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  • 101.
    Broome, M.
    Karolinska Institutet.
    MEDIQ Kinetics2003Other (Other academic)
  • 102.
    Broome, M.
    Karolinska Institutet.
    Simulation of cardiovascular physiology and pathology: The effects of mitral regurgitation on venous pulmonary flow and mitral flow.2003Other (Refereed)
    Abstract [en]

    Background: The development of simulation models and modern computers makes it possible to simulate both normal cardiovascular physiology and pathology realistically. These models can be used to aid clinicians and researchers in understanding complex phenomenon. Methods: An electrical analogue of the cardiovascular system consisting of resistances, capacitances and inductances has been constructed. The contractile function of the cardiac atria and ventricles area represented by time-varying elastances. Valvular function, pericardial volume, ventricular interaction and intrathoracic pressure are also represented by constants and functions interacting with the rest of the model. Results: A regurgitant mitral orifice of 1 cm2 during systole results in an increased volume load on the left ventricle, a decrease in cardiac output and systemic arterial blood pressures accompanied by an increase in left and right-sided cardiac filling pressures and volumes. More specifically a systolic reversal of flow in the pulmonary veins is seen. Conclusion: Simulation of cardiac normal function and pathology is a meaningful way to study the heart. Results from simulations can be used to interpret clinical invasive monitoring and echocardiography data as well as experimental research data.

  • 103.
    Broome, M.
    et al.
    Karolinska Institutet.
    Aneman, A.
    Haney, M.
    Haggmark, S.
    Johansson, G.
    Biber, B.
    Angiotensin II mesenteric and renal vasoregulation: dissimilar modulatory effects with nitroprusside2000In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 44, no 10, p. 1238-1245Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of systemic arterial pressure for the vascular effects of angiotensin II (Ang II) and the interactions between Ang II and perfusion pressure-dependent local vascular control mechanisms are not well understood. This study addresses these aspects of exogenous Ang II in the mesenteric and renal regional circulations. METHODS: Ang II was infused in incremental doses (0-200 microg/h) in anesthetized instrumented pigs (n=10). Renal and portal blood flows were measured by perivascular ultrasound. In the second part of the study, sodium nitroprusside (SNP) was infused at doses titrated to keep mean arterial pressure constant, in spite of concurrent Ang II administration. RESULTS: Powerful dose-dependent vasoconstrictions by Ang II were found in renal and mesenteric vascular beds (at highest Ang II doses vascular resistances increased by 109% and 88% respectively). Ang II-induced vasoconstriction was fully inhibited in the mesenteric, but not in the renal circulation, during conditions of constant mean arterial pressures achieved by SNP infusion. CONCLUSIONS: Mesenteric, but not renal, vasoconstriction by Ang II was inhibited by pharmacological maintenance of perfusion pressure. This could reflect differences between these vascular beds as regards the importance of co-acting myogenic pressure-dependent vasoconstriction. Alternatively, as the drug chosen for pressure control, sodium nitroprusside, serves as a nitric oxide donor, the relative balance between nitric oxide-mediated vasodilation and Ang II-induced vasoconstriction could have regional differences.

  • 104.
    Broome, M.
    et al.
    Umeå Universitet.
    Haney, M.
    Haggmark, S.
    Johansson, G.
    Aneman, A.
    Biber, B.
    Acute effects of angiotensin II on myocardial performance2001In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 45, no 9, p. 1147-1154Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Specific angiotensin II (Ang II) receptors exist in many organs including peripheral blood vessels, cardiac myocytes and the central nervous system. This suggests multiple sites of actions for Ang II throughout the cardiovascular system. Cardiac effects of Ang II are not completely understood, though its prominent vasoconstrictor actions are well described. This study was designed to assess left ventricular function during administration of Ang II using relatively load-independent methods in a whole-animal model. METHODS: Ang II was infused in incremental doses (0-200 microg x h(-1)) in anaesthetised instrumented pigs (n=10). Cardiac systolic and diastolic function were evaluated by analysis of the left ventricular pressure-volume relationship. RESULTS: Heart rate (HR), mean arterial pressure (MAP) and systemic vascular resistance (SVR) increased dose-dependently with Ang II, while cardiac output (CO) remained unchanged. Systolic function indices, end-systolic elastance (Ees) and preload recruitable stroke work (PRSW), demonstrated dose-dependent increases. The diastolic function parameter tau (tau) did not change with increasing Ang II dose. CONCLUSION: Ang II infusion caused increases in contractility indices in anaesthetised pigs in the doses used in this study. The mechanisms for these systolic function effects may be a direct myocardial effect or modulated through changes in autonomic nervous system activity.

  • 105.
    Broome, M.
    et al.
    Umeå Universitet.
    Haney, M.
    Osterlund, B.
    Haggmark, S.
    Johansson, G.
    Biber, B.
    The cardiac effects of intracoronary angiotensin II infusion2002In: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598, Vol. 94, no 4, p. 787-793Article in journal (Refereed)
    Abstract [en]

    Angiotensin II (Ang II) is a potent vasoconstrictor, which recently has been shown to also have significant inotropic effects. Previous results regarding the mechanisms of the acute inotropic effects of Ang II are not conclusive. We designed this study to investigate the local cardiac effects of intracoronary Ang II infusion in doses not affecting systemic circulation. Ang II (2.5-40 microg/h) was infused in the left coronary artery of Yorkshire pigs (n = 9) reaching calculated intracoronary Ang II concentrations of 842 +/- 310, 3342 +/- 1238, and 12448 +/- 4393 pg/mL, respectively. Cardiac systolic and diastolic function was evaluated by analysis of the left ventricular pressure-volume relationship. Coronary flow was measured by using a coronary sinus catheter and the retrograde thermodilution technique. No significant changes were seen in the systolic and diastolic function variables of heart rate, end-systolic elastance, preload recruitable stroke work, the time constant for isovolumetric relaxation, or in coronary vascular resistance and flow. The positive inotropic and chronotropic effects of Ang II seen in previous studies seem thus to be mediated via extracardiac actions of Ang II. Coronary vascular tone is not affected by local Ang II infusion in anesthetized pigs. IMPLICATIONS: The positive inotropic and chronotropic effects of angiotension II (Ang II) seen in previous studies seem to be mediated via extracardiac actions of Ang II. Coronary vascular tone is not affected by local Ang II infusion in anesthetized pigs.

  • 106.
    Broome, Michael
    KTH, School of Technology and Health (STH), Medical Engineering.
    Aplysia CorVascSim2012Other (Other academic)
  • 107.
    Broome, Michael
    Karolinska Institutet.
    MEDIQ CorVascSim2011Other (Other academic)
  • 108.
    Broome, Michael
    Karolinska Institutet.
    Simulation of Cardiovascular Physiology and Pathology: The Effects of Mitral Regurgitation on Mitral and Pulmonary Venous Flow2004Other (Other academic)
    Abstract [en]

    Background: The development of simulation models and modern computers makes it possible to simulate both normal cardiovascular physiology and pathology realistically. These models can be used to aid clinicians and researchers in understanding complex phenomenon. Methods: An electrical analogue of the cardiovascular system consisting of resistances, capacitances and inductances has been constructed. The contractile function of the cardiac atria and ventricles area represented by time-varying elastances. Valvular function, pericardial volume, ventricular interaction and intrathoracic pressure are also represented by constants and functions interacting with the rest of the model. Results: A regurgitant mitral orifice of 1 cm2 during systole results in an increased volume load on the left ventricle, a decrease in cardiac output and systemic arterial blood pressures accompanied by an increase in left and right-sided cardiac filling pressures and volumes. A systolic reversal of flow in the pulmonary veins is seen. The magnitude of systolic flow reversal in the pulmonary veins is dependent on left atrial compliance. Conclusion: Simulation of cardiac normal function and pathology is a meaningful way to study the heart. Results from simulations can be used to interpret clinical invasive monitoring and echocardiography data as well as experimental research data. Left atrial compliance may be of importance for interpretation of pulmonary venous flow profiles in mitral regurgitation.

