodiamide and iohexol was significant (P = 0.01). Reduction in GFR, as a marker of nephrotoxicity, induced by gadopentetate correlated with its high osmolality, while the effect of gadodiamide and iohexol may include chemotoxicity. Iohexol molecules were less nephrotoxic than the Gd-CM molecules and contain three-times the number of attenuating atoms per molecule.
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44.
  • Elmståhl, Barbara, et al. (författare)
  • Histomorphological Changes after Renal X-Ray Arteriography Using Iodine and Gadolinium Contrast Media in an Ischemic Porcine Model.
  • 2007
  • Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 48:10, s. 1109-1119
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Gadolinium contrast media (Gd-CM) are regarded as non-nephrotoxic or considerably less nephrotoxic than iodine contrast media (I-CM), and have therefore come to be used as a substitute for I-CM in patients with renal insufficiency in a variety of radiographic examinations. Purpose: To investigate renal histomorphological changes caused by Gd-CM in comparison with I-CM after renal X-ray arteriography in an ischemic porcine model, and to evaluate these changes in relation to the nephrotoxicity of the CM used. Material and Methods: Test solutions: gadopentetate, gadodiamide, iohexol, gadobutrol, iopromide, iodixanol, mannitol, and saline. The experiments were performed on 152 animals. Each pig was randomized to receive one test solution injected into the balloon-occluded (10 min) right renal artery. The kidneys were evaluated histomorphologically. The severity of histomorphological changes was graded subjectively: 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked. Results: The main histological changes were 1) proximal tubular and glomerular necrosis, 2) hemorrhage/congestion of the cortex, medulla, and glomeruli, 3) proximal tubular vacuolation, and 4) protein-filled tubules in the cortex and medulla. Necrosis and hemorrhage/congestion were more frequent after injections with gadopentetate, mannitol solution iso-osmotic to gadopentetate, and gadobutrol compared to all other groups (P<0.001). The degree of necrosis and hemorrhage/congestion was related to the degree of impairment of renal function, but inversely related to vacuolation and tubular protein filling. Conclusion: In ischemic porcine kidneys, the histomorphological changes caused by Gd-CM are similar to those caused by I-CM. Vacuolation appears to be independent of the osmolality and viscosity of the CM, and does not seem to be an indicator of renal impairment. “High-osmolal” Gd-CM are more nephrotoxic than “low- and iso-osmolal” I-CM when compared in equal volumes of concentrations, resulting in equal X-ray attenuation.
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45.
  • Elmståhl, Barbara, et al. (författare)
  • Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: Arteriography in ischemic porcine kidneys
  • 2008
  • Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 247:1, s. 88-97
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1: 1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3: 1 or 6: 1) after renal arteriography in ischemic porcine kidneys. Materials and Methods: The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H2O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. Results: Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P = .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. Conclusion: Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures. (c) RSNA, 2008.
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46.
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47.
  • Fernström, Erik, et al. (författare)
  • Cerebrospinal fluid markers of extracellular matrix remodelling, synaptic plasticity and neuroinflammation before and after cranial radiotherapy
  • 2018
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820. ; 284:2, s. 211-225
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Advances in the treatment of brain tumours have increased the number of long-term survivors, but at the cost of side effects following cranial radiotherapy ranging from neurocognitive deficits to outright tissue necrosis. At present, there are no tools reflecting the molecular mechanisms underlying such side effects, and thus no means to evaluate interventional effects after cranial radiotherapy. Therefore, fluid biomarkers are of great clinical interest. Objective Cerebrospinal fluid (CSF) levels of proteins involved in inflammatory signalling, synaptic plasticity and extracellular matrix (ECM) integrity were investigated following radiotherapy to the brain. Methods Patients with small-cell lung cancer (SCLC) eligible for prophylactic cranial irradiation (PCI) were asked to participate in the study. PCI was prescribed either as 2 Gy/fraction to a total dose of 30 Gy (limited disease) or 4 Gy/fraction to 20 Gy (extensive disease). CSF was collected by lumbar puncture at baseline, 3 months and 1 year following PCI. Protein concentrations were measured using immunobased assays or mass spectrometry. Results The inflammatory markers IL-15, IL-16 and MCP-1/CCL2 were elevated in CSF 3 months following PCI compared to baseline. The plasticity marker GAP-43 was elevated 3 months following PCI, and the same trend was seen for SNAP-25, but not for SYT1. The investigated ECM proteins, brevican and neurocan, showed a decline following PCI. There was a strong correlation between the progressive decline of soluble APP and brevican levels. Conclusion To our knowledge, this is the first time ECM-related proteins have been shown to be affected by cranial radiotherapy in patients with cancer. These findings may help us to get a better understanding of the mechanisms behind side effects following radiotherapy.
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48.
