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  • Public defence: 2019-04-26 09:00 Ång 4101, Uppsala
    Ryeznik, Yevgen
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Optimal adaptive designs and adaptive randomization techniques for clinical trials2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this Ph.D. thesis, we investigate how to optimize the design of clinical trials by constructing optimal adaptive designs, and how to implement the design by adaptive randomization. The results of the thesis are summarized by four research papers preceded by three chapters: an introduction, a short summary of the results obtained, and possible topics for future work.

    In Paper I, we investigate the structure of a D-optimal design for dose-finding studies with censored time-to-event outcomes. We show that the D-optimal design can be much more efficient than uniform allocation design for the parameter estimation. The D-optimal design obtained depends on true parameters of the dose-response model, so it is a locally D-optimal design. We construct two-stage and multi-stage adaptive designs as approximations of  the D-optimal design when prior information about model parameters is not available. Adaptive designs provide very good approximations to the locally D-optimal design, and can potentially reduce total sample size in a study with a pre-specified stopping criterion.

    In Paper II, we investigate statistical properties of several restricted randomization procedures which target unequal allocation proportions in a multi-arm trial. We compare procedures in terms of their operational characteristics such as balance, randomness, type I error/power, and allocation ratio preserving (ARP) property. We conclude that there is no single “best” randomization procedure for all the target allocation proportions, but the choice of randomization can be done through computer-intensive simulations for a particular target allocation.

    In Paper III, we combine the results from the papers I and II to implement optimal designs in practice when the sample size is small. The simulation study done in the paper shows that the choice of randomization procedure has an impact on the quality of dose-response estimation. An adaptive design with a small cohort size should be implemented with a procedure that ensures a “well-balanced” allocation according to the D-optimal design at each stage.

    In Paper IV, we obtain an optimal design for a comparative study with unequal treatment costs and investigate its properties. We demonstrate that unequal allocation may decrease the total study cost while having the same power as traditional equal allocation. However, a larger sample size may be required. We suggest a strategy on how to choose a suitable randomization procedure which provides a good trade-off between balance and randomness to implement optimal allocation. If there is a strong linear trend in observations, then the ARP property is important to maintain the type I error and power at a certain level. Otherwise, a randomization-based inference can be a good alternative for non-ARP procedures.

    List of papers
    1. Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event Outcomes
    Open this publication in new window or tab >>Adaptive Optimal Designs for Dose-Finding Studies with Time-to-Event Outcomes
    2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 1, article id 24Article in journal (Refereed) Published
    Abstract [en]

    We consider optimal design problems for dose-finding studies with censored Weibull time-to-event outcomes. Locally D-optimal designs are investigated for a quadratic dose-response model for log-transformed data subject to right censoring. Two-stage adaptive D-optimal designs using maximum likelihood estimation (MLE) model updating are explored through simulation for a range of different dose-response scenarios and different amounts of censoring in the model. The adaptive optimal designs are found to be nearly as efficient as the locally D-optimal designs. A popular equal allocation design can be highly inefficient when the amount of censored data is high and when the Weibull model hazard is increasing. The issues of sample size planning/early stopping for an adaptive trial are investigated as well. The adaptive D-optimal design with early stopping can potentially reduce study size while achieving similar estimation precision as the fixed allocation design.

    Place, publisher, year, edition, pages
    Springer, 2018
    Keywords
    adaptive design, censoring, D-optimal design, dose finding, Weibull distribution
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-347660 (URN)10.1208/s12248-017-0166-5 (DOI)000424638500012 ()29285730 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, FP7/2007–2013
    Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-04-25Bibliographically approved
    2. A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios
    Open this publication in new window or tab >>A comparative study of restricted randomization procedures for multiarm trials with equal or unequal treatment allocation ratios
    2018 (English)In: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 37, no 21, p. 3056-3077Article in journal (Refereed) Published
    Abstract [en]

    Randomization designs for multiarm clinical trials are increasingly used in practice, especially in phase II dose-ranging studies. Many new methods have been proposed in the literature; however, there is lack of systematic, head-to-head comparison of the competing designs. In this paper, we systematically investigate statistical properties of various restricted randomization procedures for multiarm trials with fixed and possibly unequal allocation ratios. The design operating characteristics include measures of allocation balance, randomness of treatment assignments, variations in the allocation ratio, and statistical characteristics such as type I error rate and power. The results from the current paper should help clinical investigators select an appropriate randomization procedure for their clinical trial. We also provide a web-based R shiny application that can be used to reproduce all results in this paper and run simulations under additional user-defined experimental scenarios.