  • 109.
    Broome, Michael
    Karolinska Institutet.
    Simulation of cardiovascular physiology and pathology with CorVascSim: A PC software for advanced education and research2004Other (Other academic)
    Abstract [en]

    Background and Goal: The rapid development of computer technology makes simulation of cardiovascular physiology and pathology possible. The current work presents a scientifically based cardiovascular model, with a self-explanatory interface. Material and Methods: An electrical analogue of the cardiovascular system including resistances, capacitances and inductances was constructed. The contractile function of the cardiac atria and ventricles are represented by time-varying elastances. Valvular function, pericardial volume, ventricular interaction and intrathoracic pressure are represented by constants and functions, which can interact. Pressures, flows and volumes are recalculated every millisecond and presented on-line as numerical and high-resolution graphics. Results and Discussion: The validity of the simulation models is based on the references (1-4). The software makes it possible to illustrate a great diversity of circulatory pathological findings including systolic and diastolic heart failure, valve diseases, pericardial effusion, arteriosclerosis and effects of changes in intrathoracic pressure. The model is being used to educate doctors and nurses in cardiac surgery, cardiac anaesthesia, and cardiology, but its pedagogical value remains to be validated. Conclusion: Simulation of cardiac physiology and pathology provides a new way to study the heart. Results from simulations can be used in education as well as in interpretation of clinical invasive monitoring, echocardiography and experimental research.

  • 110.
    Broome, Michael
    Karolinska Institutet.
    The Effects of Mitral Regurgitation on Venous Pulmonary Flow and Mitral Flow2004Other (Other academic)
  • 111.
    Broome, Michael
    et al.
    Umeå Universitet.
    Aneman, A.
    Lehtipalo, S.
    Arnerlov, C.
    Johansson, G.
    Winso, O.
    Biber, B.
    Splanchnic vasoconstriction by angiotensin II is arterial pressure dependent2002In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 46, no 1, p. 57-63Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Our hypothesis was that splanchnic vasoconstriction by exogenous angiotensin II (Ang II) is significantly potentiated by local mechanisms increasing vasomotor tone and that splanchnic tissue oxygenation during administration of Ang II is perfusion pressure dependent. The aim was to study local splanchnic circulatory effects and tissue oxygenation during intravenous infusion of Ang II at different levels of regional arterial driving pressure in a whole-body large animal model. METHODS: Ang II was infused in incremental doses (0-200 microg x h-1) in anaesthetised instrumented pigs (n=8). Mean superior mesenteric arterial pressure (PSMA) was adjusted by a local variable perivascular occluder. Perivascular ultrasound and laser-Doppler flowmetry were used for measurements of mesenteric venous blood flow and superficial intestinal blood flow, respectively. Intestinal oxygenation was evaluated by oxygen tissue tension (PtiO2) and lactate fluxes. RESULTS: Ang II produced prominent and dose-dependent increases in mesenteric vascular resistance (RSMA) when the intestine was exposed to systemic arterial pressure, but Ang II increased RSMA only minimally when PSMA was artificially kept constant at a lower level (50 mmHg) by the occluder. Although Ang II decreased PtiO2 at a PSMA of 50 mmHg, splanchnic lactate production was not observed. CONCLUSION: We demonstrate that splanchnic vasoconstriction by exogenous Ang II is dependent on arterial driving pressure, suggesting significant potentiation through autoregulatory increases in vasomotor tone. Intestinal hypoxaemia does not seem to occur during short-term infusion of Ang II in doses that significantly increases systemic arterial pressure.

  • 112.
    Broome, Michael
    et al.
    Karolinska Institutet.
    Palmer, K.
    Schersten, H.
    Frenckner, B.
    Nilsson, F.
    Prolonged extracorporeal membrane oxygenation and circulatory support as bridge to lung transplant2008In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 86, no 4, p. 1357-1360Article in journal (Refereed)
    Abstract [en]

    A 38-year-old man with progressive alveolitis secondary to polymyositis was treated for 52 days with venovenous and venoarterial extracorporeal membrane oxygenation as a bridge to bilateral lung transplantation. The patient survived, despite multiple complications, and is now back home with good pulmonary function. He is working part-time nearly 3 years post-transplant. This case shows that long-term extracorporeal lung assist is a viable but demanding alternative for bridging patients to pulmonary transplantation. This case also shows that right ventricular failure necessating conversion to veno-arterial assist does not necessarily predict right ventricular failure post-transplant.

  • 113.
    Broomé, Michael
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska Univ Hosp, Sweden.
    Scarce resources call for us to weigh the pros and cons of every single decision2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 8, p. 880-880Article in journal (Other academic)
  • 114.
    Broomé, Michael
    et al.
    KTH, School of Technology and Health (STH), Medical Engineering, Medical Imaging. Karolinska University Hospital and Karolinska Institutet, Sweden.
    Donker, D. W.
    Individualized real-time clinical decision support to monitor cardiac loading during venoarterial ECMO2016In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    Veno-arterial extracoporeal membrane oxygenation (VA ECMO) is increasingly used for acute and refractory cardiogenic shock. Yet, in clinical practice, monitoring of cardiac loading conditions during VA ECMO can be cumbersome. To this end, we illustrate the validity and clinical applicability of a real-time cardiovascular computer simulation, which allows to integrate hemodynamics, cardiac dimensions and the corresponding degree of VA ECMO support and ventricular loading in individual patients over time.

  • 115.
    Broomé, Michael
    et al.
    Umeå Universitet.
    Haney, M.
    Häggmark, S.
    Johansson, G.
    Åneman, A.
    Biber, B.
    Pressure-independent cardiac effects of angiotensin II in pigs2004In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 182, no 2, p. 111-119Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor with an important role in the development of cardiovascular disease. Earlier results have shown a positive acute inotropic effect of Ang II in anaesthetized pigs together with significant vasoconstriction. This investigation was designed to study cardiac effects of Ang II, when blood pressure was maintained constant by experimental means. METHODS: Ang II (200 microg h(-1)) was infused in anaesthetized pigs (n = 10) at two different arterial blood pressures, the first determined by the effects of Ang II alone, and the second maintained at baseline blood pressure with nitroprusside. Cardiac systolic and diastolic function was evaluated by analysis of left ventricular pressure-volume relationships. RESULTS: Heart rate, end-systolic elastance (Ees) and pre-load adjusted maximal power (PWRmax EDV(-2)) increased at both blood pressure levels, although less when blood pressure was kept constant with nitroprusside. The time constant for isovolumetric relaxation (tau(1/2)) was prolonged with Ang II alone and shortened with Ang II infused together with nitroprusside. CONCLUSION: Ang II infusion in the pig has inotropic and chronotropic properties independent of arterial blood pressure levels, although the effects seem to be blunted by pharmacological actions of the nitric oxide donor nitroprusside.