  • Ferrari, Desiree, et al. (författare)
  • Concentration of carprofen in the milk of lactating bitches after cesarean section and during inflammatory conditions
  • 2022
  • Ingår i: Theriogenology. - : Elsevier. - 0093-691X .- 1879-3231. ; 181, s. 59-68
  • Tidskriftsartikel (refereegranskat)abstract
    • Pain treatment of lactating bitches is a clinically relevant, but complicated issue. Published scientific studies regarding the excretion of drugs in canine milk are scarce. When considering the risk of side effects in their offspring, lactating bitches have traditionally received very restricted analgesic and anti-inflammatory therapy. Our aim was to quantify the concentrations of carprofen in milk from lactating bitches and relate those to potential risks for the puppies. A second aim was to evaluate the impact mastitis may have on the concentration of carprofen in milk. A population of 100 bitches was enrolled in the study, among which 88 were bitches treated with carprofen after cesarean section (Group CS), eight were bitches with painful inflammatory conditions (Group I) and four were bitches with mastitis (Group M). The patients enrolled in the study received carprofen 4 mg/kg sc at day 1 followed by 2 mg/kg po every 12 h for the following 2-5 days. Owners were instructed to collect milk once a day for five days. The concentration of carprofen in the milk was quantified with ultra-performance liquid chromatography-tandem mass spectrometry. The data obtained were statistically analyzed as repeated-measures data with a mixed-model approach. Data were used to calculate the theoretical maximum total daily intake of carprofen by the puppies in order to perform a computerized simulation of the plasma concentration of carprofen in the puppies. Follow-up telephone interviews to check the status of the enrolled bitches and their litters occurred at one week and three-six months after treatment with car-profen. The major finding of the study was that the concentration of carprofen in the milk was <700 ng/ mL from bitches undergoing CS or suffering painful conditions other than mastitis. In comparison, administration of 2 mg/kg of carprofen sc or po to adult dogs, results in mean maximal plasma con-centrations of 19480 +/- 5420 ng/mL (mean +/- SD). Moreover, data suggests that inflammation of the mammary gland results in a higher concentration of carprofen in milk (up to 1300 ng/mL). In the computerized simulation, the plasma concentrations of carprofen in puppies in group CS and in group I are one tenth of the concentration in adult dogs receiving carprofen at standard doses. Considering the low excretion into milk, carprofen provides an analgesic alternative to lactating bitches without mastitis.(c) 2022 Published by Elsevier Inc.
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49.
  • Flinck, Marianne, et al. (författare)
  • Cardiac output measured by electrical velocimetry in the CT suite correlates with coronary artery enhancement: a feasibility study.
  • 2010
  • Ingår i: Acta radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 51:8, s. 895-902
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cardiac output (CO) is inversely related to vascular contrast medium (CM) enhancement during computed tomography (CT). Impedance cardiography with a new technique, electrical velocimetry (EV), may create opportunities to measure CO pre-examination for adaptation of CM injection parameters. Purpose: To relate COEV measured by radiology staff to aortic attenuation as a measure of coronary artery attenuation during CT coronary angiography (CTCA), and to formulate a tentative statistical model to adapt CM injection parameters to CO. Material and Methods: COEV was measured immediately before 100 kVp CTCA (64-multirow detector) in 27 patients with presumed coronary artery disease. For CTCA, 260 mg I/kg (maximum dosage weight: 80/90 kg for women/men) was injected intravenously during 12 s. Simple linear regression analysis was performed to explore the correlation between aortic attenuation (Hounsfield units, HU) and body weight, the influence of COEV on aortic attenuation adjusted to injected CM dose rate (HU per mg I/kg/s), and to establish a tentative formula on how to adapt CM injection parameters to COEV and desired aortic attenuation. Results: The correlation between aortic attenuation and body weight was weak and non-significant (r=−0.14 after outlier exclusion). A significant negative correlation (r=−0.63) was found between aortic attenuation adjusted to injected CM dose rate (HU per mg I/kg/s) and COEV. The resulting formula, CM dose rate=COEV×(aortic attenuation−240)/55, made it possible to calculate CM volumes and injection rates at various COs and, for example, the present mean aortic attenuation (438 HU), injection time (12 s), CM concentration (320 mg I/ml), and a certain body weight. Conclusion: EV makes it possible to measure CO in the CT suite before vascular examinations. Hence, CM doses may be decreased in low CO states to reduce the risk of CM-induced nephropathy without jeopardizing diagnostic quality and may be increased in high CO states to avoid poor enhancement.
  •  
50.
  • Fåk, Frida, et al. (författare)
  • The physico-chemical properties of dietary fibre determine metabolic responses, short-chain Fatty Acid profiles and gut microbiota composition in rats fed low- and high-fat diets.
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate how physico-chemical properties of two dietary fibres, guar gum and pectin, affected weight gain, adiposity, lipid metabolism, short-chain fatty acid (SCFA) profiles and the gut microbiota in male Wistar rats fed either low- or high-fat diets for three weeks. Both pectin and guar gum reduced weight gain, adiposity, liver fat and blood glucose levels in rats fed a high-fat diet. Methoxylation degree of pectin (low, LM and high (HM)) and viscosity of guar gum (low, medium or high) resulted in different effects in the rats, where total blood and caecal amounts of SCFA were increased with guar gum (all viscosities) and with high methoxylated (HM) pectin. However, only guar gum with medium and high viscosity increased the levels of butyric acid in caecum and blood. Both pectin and guar gum reduced cholesterol, liver steatosis and blood glucose levels, but to varying extent depending on the degree of methoxylation and viscosity of the fibres. The medium viscosity guar gum was the most effective preparation for prevention of diet-induced hyperlipidaemia and liver steatosis. Caecal abundance of Akkermansia was increased with high-fat feeding and with HM pectin and guar gum of all viscosities tested. Moreover, guar gum had distinct bifidogenic effects independent of viscosity, increasing the caecal abundance of Bifidobacterium ten-fold. In conclusion, by tailoring the viscosity and possibly also the degree of methoxylation of dietary fibre, metabolic effects may be optimized, through a targeted modulation of the gut microbiota and its metabolites.
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