    Keywords
    allocation ratio preserving, dose ranging, multiarm trial, randomization design, unequal allocation
    National Category
    Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-362628 (URN)10.1002/sim.7817 (DOI)000441861400003 ()29869347 (PubMedID)
    Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2019-02-22Bibliographically approved
    3. Implementing Optimal Designs for Dose-Response Studies Through Adaptive Randomization for a Small Population Group
    Open this publication in new window or tab >>Implementing Optimal Designs for Dose-Response Studies Through Adaptive Randomization for a Small Population Group
    2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 5, article id 85Article in journal (Refereed) Published
    Abstract [en]

    In dose-response studies with censored time-to-event outcomes, D-optimal designs depend on the true model and the amount of censored data. In practice, such designs can be implemented adaptively, by performing dose assignments according to updated knowledge of the dose-response curve at interim analysis. It is also essential that treatment allocation involves randomization-to mitigate various experimental biases and enable valid statistical inference at the end of the trial. In this work, we perform a comparison of several adaptive randomization procedures that can be used for implementing D-optimal designs for dose-response studies with time-to-event outcomes with small to moderate sample sizes. We consider single-stage, two-stage, and multi-stage adaptive designs. We also explore robustness of the designs to experimental (chronological and selection) biases. Simulation studies provide evidence that both the choice of an allocation design and a randomization procedure to implement the target allocation impact the quality of dose-response estimation, especially for small samples. For best performance, a multi-stage adaptive design with small cohort sizes should be implemented using a randomization procedure that closely attains the targeted D-optimal design at each stage. The results of the current work should help clinical investigators select an appropriate randomization procedure for their dose-response study.

    Place, publisher, year, edition, pages
    SPRINGER, 2018
    Keywords
    D-optimal, randomization design, small population group, time-to-event outcome, unequal allocation
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-361482 (URN)10.1208/s12248-018-0242-5 (DOI)000439535200001 ()30027336 (PubMedID)
    Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2019-02-22Bibliographically approved
    4. Implementing Unequal Randomization in Clinical Trials with Heterogeneous Treatment Costs
    Open this publication in new window or tab >>Implementing Unequal Randomization in Clinical Trials with Heterogeneous Treatment Costs
    2019 (English)In: Statistics in MedicineArticle in journal (Refereed) Submitted
    Abstract [en]

    Equal randomization has been a popular choice in clinical trial practice. However, in trials with heterogeneous variances and/or variable treatment costs, as well as in the settings where maximization of every trial participant’s benefit is an important design consideration, optimal allocation proportions may be unequal across study treatment arms. In this paper, we investigate optimal allocation designs minimizing study cost under statistical efficiency constraints for parallel group clinical trials comparing several investigational treatments against the control. We show theoretically that equal allocation designs may be suboptimal, and unequal allocation designs can provide higher statistical power for the same budget, or result in a smaller cost for the same level of power. We also show how the optimal allocation can be implemented in practice by means of restricted randomization procedures, and how to perform statistical inference following these procedures, using invoked population-based or randomization-based approaches. Our results provide further support to some previous findings in the literature that unequal randomization designs can be cost-efficient and can be successfully implemented in practice. We conclude that the choice of the target allocation, the randomization procedure and the statistical methodology for data analysis are essential components to ensure valid, powerful, and robust clinical trial results.

    National Category
    Other Natural Sciences Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-377608 (URN)
    Available from: 2019-02-22 Created: 2019-02-22 Last updated: 2019-02-22
  • Public defence: 2019-04-26 09:00 Humanistiska Teatern, Uppsala
    von der Heyde, Benedikt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Translating Cardiac and Cardiometabolic GWAS Using Zebrafish2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified thousands of loci associated with cardiac and cardiometabolic traits. However, the trait-associated variants usually do not clearly point to causal gene(s), mechanism(s) or tissue(s). Model systems that allow for a comprehensive and quick candidate gene screening are necessary, ideally in vivo. The overall objective of my thesis is to establish large-scale, imaged-based screens in zebrafish embryos and larvae to examine candidate genes for their effects on heart rate and rhythm, as well as on early-onset atherosclerosis and dyslipidemia.