  • 116.
    Brown, Lisa G.
    et al.
    IBM Thomas J. Watson Research Center and Columbia University.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    Noz, Marilyn E.
    New York University.
    Landmark-based 3D fusion of SPECT and CT images1993In: Sensor fusion VI: 7-8 September 1993, Boston, Massachusetts / [ed] Paul S. Schenker, SPIE - International Society for Optical Engineering, 1993, Vol. 2059, p. 166-174Conference paper (Refereed)
    Abstract [en]

    In this paper we present interactive visualization procedures for registration of SPECT and CT images based on landmarks. Because of the poor anatomic detail available in many SPECT images, registration of SPECT images with other modalities often requires the use of external markers. These markers may correspond to anatomic structures identifiable in the other modality image. In this work, we present a method to nonrigidly register SPECT and CT images based on automatic marker localization and interactive anatomic localization using 3D surface renderings of skin. The images are registered in 3D by fitting low order polynomials which are constrained to be near rigid. The method developed here exploits 3D information to attain greater accuracy and reduces the amount of time needed for expert interaction.

  • 117.
    Brudfors, Mikael
    et al.
    KTH, School of Computer Science and Communication (CSC).
    Seitel, Alexander
    University of British Columbia.
    Rasoulian, Abtin
    University of British Columbia.
    Lasso, Andras
    Queens University, Canada.
    Lessoway, Victoria
    Woman's Hospital, Vancouver, Canada.
    Osborn, Jill
    St Pauls Hospital, Vancouver, Canada.
    Maki, Atsuto
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP.
    Rohling, Robert
    University of British Columbia.
    Abolmaesumi, Purang
    University of British Columbia.
    Towards real-time, tracker-less 3D ultrasound guidance for spine anaesthesia2015In: International Conference on Information Processing in Computer-Assisted Interventions, 2015Conference paper (Refereed)
  • 118.
    Brudfors, Mikael
    et al.
    KTH, School of Computer Science and Communication (CSC).
    Seitel, Alexander
    University of British Columbia.
    Rasoulian, Abtin
    University of British Columbia.
    Lasso, Andras
    Queens University, Canada.
    Lessoway, Victoria
    Woman's Hospital, Vancouver, Canada.
    Osborn, Jill
    St Pauls Hospital, Vancouver, Canada.
    Maki, Atsuto
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP.
    Rohling, Robert
    University of British Columbia.
    Abolmaesumi, Purang
    University of British Columbia.
    Towards real-time, tracker-less 3D ultrasound guidance for spine anaesthesia2015In: International Journal of Computer Assisted Radiology and Surgery, ISSN 1861-6410, E-ISSN 1861-6429, Vol. 10, no 6, p. 855-865Article in journal (Refereed)
    Abstract [en]

    Purpose: Epidural needle insertions and facet joint injections play an important role in spine anaesthesia. The main challenge of safe needle insertion is the deep location of the target, resulting in a narrow and small insertion channel close to sensitive anatomy. Recent approaches utilizing ultrasound (US) as a low-cost and widely available guiding modality are promising but have yet to become routinely used in clinical practice due to the difficulty in interpreting US images, their limited view of the internal anatomy of the spine, and/or inclusion of cost-intensive tracking hardware which impacts the clinical workflow. Methods: We propose a novel guidance system for spine anaesthesia. An efficient implementation allows us to continuously align and overlay a statistical model of the lumbar spine on the live 3D US stream without making use of additional tracking hardware. The system is evaluated in vivo on 12 volunteers. Results: The in vivo study showed that the anatomical features of the epidural space and the facet joints could be continuously located, at a volume rate of 0.5 Hz, within an accuracy of 3 and 7 mm, respectively. Conclusions: A novel guidance system for spine anaesthesia has been presented which augments a live 3D US stream with detailed anatomical information of the spine. Results from an in vivo study indicate that the proposed system has potential for assisting the physician in quickly finding the target structure and planning a safe insertion trajectory in the spine.

  • 119. Bruzelius, M.
    et al.
    Bottai, M.
    Sabater-Lleal, M.
    Strawbridge, R. J.
    Bergendal, A.
    Silveira, A.
    Sundstrom, A.
    Kieler, H.
    Hamsten, A.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital Solna, Sweden; Karolinska Institutet, Sweden .
    Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no 2, p. 219-227Article in journal (Refereed)
    Abstract [en]

    BackgroundFamily history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. ObjectivesWe investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. Patients/MethodA total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). ResultsSeven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. ConclusionPrediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.

  • 120. Bruzelius, M.
    et al.
    Iglesias, Maria Jesus
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sanchez-Rivera, Laura
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gyorgy, B.
    Souto, J. C.
    Franberg, M.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Strawbridge, R. J.
    Holmström, M.
    Hamsten, A.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Silveira, A.
    Soria, J. M.
    Smadja, D. M.
    Butler, L. M.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Morange, P. -E
    Trégouët, D. -A
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    PDGFB, a new candidate plasma biomarker for venous thromboembolism: Results from the VEREMA affinity proteomics study2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish ¡°Venous Thromboembolism Biomarker Study,¡± using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor β (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (p ~ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P 5 .002). PDGF was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.

  • 121. Bruzelius, Maria
    et al.
    Strawbridge, Rona J.
    Tregouet, David-Alexandre
    Wiggins, Kerri L.
    Gertow, Karl
    Sabater-Lleal, Maria
    Ohrvik, John
    Bergendal, Annica
    Silveira, Angela
    Sundstrom, Anders
    Kieler, Helle
    Syvanen, Ann-Christine
    Smith, Nicholas L.
    Morange, Pierre-Emmanuel
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Coagulation Unit, Hematology Centre; Atherosclerosis Research Unit, Centre for Molecular Medicine Karolinska University Hospital Solna, Sweden.
    Hamsten, Anders
    Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 426-432Article in journal (Refereed)
    Abstract [en]

    Introduction: We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n = 2753) from Sweden. Materials and Methods: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. Results: Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181). Conclusions: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.

  • 122. Bucht, C.
    et al.
    Söderberg, P.
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Fully automated corneal endothelial morphometry of images captured by clinical specular microscopy2009In: Ophthalmic Technologies XIX, SPIE - International Society for Optical Engineering, 2009, p. 716315-Conference paper (Refereed)
    Abstract [en]

    The corneal endothelium serves as the posterior barrier of the cornea. Factors such as clarity and refractive properties of the cornea are in direct relationship to the quality of the endothelium. The endothelial cell density is considered the most important morphological factor. Morphometry of the corneal endothelium is presently done by semi-automated analysis of pictures captured by a Clinical Specular Microscope (CSM). Because of the occasional need of operator involvement, this process can be tedious, having a negative impact on sampling size. This study was dedicated to the development of fully automated analysis of images of the corneal endothelium, captured by CSM, using Fourier analysis. Software was developed in the mathematical programming language Matlab. Pictures of the corneal endothelium, captured by CSM, were read into the analysis software. The software automatically performed digital enhancement of the images. The digitally enhanced images of the corneal endothelium were transformed, using the fast Fourier transform (FFT). Tools were developed and applied for identification and analysis of relevant characteristics of the Fourier transformed images. The data obtained from each Fourier transformed image was used to calculate the mean cell density of its corresponding corneal endothelium. The calculation was based on well known diffraction theory. Results in form of estimated cell density of the corneal endothelium were obtained, using fully automated analysis software on images captured by CSM. The cell density obtained by the fully automated analysis was compared to the cell density obtained from classical, semiautomated analysis and a relatively large correlation was found.