    In Study 1, I prioritized 18 candidate genes in eight loci identified in a meta-analysis of GWAS for heart rate variability. Some of these genes were already known to be involved in cardiac pacemaking, whereas others require functional characterization.

    In Study 2, I established an experimental pipeline to examine genetic effects on cardiac rate and rhythm and used it to characterize orthologues of six human candidate genes for heart rate and rhythm. I confirmed known effects of rgs6 and hcn4, and established a role for KIAA1755 in HRV.

    In Study 3, I contributed to large-scale experiments to establish the zebrafish as a model system for early-onset atherosclerosis and dyslipidemia. Overfeeding and cholesterol-supplementation of the diet were shown to propel independent pro-atherogenic effects. Atherosclerotic burden was alleviated using commonly prescribed drugs in humans. Lastly, the effects of proof-of-concept genes known to be involved in lipid metabolism were examined and showed higher LDLc (apoea) and early-onset atherosclerosis (apobb1).

    In Study 4, I characterized genes in GWAS-identified loci for triglyceride levels for a role in lipid metabolism and early-stage atherosclerosis. I identified three previously unanticipated genes that influence triglyceride levels in zebrafish larvae. Several additional genes influence other cardiometabolic risk factors. Interestingly, two genes showed trends towards lower triglycerides levels (dock7 and lpar2a), with directionally opposite effects on vascular inflammation. This emphasizes that candidate genes need to be examined comprehensively to guide further mechanistic studies.

    List of papers
    1. Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Open this publication in new window or tab >>Genetic loci associated with heart rate variability and their effects on cardiac disease risk
    Show others...
    2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed) Published
    Abstract [en]

    Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2017
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-329672 (URN)10.1038/ncomms15805 (DOI)000403216600001 ()28613276 (PubMedID)
    Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2019-03-11Bibliographically approved
    2. Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
    Open this publication in new window or tab >>Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo, image-based, large-scale genetic screen in zebrafish
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV) in data from 53,174 individuals. However, functional follow-up experiments - aiming to identify and characterize causal genes in these loci - have not yet been performed. We developed an image- and CRISPR-Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos and larvae. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in fertilized eggs from fish that transgenically express GFP on smooth muscle cells (Tg(acta2:GFP)), to visualize the beating heart using a fluorescence microscope. An automated analysis of repeated 30s recordings of 381 live zebrafish atria at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and kiaa1755); heart rate (rgs6 and hcn4) and the risk of sinoatrial pauses and arrests (hcn4). Hence, our screen confirmed the role of established genes for heart rate (rgs6 and hcn4), and highlighted a novel gene implicated in HRV (kiaa1755).

    Keywords
    GWAS, Zebrafish
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-378938 (URN)
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
    3. Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Open this publication in new window or tab >>Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    Abstract [en]

    Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

    Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

    Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

    Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-378939 (URN)
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
    4. Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
    Open this publication in new window or tab >>Characterising candidate genes for cardiometabolic risk factors in GWAS-identified loci for triglyceride levels using a high-throughput zebrafish screen
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-378940 (URN)
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
  • Public defence: 2019-04-26 09:15 Sal X, Uppsala
    Berglund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Adherence to drug treatment and interpretation of treatment effects2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Suboptimal adherence to medical treatments is prevalent across several clinical conditions and can lead to treatment failure. Adherence is a far from fully explored phenomenon and there is little knowledge about how patients interpret treatment effects. Commonly used treatment evaluation measures are often relative measures, which may be difficult for lay people and patients to understand.

    The overall aim of this thesis was to investigate factors with relevance to adherence, to estimate treatment effects with the time-based Delay of Event (DoE) measure in anticoagulant preventive treatments, and to explore how lay people responded to the DoE measure, as compared with established measures, regarding treatment decisions and effect interpretation.

    A quantitative population-based cross-sectional design was used for Study I. Study II used data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial and estimated effects as DoEs. Studies III and IV were carried out as randomised survey experiments.

    The results showed that general adherence behaviour was associated with both environmental and social factors. Estimations of DoE showed that stroke or systemic embolism was delayed 181 (95% CI 76 to 287) days through twenty-two months of apixaban use, as compared with  warfarin use. The delay of major and intracranial bleeding was 206 (95% CI 130 to 281) and 392 (95% CI 249 to 535) days, respectively, due to apixaban use for twenty-two months, as compared with  warfarin use. Presenting preventive treatment effects as DoEs to lay people was associated with high willingness to initiate treatment and positive views on treatment benefits and willingness to pay for treatment.