  • 123. Bucht, C.
    et al.
    Söderberg, P.
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Fully automated corneal endothelial morphometry of images captured by clinical specular microscopy2010In: Ophthalmic Technologies XX, SPIE - International Society for Optical Engineering, 2010, p. 75501E-Conference paper (Refereed)
    Abstract [en]

    The corneal endothelium serves as the posterior barrier of the cornea. Factors such as clarity and refractive properties of the cornea are in direct relationship to the quality of the endothelium. The endothelial cell density is considered the most important morphological factor of the corneal endothelium. Pathological conditions and physical trauma may threaten the endothelial cell density to such an extent that the optical property of the cornea and thus clear eyesight is threatened. Diagnosis of the corneal endothelium through morphometry is an important part of several clinical applications. Morphometry of the corneal endothelium is presently carried out by semi automated analysis of pictures captured by a Clinical Specular Microscope (CSM). Because of the occasional need of operator involvement, this process can be tedious, having a negative impact on sampling size. This study was dedicated to the development and use of fully automated analysis of a very large range of images of the corneal endothelium, captured by CSM, using Fourier analysis. Software was developed in the mathematical programming language Matlab. Pictures of the corneal endothelium, captured by CSM, were read into the analysis software. The software automatically performed digital enhancement of the images, normalizing lights and contrasts. The digitally enhanced images of the corneal endothelium were Fourier transformed, using the fast Fourier transform (FFT) and stored as new images. Tools were developed and applied for identification and analysis of relevant characteristics of the Fourier transformed images. The data obtained from each Fourier transformed image was used to calculate the mean cell density of its corresponding corneal endothelium. The calculation was based on well known diffraction theory. Results in form of estimated cell density of the corneal endothelium were obtained, using fully automated analysis software on 292 images captured by CSM. The cell density obtained by the fully automated analysis was compared to the cell density obtained from classical, semiautomated analysis and a relatively large correlation was found.

  • 124.
    Bucht, Curry
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Söderberg, P.
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    A model for corneal endothelial morphometry by diffraction2006In: Progr. Biomed. Opt. Imaging Proc. SPIE, 2006Conference paper (Refereed)
    Abstract [en]

    As a part of an ongoing project on corneal endothelium morphometry by diffraction, a model for corneal endothelium simulation has been developed. The model has been developed in the mathematical programming language Matlab™. Images of corneal endothelium were simulated and the diffraction pattern of the image was calculated. The diffraction pattern was calculated for a series of endothelial images while varying important variables in the simulated image. This rendered the theoretical relationships between values of variables in the diffraction pattern and values of morphometric variables in the image. At this stage, the analysis focused on the expression of endothelial mean cell size and coefficient of variation in the diffraction pattern, respectively. As expected from diffraction theory, it was found that there is a direct linear relationship between mean cell size and distance between periodic variations in the diffraction pattern. We further found that the ratio between the intensity in the central maximum and the intensity in the first harmonic of the diffraction pattern was functionally depending on the variation in cell size. The current findings demonstrate that it is possible to theoretically determine average cell size and coefficient of variation of cell size in the diffraction pattern.

  • 125.
    Bucht, Curry
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics. Karolinska Institutet, Sweden.
    Söderberg, P.
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Recording the diffraction pattern reflected from corneal endothelium2007In: Ophthalmic Technologies XVII, SPIE - International Society for Optical Engineering, 2007, p. 42610-42610Conference paper (Refereed)
    Abstract [en]

    As a part of an ongoing research project on morphometrical diagnosis of the corneal endothelium, an experimental optical setup has been created. The structure of the corneal endothelial cells could be considered a reflecting periodical aperture. Hence, the diffraction pattern reflected from the endothelium contains valuable morphometrical information. In the present work, focus has been on sampling the posterior surface of explanted corneas. Methods: An optical setup was created, using a 632.8 nm He-Ne laser as the light source. The desired diffraction pattern was produced as a collimated reflection. Hence, because the posterior surface of the cornea is concave, lenses were used to attain the right divergence of the light impingent on the corneal endothelium. These lenses also made it possible to adjust the sampling spot size. A beam splitter (BS) was used to provide an optical path for both the impinging laser beam as well as the reflected diffracted beam. The lens acting as a Fourier lens was then placed after the BS. At the back focal plane of the Fourier lens, a CCD detector was used for recording in the Fourier plane. In the process of creating the setup, explanted corneas were emulated using grated contact lenses. Results: The current optical set up allows identification of a diffraction pattern from a concave spherical surface with a radius of curvature of the same order as a human cornea.

  • 126.
    Bucht, Curry
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Söderberg, P.
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    The impact of horizontal offset of the cornea during corneal specular microscopy2008In: Progr. Biomed. Opt. Imaging Proc. SPIE, 2008Conference paper (Refereed)
    Abstract [en]

    We are developing automated morphometric analysis of the corneal endothelium. Here, the general impact of horizontal offset of the cornea on morphometry was examined. Errors due to perspective during imaging with a Clinical Specular Microscope (CSM) were analyzed considering semi automated analysis software and fully automated Fourier analysis software. Methods: A mathematical model of the cornea was created. Trigonometry was applied to find the relationship between the horizontal offset of the cornea relative to the microscope objective, and the consecutive errors from perspective changes in the image. An experimental setup was created using a cornea made of polymethyl methacrylate (PMMA). The posterior surface of the PMMA cornea was horizontally marked. The PMMA cornea was placed in a holder. Difference in refractive index between real endothelium and aqueous humor was emulated using high refractive index liquid. Images with varying horizontal offset on the PMMA corneal posterior surface, along with their relative offset coordinates were captured, using CSM. Results: Experiments using controlled offset of the cornea in relation to its center estimated that analyzable images can be acquired within an interval of 1.26 mm, using central cornea sampling CSM. Because of refractive indices along with light scattering differences between the corneal tissue and PMMA , the 1.26 mm interval should be considered a first estimate for feasible CSM images. The effect of corneal endothelial offset during imaging with CSM or fully automated Fourier analysis should be considered.

  • 127.
    Bucht, Curry
    et al.
    KTH, School of Engineering Sciences (SCI), Physics.
    Söderberg, Per
    Manneberg, Göran
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Simulation of specular microscopy images of corneal endothelium, a tool for control of measurement errors2011In: ACTA OPHTHALMOLOGICA, ISSN 1755-375X, Vol. 89, no 3, p. e242-e250Article in journal (Refereed)
    Abstract [en]

    Purpose: We aimed at developing simulation software capable of producing images of corneal endothelium close to identical to images captured by clinical specular microscopy with defined morphometrical characteristics. It was further planned to demonstrate the usefulness of the simulator by analysing measurement errors associated with a trained operator using a commercially available semi-automatic algorithm for analysis of simulated images. Methods: Software was developed that allows creation of unique images of the corneal endothelium expressing morphology close to identical with that seen in images of corneal specular microscopy. Several hundred unique images of the corneal endothelium were generated with randomization, spanning a physiological range of endothelial cell density. As an example of the usefulness of the simulator for analysis of measurement errors in corneal specular microscopy, a total of 12 of all the images generated were randomly selected such that the endothelial cell density expressed was evenly distributed over the physiological range of endothelial cell density. The images were transferred to a personal computer. The imagenet-640 software was used to analyse endothelial cell size variation, percentage of hexagonal endothelial cells, and endothelial cell density. Results: The simulator developed allows randomized generation of corneal specular microscopy images with a preset expected average and variation of cell structure. Calculated morphometric information of each cell is stored in the simulator. The image quality can secondarily be varied with a toolbox of filters to approximate a large spectrum of clinically captured images. As an example of the use of the simulator, measurement errors associated with one trained operator using the imagenet-640 software, and focusing on endothelial cell density, were examined. The functional dependence between morphometric information estimated with the imagenet-640 software algorithm and real morphometric information as provided by the simulator was analysed with regression. It was demonstrated that that the estimations of endothelial cell size variation was associated with a scaling error and that the random error was strongly dependent on the operator. Conclusion: The newly developed simulator for randomized generation of morphometrically defined corneal specular microscopy images for the first time makes it possible to estimate a spatial scaling error of an available semi-automatic algorithm and to determine the random measurement error of important morphometric estimates in a defined reference sample of images. It is anticipated that the simulator will be a valuable tool for the generation of a large set of morphometrically well-characterized corneal specular microscopy images that can be used for calibration among research centres, for minimization of random errors and for measurement of quality control. Simulated images will be useful for the development of fully automatic analysis of corneal endothelial cell morphometry.