    Non-optimal adherence was partly associated with modifiable factors and it might be possible to increase adherence by managing these factors. Estimations of DoEs in preventive treatments gave information on effects regarding delay of different outcomes; the estimation also provides tools that might be useful for interpreting and communicating treatment effects in clinical decision-making. Lay people seemed to react rationally to variations in DoE magnitude; a higher proportion accepted treatment when the magnitude was greater.

    List of papers
    1. Living environment, social support and informal caregiving are associated with health care seeking behaviour and adherence to medication treatment: a cross-sectional population study
    Open this publication in new window or tab >>Living environment, social support and informal caregiving are associated with health care seeking behaviour and adherence to medication treatment: a cross-sectional population study
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Despite the well-known associations between local environment and health, few studies have focused on environment and health care utiliza-tion, for instance health care seeking behaviour or adherence. This study was aimed at analysing housing type, behaviour based on perceived local outdoor safety, social support, informal caregiving, demographics, socioeconomics, and long-term illness, and associations with health-seeking and adherence behaviours at a population level. This study used data from the Swedish National Public Health Survey 2004–2014, an annually repeated, large sample, cross-sectional, population-based sur-vey study. In all, questionnaires from 100,433 individuals were returned by post, making the response rate 52.9% (100,433/190,000). Descrip-tive statistics and multiple logistic regressions were used to investigate associations between explanatory variables and the outcomes of refrain-ing from seeking care and non-adherence behaviour. Living in rented apartment, lodger, a dorm or other was associated with reporting refrain-ing from seeking care (adjusted OR 1.16, 95% CI 1.00–1.22), and non-adherence (adjusted OR 1.22; 95% CI 1.13–1.31). Refraining from go-ing out due to a perceived unsafe neighbourhood was associated with refraining from seeking care (adjusted OR 1.59, 95% CI 1.51–1.67) and non-adherence (adjusted OR 1.26, 95% CI 1.17–1.36). Social support and status as an informal caregiver was associated with higher odds of refraining from seeking medical care and non-adherence. This study suggests that living in rental housing, refraining from going out due to neighbourhood safety concerns, lack of social support or informal care-giver status are associated with lower health-seeking behaviour and non-adherence to prescribed medication.

    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-379066 (URN)
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
    2. Effects of apixaban compared with warfarin as gain in event-free time – a novel assessment of the results of the ARISTOTLE trial
    Open this publication in new window or tab >>Effects of apixaban compared with warfarin as gain in event-free time – a novel assessment of the results of the ARISTOTLE trial
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-379073 (URN)
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11
    3. Treatment effect expressed as the novel Delay of Event measure is associated with high willingness to initiate preventive treatment - A randomized survey experiment comparing effect measures
    Open this publication in new window or tab >>Treatment effect expressed as the novel Delay of Event measure is associated with high willingness to initiate preventive treatment - A randomized survey experiment comparing effect measures
    2016 (English)In: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 99, no 12, p. 2005-2011Article in journal (Refereed) Published
    Abstract [en]

    Objectives: This study aimed to investigate patients' willingness to initiate a preventive treatment and compared two established effect measures to the newly developed Delay of Events (DoE) measure that expresses treatment effect as a gain in event-free time. Methods: In this cross-sectional, randomized survey experiment in the general Swedish population, 1079 respondents (response rate 60.9%) were asked to consider a preventive cardiovascular treatment. Respondents were randomly allocated to one of three effect descriptions: DoE, relative risk reduction (RRR), or absolute risk reduction (ARR). Univariate and multivariate analyses were performed investigating willingness to initiate treatment, views on treatment benefit, motivation and importance to adhere and willingness to pay for treatment. Results: Eighty-one percent were willing to take the medication when the effect was described as DoE, 83.0% when it was described as RRR and 62.8% when it was described as ARR. DoE and RRR was further associated with positive views on treatment benefit, motivation, importance to adhere and WTP. Conclusions: Presenting treatment effect as DoE or RRR was associated with a high willingness to initiate treatment. Practice implications: An approach based on the novel time-based measure DoE may be of value in clinical communication and shared decision making.