  • 128.
    Buizza, Giulia
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems. Politecn Milan, CartCasLab, Dept Elect Informat & Bioengn, Piazza Leonardo Da Vinci 42, I-20133 Milan, Italy..
    Toma-Dasu, Iuliana
    Karolinska Univ Sjukhuset, Karolinska Inst, Dept Oncol Pathol, Med Radiat Phys, S-17176 Solna, Sweden..
    Lazzeroni, Marta
    Karolinska Univ Sjukhuset, Karolinska Inst, Dept Oncol Pathol, Med Radiat Phys, S-17176 Solna, Sweden..
    Paganelli, Chiara
    Politecn Milan, CartCasLab, Dept Elect Informat & Bioengn, Piazza Leonardo Da Vinci 42, I-20133 Milan, Italy..
    Riboldi, Marco
    Politecn Milan, CartCasLab, Dept Elect Informat & Bioengn, Piazza Leonardo Da Vinci 42, I-20133 Milan, Italy.;Ludwig Maximilians Univ Munchen, Fac Phys, Coloumbwall 1, D-5748 Garching, Germany..
    Chang, Yong Jun
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems.
    Smedby, Örjan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Wang, Chunliang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Early tumor response prediction for lung cancer patients using novel longitudinal pattern features from sequential PET/CT image scans2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 54, p. 21-29Article in journal (Refereed)
    Abstract [en]

    Purpose: A new set of quantitative features that capture intensity changes in PET/CT images over time and space is proposed for assessing the tumor response early during chemoradiotherapy. The hypothesis whether the new features, combined with machine learning, improve outcome prediction is tested. Methods: The proposed method is based on dividing the tumor volume into successive zones depending on the distance to the tumor border. Mean intensity changes are computed within each zone, for CT and PET scans separately, and used as image features for tumor response assessment. Doing so, tumors are described by accounting for temporal and spatial changes at the same time. Using linear support vector machines, the new features were tested on 30 non-small cell lung cancer patients who underwent sequential or concurrent chemoradiotherapy. Prediction of 2-years overall survival was based on two PET-CT scans, acquired before the start and during the first 3 weeks of treatment. The predictive power of the newly proposed longitudinal pattern features was compared to that of previously proposed radiomics features and radiobiological parameters. Results: The highest areas under the receiver operating characteristic curves were 0.98 and 0.93 for patients treated with sequential and concurrent chemoradiotherapy, respectively. Results showed an overall comparable performance with respect to radiomics features and radiobiological parameters. Conclusions: A novel set of quantitative image features, based on underlying tumor physiology, was computed from PET/CT scans and successfully employed to distinguish between early responders and non-responders to chemoradiotherapy.

  • 129.
    Bujila, Robert
    et al.
    KTH, School of Engineering Sciences (SCI), Physics. Karolinska Univ Hosp, Med Radiat Phys & Nucl Med, Stockholm, Sweden.
    Kull, Love
    Sunderby Hosp, Dept Radiat Phys, Lulea, Sweden..
    Danielsson, Mats
    KTH, School of Engineering Sciences (SCI), Physics.
    Andersson, Jonas
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Applying three different methods of measuring CTDIfree air to the extended CTDI formalism for wide-beam scanners (IEC 60601-2-44): A comparative study2018In: Journal of Applied Clinical Medical Physics, ISSN 1526-9914, E-ISSN 1526-9914, Vol. 19, no 4, p. 281-289Article in journal (Refereed)
    Abstract [en]

    Purpose: The weighted CT dose index (CTDIw) has been extended for a nominal total collimation width (nT) greater than 40 mm and relies on measurements of CTDfree air. The purpose of this work was to compare three methods of measuring CTDIfree air and subsequent calculations of CTDIw to investigate their clinical appropriateness. Methods: The CTDIfree air, for multiple nTs up to 160 mm, was calculated from (1) high-resolution air kerma profiles from a step-and-shoot translation of a liquid ionization chamber (LIC) (considered to be a dosimetric reference), (2) pencil ionization chamber (PIC) measurements at multiple contiguous positions, and (3) air kerma profiles obtained through the continuous translation of a solid-state detector. The resulting CTDIfree air was used to calculate the CTDIw, per the extended formalism, and compared. Results: The LIC indicated that a 40 mm nT should not be excluded from the extension of the CTDIw formalism. The solid-state detector differed by as much as 8% compared to the LIC. The PIC was the most straightforward method and gave equivalent results to the LIC. Conclusions: The CTDIw calculated with the latest CTDI formalism will differ most for 160 mm nTs (e.g., whole-organ perfusion or coronary CT angiography) compared to the previous CTDI formalism. Inaccuracies in the measurement of CTDIfree air will subsequently manifest themselves as erroneous calculations of the CTDIw, for nTs greater than 40 mm, with the latest CTDI formalism. The PIC was found to be the most clinically feasible method and was validated against the LIC.

  • 130. Burlaka, Ievgeniia
    et al.
    Liu, Xiao Li
    Rebetz, Johan
    Arvidsson, Ida
    Yang, Liping
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Karpman, Diana
    Aperia, Anita
    Ouabain Protects against Shiga Toxin-Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL2013In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 24, no 9, p. 1413-1423Article in journal (Refereed)
    Abstract [en]

    Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-B pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-B antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.

  • 131. Burlaka, Ievgeniia
    et al.
    Nilsson, Linnea M.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Scott, Lena
    Holtback, Ulla
    Eklöf, Ann-Christine
    Fogo, Agnes B.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Aperia, Anita
    Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease2016In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 90, no 1, p. 135-148Article in journal (Refereed)
    Abstract [en]

    There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time-and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.