    Keywords
    Preventive measures, Adherence, Decision-making, Treatment outcome, Randomized, Survey experiment
    National Category
    Health Care Service and Management, Health Policy and Services and Health Economy
    Identifiers
    urn:nbn:se:uu:diva-315088 (URN)10.1016/j.pec.2016.07.028 (DOI)000391223200012 ()27499030 (PubMedID)
    Funder
    Swedish Society of Medicine
    Available from: 2017-02-08 Created: 2017-02-08 Last updated: 2019-03-11Bibliographically approved
    4. Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment
    Open this publication in new window or tab >>Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment
    2018 (English)In: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 18, article id 106Article in journal (Refereed) Published
    Abstract [en]

    Background Common measures used to describe preventive treatment effects today are proportional, i.e. they compare the proportions of events in relative or absolute terms, however they are not easily interpreted from the patient's perspective and different magnitudes do not seem to clearly discriminate between levels of effect presented to people. Methods In this randomised cross-sectional survey experiment, performed in a Swedish population-based sample (n=1041, response rate 58.6%), the respondents, aged between 40 and 75years were given information on a hypothetical preventive cardiovascular treatment. Respondents were randomised into groups in which the treatment was described as having the effect of delaying a heart attack for different periods of time (Delay of Event,DoE): 1month, 6months or 18months. Respondents were thereafter asked about their willingness to initiate such therapy, as well as questions about how they valued the proposed therapy. ResultsLonger DoE:s were associated with comparatively greater willingness to initiate treatment. The proportions accepting treatment were 81, 71 and 46% when postponement was 18months, 6months and 1month respectively. In adjusted binary logistic regression models the odds ratio for being willing to take therapy was 4.45 (95% CI 2.72-7.30) for a DoE of 6months, and 6.08 (95% CI 3.61-10.23) for a DoE of 18months compared with a DoE of 1month. Greater belief in the necessity of medical treatment increased the odds of being willing to initiate therapy. ConclusionsLay people's willingness to initiate preventive therapy was sensitive to the magnitude of the effect presented as DoE. The results indicate that DoE is a comprehensible effect measure, of potential value in shared clinical decision-making.

    Place, publisher, year, edition, pages
    BMC, 2018
    Keywords
    Medical decision-making, Risk communication, Risk perception, Necessity-concern framework
    National Category
    Health Care Service and Management, Health Policy and Services and Health Economy
    Identifiers
    urn:nbn:se:uu:diva-371868 (URN)10.1186/s12911-018-0662-2 (DOI)000450786000002 ()30458757 (PubMedID)
    Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-03-11Bibliographically approved
  • Public defence: 2019-04-26 10:00 Zootissalen, Uppsala
    Jones, William
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Avian Malaria and Interspecific Interactions in Ficedula Flycatchers2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Parasitism is a core theme in ecological and evolutionary studies. Despite this, there are still gaps in our knowledge regarding host-parasite interactions in nature. Furthermore, in an era of human-induced, global climatic and environmental change revealing the roles that parasites play in host life-histories, interspecific interactions and host distributions is of the utmost importance. In this thesis, I explore avian malaria parasites (haemosporidians) in two species of passerine birds: the collared flycatcher Ficedula albicollis and the pied flycatcher F. hypoleuca. In Paper I, I show that an increase in spring temperature has led to rapid divergence in breeding times for the two flycatcher species, with collared flycatchers breeding significantly earlier than pied flycatchers. This has facilitated regional coexistence through the build up of temporal isolation. In Paper II, I explore how malaria assemblages across the breeding ranges of collared and pied flycatchers vary. I find that pied flycatcher populations have significantly higher infection prevalence than collared flycatchers, but collared flycatchers have a higher diversity of parasites. Additionally, I find that recently colonised flycatchers have kept their original parasite assemblages while gaining further parasites from native pied flycatchers. In Paper III, I explore age-related patterns of malaria infections in collared flycatchers. I find that female collared flycatchers have higher overall infection rates than males and that infected female collared flycatchers have significantly higher mortality rates than uninfected females while males pay no survival cost. Despite this, female collared flycatchers do not pay a fitness cost, despite their shorter lifespans. In Paper IV, I explore nest defence behaviours of infected and uninfected collared flycatchers. I find that malaria infection significantly interacts with age and that young, infected collared flycatchers have a lower intensity of defence behaviours than uninfected individuals, while the opposite pattern is present in older collared flycatchers, with infected birds having higher defence behaviours. Therefore, I argue that Papers III and VI suggest patterns of terminal investment are present in collared flycatchers. Finally, in Paper V, I investigate parasite transmission in pied and collared flycatchers. I find that infected individuals of both species produce higher quantities of volatile organic compounds (VOCs) than uninfected individuals. Additionally, there is a significant increase in VOCs produced when the number of malaria gametocytes is higher. This suggests that malaria parasites are able to manipulate their hosts into producing insect-vector attracting compounds and that this is further increased at peak infectivity. These findings help to fill in some of the gaps in the literature regarding host-parasite relationships and the role of environmental change on hosts.