  • 132. Butt, Linus
    et al.
    Unnersjö-Jess, David
    Rinschen, Markus
    Höhne, Martin
    Edwards, Aurelie
    Ebert, Lena
    Castrop, Hayo
    Brismar, Hjalmar
    Blom, Hans
    Brinkkötter, Paul
    Schermer, Bernhard
    Benzing, Thomas
    Elucidating the pathogenesis of focal segmental glomerulosclerosis using CRISPR/Cas9 mediated genome editingManuscript (preprint) (Other academic)
  • 133.
    Byström, Sanna
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Eklund, Martin
    Hong, Mun-Gwan
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Fredolini, Claudia
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Eriksson, Mikael
    Czene, Kamila
    Hall, Per
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO).
    Gabrielson, Marike
    Affinity proteomic profiling of plasma for proteins associated to area-based mammographic breast density2018In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 20, article id 14Article in journal (Refereed)
    Abstract [en]

    Background: Mammographic breast density is one of the strongest risk factors for breast cancer, but molecular understanding of how breast density relates to cancer risk is less complete. Studies of proteins in blood plasma, possibly associated with mammographic density, are well-suited as these allow large-scale analyses and might shed light on the association between breast cancer and breast density. Methods: Plasma samples from 1329 women in the Swedish KARMA project, without prior history of breast cancer, were profiled with antibody suspension bead array (SBA) assays. Two sample sets comprising 729 and 600 women were screened by two different SBAs targeting a total number of 357 proteins. Protein targets were selected through searching the literature, for either being related to breast cancer or for being linked to the extracellular matrix. Association between proteins and absolute area-based breast density (AD) was assessed by quantile regression, adjusting for age and body mass index (BMI). Results: Plasma profiling revealed linear association between 20 proteins and AD, concordant in the two sets of samples (p < 0.05). Plasma levels of seven proteins were positively associated and 13 proteins negatively associated with AD. For eleven of these proteins evidence for gene expression in breast tissue existed. Among these, ABCC11, TNFRSF10D, F11R and ERRF were positively associated with AD, and SHC1, CFLAR, ACOX2, ITGB6, RASSF1, FANCD2 and IRX5 were negatively associated with AD. Conclusions: Screening proteins in plasma indicates associations between breast density and processes of tissue homeostasis, DNA repair, cancer development and/or progression in breast cancer. Further validation and follow-up studies of the shortlisted protein candidates in independent cohorts will be needed to infer their role in breast density and its progression in premenopausal and postmenopausal women.

  • 134.
    Byström, Sanna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Eklund, Martin
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Eriksson, Mikael
    Czene, Kamila
    Hall, Per
    Schwenk, Jochen. M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Gabrielson, Marike
    Affinity proteomic profiling of plasma for proteins associated to mammographic breast densityManuscript (preprint) (Other academic)
  • 135.
    Byström, Sanna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Edqvist, P. -H
    Nyaiesh, Etienne-Nicholas
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Drobin, Kimi
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Matthias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bergqvist, M.
    Pontén, F.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Affinity Proteomics Exploration of Melanoma Identifies Proteins in Serum with Associations to T-Stage and Recurrence2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 3, p. 385-395Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Blood-based proteomic profiling may aid and expand our understanding of diseases and their different phenotypes. The aim of the presented study was to profile serum samples from patients with malignant melanoma using affinity proteomic assays to describe proteins in the blood stream that are associated to stage or recurrence of melanoma. MATERIAL AND METHODS: Multiplexed protein analysis was conducted using antibody suspension bead arrays. A total of 232 antibodies against 132 proteins were selected from (i) a screening with 4595 antibodies and 32 serum samples from melanoma patients and controls, (ii) antibodies used for immunohistochemistry, (iii) protein targets previously related with melanoma. The analysis was performed with 149 serum samples from patients with malignant melanoma. Antibody selectivity was then assessed by Western blot, immunocapture mass spectrometry, and epitope mapping. Lastly, indicative antibodies were applied for IHC analysis of melanoma tissues. RESULTS: Serum levels of regucalcin (RGN) and syntaxin 7 (STX7) were found to be lower in patients with both recurring tumors and a high Breslow's thickness (T-stage 3/4) compared to low thickness (T-stage 1/2) without disease recurrence. Serum levels of methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) were instead elevated in sera of T3/4 patients with recurrence. The analysis of tissue sections with S100A6 and MTHFD1L showed positive staining in a majority of patients with melanoma, and S100A6 was significantly associated to T-stage. CONCLUSIONS: Our findings provide a starting point to further study RGN, STX7, MTHFD1L and S100A6 in serum to elucidate their involvement in melanoma progression and to assess a possible contribution to support clinical indications.

  • 136.
    Byström, Sanna
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Edqvist, Per-Henrik
    Nyaiesh, Etienne-Nicholas
    Drobin, Kimi
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Uhlén, Matthias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Bergqvist, Michael
    Pontén, Fredrik
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Affinity proteomics exploration of melanoma identifies proteins in serum with associations to T-stage and recurrenceManuscript (preprint) (Other academic)
  • 137.
    Böck, Michelle
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory. RaySearch Labs AB, Sweden.
    Eriksson, Kjell
    Forsgren, Anders
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.
    Hardemark, Bjorn
    Toward robust adaptive radiation therapy strategies2017In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 44, no 6, p. 2054-2065Article in journal (Refereed)
    Abstract [en]

    Purpose: To set up a framework combining robust treatment planning with adaptive re-optimization in order to maintain high treatment quality, to respond to interfractional geometric variations and to identify those patients who will benefit the most from an adaptive fractionation schedule. Methods: The authors propose robust adaptive strategies based on stochastic minimax optimization for a series of simulated treatments on a one-dimensional patient phantom. The plan applied during the first fractions should be able to handle anticipated systematic and random errors. Information on the individual geometric variations is gathered at each fraction. At scheduled fractions, the impact of the measured errors on the delivered dose distribution is evaluated. For a patient having received a dose that does not satisfy specified plan quality criteria, the plan is re-optimized based on these individually measured errors. The re-optimized plan is then applied during subsequent fractions until a new scheduled adaptation becomes necessary. In this study, three different adaptive strategies are introduced and investigated. (a) In the first adaptive strategy, the measured systematic and random error scenarios and their assigned probabilities are updated to guide the robust re-optimization. (b) In the second strategy, the degree of conservativeness is adapted in response to the measured dose delivery errors. (c) In the third strategy, the uncertainty margins around the target are recalculated based on the measured errors. The simulated treatments are subjected to systematic and random errors that are either similar to the anticipated errors or unpredictably larger in order to critically evaluate the performance of these three adaptive strategies. Results: According to the simulations, robustly optimized treatment plans provide sufficient treatment quality for those treatment error scenarios similar to the anticipated error scenarios. Moreover, combining robust planning with adaptation leads to improved organ-at-risk protection. In case of unpredictably larger treatment errors, the first strategy in combination with at most weekly adaptation performs best at notably improving treatment quality in terms of target coverage and organ-at-risk protection in comparison with a non-adaptive approach and the other adaptive strategies. Conclusion: The authors present a framework that provides robust plan re-optimization or margin adaptation of a treatment plan in response to interfractional geometric errors throughout the fractionated treatment. According to the simulations, these robust adaptive treatment strategies are able to identify candidates for an adaptive treatment, thus giving the opportunity to provide individualized plans, and improve their treatment quality through adaptation. The simulated robust adaptive framework is a guide for further development of optimally controlled robust adaptive therapy models.