    List of papers
    1. Climate-driven build-up of temporal isolation within a recently formed avian hybrid zone.
    Open this publication in new window or tab >>Climate-driven build-up of temporal isolation within a recently formed avian hybrid zone.
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    2018 (English)In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 72, no 2, p. 363-374Article in journal (Refereed) Published
    Abstract [en]

    Divergence in the onset of reproduction can act as an important source of reproductive isolation (i.e., allochronic isolation) between co-occurring young species, but evidence for the evolutionary processes leading to such divergence is often indirect. While advancing spring seasons strongly affect the onset of reproduction in many taxa, it remains largely unexplored whether contemporary spring advancement directly affects allochronic isolation between young species. We examined how increasing spring temperatures affected onset of reproduction and thereby hybridization between pied and collared flycatchers (Ficedula spp.) across habitat types in a young secondary contact zone. We found that both species have advanced their timing of breeding in 14 years. However, selection on pied flycatchers to breed earlier was weaker, resulting in a slower response to advancing springs compared to collared flycatchers and thereby build-up of allochronic isolation between the species. We argue that a preadaptation to a broader niche use (diet) of pied flycatchers explains the slower response to raising spring temperature, but that reduced risk to hybridize may contribute to further divergence in the onset of breeding in the future. Our results show that minor differences in the response to environmental change of co-occurring closely related species can quickly cause allochronic isolation.

    Keywords
    Competitive exclusion, ecological speciation, prezygotic isolation, reinforcement, speciation, temporal segregation
    National Category
    Evolutionary Biology Ecology
    Identifiers
    urn:nbn:se:uu:diva-341102 (URN)10.1111/evo.13404 (DOI)000424131100011 ()29214649 (PubMedID)
    Funder
    Swedish Research CouncilAcademy of Finland
    Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2019-03-10Bibliographically approved
    2. Interspecific transfer of parasites following a range‐shift in Ficedula flycatcher
    Open this publication in new window or tab >>Interspecific transfer of parasites following a range‐shift in Ficedula flycatcher
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    2018 (English)In: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 8, no 23, p. 12183-12192Article in journal (Refereed) Published
    Abstract [en]

    Human‐induced climate change is expected to cause major biotic changes in species distributions and thereby including escalation of novel host‐parasite associations. Closely related host species that come into secondary contact are especially likely to exchange parasites and pathogens. Both the Enemy Release Hypothesis (where invading hosts escape their original parasites) and the Novel Weapon Hypothesis (where invading hosts bring new parasites that have detrimental effects on native hosts) predict that the local host will be most likely to experience a disadvantage. However, few studies evaluate the occurrence of interspecific parasite transfer by performing wide‐scale geographic sampling of pathogen lineages, both within and far from host contact zones. In this study, we investigate how haemosporidian (avian malaria) prevalence and lineage diversity vary in two, closely related species of passerine birds; the pied flycatcher Ficedula hypoleuca and the collared flycatcher F. albicollis in both allopatry and sympatry. We find that host species is generally a better predictor of parasite diversity than location, but both prevalence and diversity of parasites vary widely among populations of the same bird species. We also find a limited and unidirectional transfer of parasites from pied flycatchers to collared flycatchers in a recent contact zone. This study therefore rejects both the Enemy Release Hypothesis and the Novel Weapon Hypothesis and highlights the complexity and importance of studying host‐parasite relationships in an era of global climate change and species range shifts.