  • 138.
    Cadirci, Kenan
    et al.
    Hlth Sci Univ, Erzurum Reg Training & Res Hosp, Dept Internal Med, Erzurum, Turkey..
    Ozdemir Tozlu, Ozlem
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkey..
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey.;Univ G dAnnunzio, Dept Pharm, Chieti, Italy..
    Mardinoglu, Adil
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE19 1RT, England..
    The in vitro cytotoxic, genotoxic, and oxidative damage potentials of the oral artificial sweetener aspartame on cultured human blood cells2020In: Turkish Journal of Medical Sciences, ISSN 1300-0144, E-ISSN 1303-6165, Vol. 50, no 2, p. 448-454Article in journal (Refereed)
    Abstract [en]

    Background/aim: Aspartame (APM, L-aspartyl-L-phenylalanine methylester) is a low-calorie, nonsaccharide artificial sweetener widely used in foods and beverages. When metabolized by the body, APM is broken down into aspartic acid, phenylalanine amino acids, and a third substance, methanol. Since the amino acid phenylalanine serves as a neurotransmitter building block affecting the brain, and methanol is converted into toxic formaldehyde, APM has deleterious effects on the body and brain. Thus, its safety and, toxicity have been the subjects of concern ever since it was first discovered. Although many studies have been performed on it, due to the presence of conflicting data in the literature, there are still numerous question marks concerning APM. Therefore, the safety of aspartame was tested using in vitro methods. Materials and methods: We aimed to evaluate the in vitro cytotoxic effects by using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release tests, genotoxic damage potential by using chromosome aberration (CA) assay, and antioxidant/oxidant activity by using total antioxidant capacity (TAC) and total oxidative stress (TOS) analysis in primary human whole blood cell cultures. Results: The results of the MTT test showed that APM led to significant decreases in cell viability in a clear concentration-dependent manner. Moreover, an increase in CA frequency was found in the cells treated with APM. However, APM treatments did not cause any significant changes in TAC and TOS levels in whole blood cultures. Conclusion: Overall, the obtained results showed that APM had genotoxicity potential and a concentration-dependent cytotoxic activity in human blood cells.

  • 139. Cai, Fuhong
    et al.
    He, Sailing
    KTH, School of Electrical Engineering (EES), Electromagnetic Engineering. KTH, School of Information and Communication Technology (ICT), Centres, Zhejiang-KTH Joint Research Center of Photonics, JORCEP.
    Electric field Monte Carlo simulation of focused stimulated emission depletion beam, radially and azimuthally polarized beams for in vivo deep bioimaging2014In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 19, no 1, p. 011022-Article in journal (Refereed)
    Abstract [en]

    An electric field Monte Carlo method is used to study the focal spot of a stimulated emission depletion (STED) beam, radially and azimuthally polarized beams in a turbid medium as a function of the scattering coefficient. To consider the diffraction of light of the wave nature, the wavefront is decomposed into a set of secondary spherical subwaves according to the Huygens principle. From the simulation results, we can find that the STED beam can still form a doughnut focal spot inside the turbid medium. These simulation results are important for the feasibility study of STED microscopy for in vivo deep bioimaging. Similarly, the focal spot for an azimuthally polarized beam can also keep a doughnut spot at the focal plane in a turbid medium.

  • 140. Cai, Fuhong
    et al.
    He, Sailing
    KTH, School of Electrical Engineering (EES), Electromagnetic Engineering.
    Using graphics processing units to accelerate perturbation Monte Carlo simulation in a turbid medium2012In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 17, no 4, p. 040502-Article in journal (Refereed)
    Abstract [en]

    We report a fast perturbation Monte Carlo (PMC) algorithm accelerated by graphics processing units (CPU). The two-step PMC simulation [Opt. Lett. 36, 2095 (2011)] is performed by storing the seeds instead of the photon's trajectory, and thus the requirement in computer random-access memory (RAM) becomes minimal. The two-step PMC is extremely suitable for implementation onto CPU. In a standard simulation of spatially-resolved photon migration in the turbid media, the acceleration ratio between using GPU and using conventional CPU is about 1000. Furthermore, since in the two-step PMC algorithm one records the effective seeds, which is associated to the photon that reaches a region of interest in this letter, and then re-run the MC simulation based on the recorded effective seeds, radiative transfer equation (RTE) can be solved by two-step PMC not only with an arbitrary change in the absorption coefficient, but also with large change in the scattering coefficient.

  • 141.
    Callerström, Emma
    KTH, School of Technology and Health (STH).
    Clinicians' demands on monitoring support in an Intensive Care Unit: A pilot study, at Capio S:t Görans Hospital2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Patients treated at intensive care units (ICUs) are failing in one or several organs and requireappropriate monitoring and treatment in order to maintain a meaningful life. Today clinicians inintensive care units (ICUs) manage a large amount of data generated from monitoring devices.The monitoring parameters can either be noted down manually on a monitoring sheet or, for some parameters, transferred automatically to storage. In both cases the information is stored withthe aim to support clinicians throughout the intensive care and be easily accessible. Patient datamanagement systems (PDMSs) facilitate ICUs to retrieve and integrate data. Before managinga new configuration of patient data system, it is required that the ICU makes careful analysis ofwhat data desired to be registered. This pilot study provides knowledge of how the monitoringis performed in an Intensive Care Unit in an emergency hospital in Stockholm.The aim of this thesis project was to collect data about what the clinicians require and whatequipment they use today for monitoring. Requirement elicitation is a technique to collectrequirements. Methods used to collect data were active observations and qualitative interviews.Patterns have been found about what the assistant nurses, nurses and physicians’ require of systems supporting the clinician’s with monitoring parameters. Assistant nurses would like tobe released from tasks of taking notes manually. They also question the need for atomized datacollection since they are present observing the patient bed-side. Nurses describe a demanding burden of care and no more activities increasing that burden of care is required. Physicians require support in order to see how an intervention leads to a certain result for individual patients.The results also show that there is information about decision support but no easy way to applythem, better than the ones used today. Clinicians state that there is a need to be able to evaluatethe clinical work with the help of monitoring parameters. The results provide knowledge about which areas the clinicians needs are not supported enough by the exciting tools.To conclude results show that depending on what profession and experience the clinicians have the demands on monitoring support di↵ers. Monitoring at the ICU is performed while observing individual patients, parameters from medical devices, results from medical tests and physical examinations. Information from all these sources is considered by the clinicians and is desired to be supported accordingly before clinicians commit to action resulting in certain treatment,diagnosis and/or care.

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    Clinicains' demands on monitoring support in an ICU
  • 142. Camargo, Zuleica
    et al.
    Salomão, Gláucia Laís
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Pinho, Sílvia
    Análise acústica e aerodinâmica da voz (Acoustic and aerodynamic assessment of voice)2011In: Tratado de Otorrinolaringologia (Treatise on Otorhinolaryngology) / [ed] Caldas, S.; Melo, J.F.; Martins, R.H.; Selaimen, S., Sao Paulo: Editora Roca , 2011, p. 794-804Chapter in book (Other academic)
  • 143. Camitz, M.
    et al.
    Liljeros, F.
    Travel restrictions for moderately contagious diseases2011In: Hospitality and Health: Issues and Developments, Apple Academic Press , 2011, p. 95-105Chapter in book (Other academic)
    Abstract [en]

    Much research in epidemiology has been focused on evaluating conventional methods of control strategies in the event of an epidemic or pandemic. Travel restrictions are often suggested as an efficient way to reduce the spread of a contagious disease that threatens public health, but few chapters have studied in depth the effects of travel restrictions. In this study, we investigated what effect different levels of travel restrictions might have on the speed and geographical spread of an outbreak of a disease similar to severe acute respiratory syndrome (SARS). 

  • 144. Carignan, C. R.
    et al.
    Olsson, A. Pontus
    KTH, School of Electrical Engineering (EES). Georgetown University, United States .
    Tang, J.
    Cooperative control of virtual objects over the internet using haptic teleoperation2005In: Journal of Endocrine Genetics, ISSN 1565-012X, Vol. 4, no 4, p. 261-267Article in journal (Refereed)
    Abstract [en]

    The feasibility of performing remote assessment and therapy of patients over the internet using robotic devices is explored. Using a force feedback device, the therapist can assess the range of motion, flexibility, strength, and spasticity of the patient's arm grasping a similar robotic device at a remote location. In addition, cooperative rehabilitation strategies can be developed whereby both the patient and therapist perform tasks in a shared virtual environment To counter the destabilizing effects of time delay in the force feedback loop, a passive wave variable architecture is used to encode velocity and force information. The control scheme is validated experimentally over the internet using a pair of InMotion2 robots located several hundred miles apart.