    National Category
    Ecology
    Identifiers
    urn:nbn:se:uu:diva-366254 (URN)10.1002/ece3.4677 (DOI)000454107200069 ()30598810 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2018-11-19 Created: 2018-11-19 Last updated: 2019-03-10Bibliographically approved
    3. Sex-specific decrease in longevity following malaria infection in a natural bird population
    Open this publication in new window or tab >>Sex-specific decrease in longevity following malaria infection in a natural bird population
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Avian malaria, BaSTA, collared flycatcher, sex bias, survival, terminal investment
    National Category
    Ecology
    Research subject
    Biology with specialization in Animal Ecology
    Identifiers
    urn:nbn:se:uu:diva-378637 (URN)
    Available from: 2019-03-07 Created: 2019-03-07 Last updated: 2019-03-10
    4. Age and malaria infection affect nest defence behaviours in collared flycatchers
    Open this publication in new window or tab >>Age and malaria infection affect nest defence behaviours in collared flycatchers
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Avian malaria, Collared flycatcher, Ficedula albicollis, nest-defence, terminal investment
    National Category
    Ecology
    Research subject
    Biology with specialization in Animal Ecology
    Identifiers
    urn:nbn:se:uu:diva-378638 (URN)
    Available from: 2019-03-07 Created: 2019-03-07 Last updated: 2019-03-10
    5. Malaria infected birds produce higher levels of vector-attracting compounds
    Open this publication in new window or tab >>Malaria infected birds produce higher levels of vector-attracting compounds
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Avian malaria, Ficedula, gametocytaemia, host manipulation, malaria vector, volatile organic compounds
    National Category
    Ecology
    Research subject
    Biology with specialization in Animal Ecology
    Identifiers
    urn:nbn:se:uu:diva-378936 (URN)
    Available from: 2019-03-10 Created: 2019-03-10 Last updated: 2019-03-10
  • Public defence: 2019-04-26 10:15 Sal IV, Uppsala
    Kadarik, Kati
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Social and Economic Geography. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Housing and Urban Research.
    Moving out, moving up, becoming employed: Studies in the residential segregation and social integration of immigrants in Sweden2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis investigates the complex relationship between residential segregation and social integration. The dominant discourse in Sweden and Europe sees residential segregation as hindering socioeconomic and cultural integration, creating parallel societies and even threatening the social cohesion of European societies. Residential segregation might be a sign of social exclusion and discrimination, but it might also result from informed choices to self-segregate into particular neighbourhoods. Minority ethnic clustering, some argue, might have positive attributes, such as providing access to social capital embedded in ethnic communities. This thesis analyses the relationship between segregation and integration from the perspectives of two research traditions: drivers of segregation and neighbourhood effects. The thesis employs individual annual Swedish registry data and a k-nearest neighbour approach to identify residential neighbourhood contexts.

    Paper I studies the out-mobility of three cohorts of young adults from large housing estates (LHEs) in Stockholm County against the backdrop of increasing inequality, stigmatization, and deteriorating conditions in these areas. From 1990 to 2014, income became more and ethnicity less important in explaining mobility. However, it is the combination of the two that determined sorting for all cohorts. The study also clarifies how different neighbourhood conditions within LHEs affect sorting patterns.

    Paper II analyses the residential mobility of immigrants towards native-dominated neighbourhoods. The study concludes that ethnic hierarchies strongly shape residential outcomes and increased income alone does not necessarily translate into residential mobility. However, spatial integration can be facilitated by a better housing market position at the start of the housing career in Sweden, improved socioeconomic outcomes, and residing outside metropolitan areas.

    Paper III examines the potential of ethnic economic capital in the neighbourhood (measured as share of employed co-ethnics) to bolster employment prospects. The results of the multi-scalar analysis of four immigrant groups show that an increase in ethnic economic capital can have a positive effect on immigrant males’ employment prospects, but the effect size varies between groups and neighbourhood scales.

    The main conclusion of this thesis is that the relationship between residential segregation and social integration is not straightforward, but rather is complex and nuanced. It varies between groups with different backgrounds, but also between settlement contexts within Sweden and between neighbourhood contexts within cities. It changes over time and is influenced by the spatial scale of neighbourhood context measurements. This thesis demonstrates the usefulness of employing flexible scalable individual neighbourhoods in conceptualising space when studying social processes.