  • 145.
    Carlberg, Konstantin
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Korotkova, Marina
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Larsson, Ludvig
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Catrina, Anca, I
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Ståhl, Patrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. Royal Inst Technol, Dept Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Malmström, Vivianne
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Exploring inflammatory signatures in arthritic joint biopsies with Spatial Transcriptomics2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 18975Article in journal (Refereed)
    Abstract [en]

    Lately it has become possible to analyze transcriptomic profiles in tissue sections with retained cellular context. We aimed to explore synovial biopsies from rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients, using Spatial Transcriptomics (ST) as a proof of principle approach for unbiased mRNA studies at the site of inflammation in these chronic inflammatory diseases. Synovial tissue biopsies from affected joints were studied with ST. The transcriptome data was subjected to differential gene expression analysis (DEA), pathway analysis, immune cell type identification using Xcell analysis and validation with immunohistochemistry (IHC). The ST technology allows selective analyses on areas of interest, thus we analyzed morphologically distinct areas of mononuclear cell infiltrates. The top differentially expressed genes revealed an adaptive immune response profile and T-B cell interactions in RA, while in SpA, the profiles implicate functions associated with tissue repair. With spatially resolved gene expression data, overlaid on high-resolution histological images, we digitally portrayed pre-selected cell types in silico. The RA displayed an overrepresentation of central memory T cells, while in SpA effector memory T cells were most prominent. Consequently, ST allows for deeper understanding of cellular mechanisms and diversity in tissues from chronic inflammatory diseases.

  • 146.
    Carlberg, Konstantin
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Vickovic, Sanja
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ståhl, Patrik
    KTH, School of Biotechnology (BIO), Gene Technology.
    Salmén, Fredrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Korotkova, Marina
    Malmstrom, Vivianne
    Lundeberg, Joakim
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    TRANSCRIPTOME VISUALISATION OF THE INFLAMED RHEUMATOID ARTHRITIS JOINT2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. A58-A59Article in journal (Refereed)
  • 147.
    Carlsson, Fredrik
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.
    Combining segment generation with direct step-and-shoot optimization in intensity-modulated radiation therapy2008In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 35, no 9, p. 3828-3838Article in journal (Refereed)
    Abstract [en]

    A method for generating a sequence of intensity-modulated radiation therapy step-and-shoot plans with increasing number of segments is presented. The objectives are to generate high-quality plans with few, large and regular segments, and to make the planning process more intuitive. The proposed method combines segment generation with direct step-and-shoot optimization, where leaf positions and segment weights are optimized simultaneously. The segment generation is based on a column generation approach. The method is evaluated on a test suite consisting of five head-and-neck cases and five prostate cases, planned for delivery with an Elekta SLi accelerator. The adjustment of segment shapes by direct step-and-shoot optimization improves the plan quality compared to using fixed segment shapes. The improvement in plan quality when adding segments is larger for plans with few segments. Eventually, adding more segments contributes very little to the plan quality, but increases the plan complexity. Thus, the method provides a tool for controlling the number of segments and, indirectly, the delivery time. This can support the planner in finding a sound trade-off between plan quality and treatment complexity.

  • 148.
    Carlsson, Fredrik
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.
    Forsgren, Anders
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Optimization and Systems Theory.
    Iterative regularization in intensity-modulated radiation therapy optimization2006In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 33, no 1, p. 225-234Article in journal (Refereed)
    Abstract [en]

    A common way to solve intensity-modulated radiation therapy (IMRT) optimization problems is to use a beamlet-based approach. The approach is usually employed in a three-step manner: first a beamlet-weight optimization problem is solved, then the fluence profiles are converted into stepand-shoot segments, and finally postoptimization of the segment weights is performed. A drawback of beamlet-based approaches is that beamlet-weight optimization problems are ill-conditioned and have to be regularized in order to produce smooth fluence profiles that are suitable for conversion. The purpose of this paper is twofold: first, to explain the suitability of solving beamlet-based IMRT problems by a BFGS quasi-Newton sequential quadratic programming method with diagonal initial Hessian estimate, and second, to empirically show that beamlet-weight optimization problems should be solved in relatively few iterations when using this optimization method. The explanation of the suitability is based on viewing the optimization method as an iterative regularization method. In iterative regularization, the optimization problem is solved approximately by iterating long enough to obtain a solution close to the optimal one, but terminating before too much noise occurs. Iterative regularization requires an optimization method that initially proceeds in smooth directions and makes rapid initial progress. Solving ten beamlet-based IMRT problems with dose-volume objectives and bounds on the beamlet-weights, we find that the considered optimization method fulfills the requirements for performing iterative regularization. After segment-weight optimization, the treatments obtained using 35 beamlet-weight iterations outperform the treatments obtained using 100 beamlet-weight iterations, both in terms of objective value and of target uniformity. We conclude that iterating too long may in fact deteriorate the quality of the deliverable plan.

  • 149.
    Cassidy, David J.
    et al.
    Alberta Centre for Injury Control and Research, Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada, Section for Personal Injury Prevention, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Carrol, Linda J.
    Alberta Centre for Injury Control and Research, Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada.
    Peloso, Paul M.
    Department of Internal Medicine, University of Iowa Health Center, Iowa City, Iowa, USA.
    Borg, Jörgen
    Department of Neuroscience, Rehabilitation Medicine, Uppsala University, Uppsala, Sweden.
    von Holst, Hans
    Department of Neurosurgery, Karolinska Institutet, Stockholm, Sweden.
    Holm, Lena
    Section for Personal Injury Prevention, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
    Kraus, Jess
    Division of Epidemiology, School of Public Health, University of California, Los Angeles, California, USA.
    Coronado, Victor G.
    National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
    Incidence, risk factors and prevention of mild traumatic brain injury: Results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury2004In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 36, no 43, p. 28-60Article in journal (Refereed)
    Abstract [en]

    Objective: We undertook a best-evidence synthesis on the incidence, risk factors and prevention of mild traumatic brain injury. Methods: Medline, Cinahl, PsycINFO and Embase were searched for relevant articles. After screening 38,806 abstracts, we critically reviewed 169 studies on incidence, risk and prevention, and accepted 121 (72%).Results: The accepted articles show that 70–90% of all treated brain injuries are mild, and the incidence of hospital- treated patients with mild traumatic brain injury is about 100–300/100,000 population. However, much mild traumatic brain injury is not treated at hospitals, and the true population-based rate is probably above 600/100,000. Mild traumatic brain injury is more common in males and in teenagers and young adults. Falls and motor-vehicle colli- sions are common causes.Conclusion: Strong evidence supports helmet use to prevent mild traumatic brain injury in motorcyclists and bicyclists. The mild traumatic brain injury literature is of varying quality, and the studies are very heterogeneous. Never- theless, there is evidence that mild traumatic brain injury is an important public health problem, but we need more high- quality research into this area.

  • 150. Cassidy, David J.
    et al.
    von Holst, Hans
    KTH, Superseded Departments, Aeronautical and Vehicle Engineering.
    Best evidence synthesis on Mild Traumatic Brain Injury: Results of the WHO collaborating centre for neurotrauma prevention, management and rehabilitation task force on Mild Traumatic Brain Injury2004In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. Feb, no Supplement 43, p. 1-144Article in journal (Refereed)
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