    List of papers
    1. Out-mobility from Stockholm’s large housing estates: local neighbourhood context and the changing importance of income over ethnicity
    Open this publication in new window or tab >>Out-mobility from Stockholm’s large housing estates: local neighbourhood context and the changing importance of income over ethnicity
    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    In political discussions, large housing estates (LHEs) in Stockholm, like in many other European cities, have become shorthand for a range of housing and socioeconomic problems. In recent decades, many such estates have displayed increasing signs of stigmatization, social exclusion, and outflow of relatively affluent people. This selective character of residential mobility from LHEs is considered problematic because it leads to neighbourhood decline. This paper improves our knowledge of how these changes in residential composition have affected out-mobility from these areas over time and how different neighbourhood conditions within LHEs affect sorting patterns. Individual annual Swedish registry data (1990–2014) are employed to longitudinally study the out-mobility patterns of three cohorts that grew up in the estates against the backdrop of growing inequality and deteriorating conditions. This study supplements the existing literature on housing estates by clarifying how income has become more and ethnicity less important over time in explaining sorting patterns from these estates. However, despite substantial changes in the importance of income and ethnic background, it is the combination of the two that has determined sorting throughout the study period. The role of neighbourhood context is, however, less clear: neighbourhoods with the lowest socioeconomic status in the estates display greater sorting based on income, but an opposite pattern is evident for ethnic background.

    Keywords
    residential mobility, neighbourhood change, large housing estates, Stockholm
    National Category
    Human Geography
    Identifiers
    urn:nbn:se:uu:diva-378588 (URN)
    Available from: 2019-03-10 Created: 2019-03-10 Last updated: 2019-03-10
    2. What affects immigrants’ mobility towards native-dominated neighbourhoods? The role of individual resources, ethnicity, and settlement context
    Open this publication in new window or tab >>What affects immigrants’ mobility towards native-dominated neighbourhoods? The role of individual resources, ethnicity, and settlement context
    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    In Sweden, immigrants’ integration and residential patterns are much disputed. Segregation is seen as a threat to social cohesion and policies at least rhetorically aim to create mixed neighbourhoods. Spatial assimilation theory argues that immigrants’ socioeconomic success translates into less segregation in housing for that group. In contrast, place stratification theory emphasizes the importance of ethnicity and structural mechanisms in residential mobility. This study investigates immigrants’ mobility towards native-dominated neighbourhoods by clarifying the role of ethnic hierarchies in association with immigrants’ social and work backgrounds, emphasizing the importance of settlement context. The paper presents a survival analysis based on everyone who migrated to Sweden from 1990 to 2010. The conclusion is that ethnic hierarchies strongly shape residential outcomes, and that spatial integration can be facilitated by a better housing market position at the start of the housing career in Sweden and by outcomes in other life domains, such as labour market participation and good educational attainment. Importantly, increased income alone does not necessarily translate into neighbourhood mobility and spatial integration. There are better prospects of ending up in native Swedish neighbourhoods outside metropolitan areas, whereas in metropolitan areas, the opportunity structures for spatial integration are much more constrained, especially for refugees.

    Keywords
    segregation, spatial assimilation, place stratification, residential mobility, k-nearest neighbour, survival analysis, Sweden
    National Category
    Human Geography
    Identifiers
    urn:nbn:se:uu:diva-378788 (URN)
    Available from: 2019-03-10 Created: 2019-03-10 Last updated: 2019-03-10
    3. Ethnic economic capital in neighbourhoods: impact on immigrants’ employment opportunities
    Open this publication in new window or tab >>Ethnic economic capital in neighbourhoods: impact on immigrants’ employment opportunities
    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    Does living in areas characterized by high co-ethnic concentrations deprive ethnic minority groups, or does potential access to an extended ethnic network with valuable resources further their integration? This paper takes a new approach to analysing the potential of ethnic economic capital in neighbourhoods to increase employment opportunities. While many studies employ aggregated administrative neighbourhood data, an important methodological advance here is that we use individualized, scalable neighbourhoods. This enables us to apply a flexible approach in studying the existence and impact of ethnic economic capital in neighbourhoods. In addition, we not only focus on the concentration of co-ethnics, or on local economic factors, but also measure ethnic economic capital in neighbourhoods as the rate of employed co-ethnics. We employ individual longitudinal Swedish registry data for 2000–2010 on working-age males of Iraqi, Iranian, Turkish, and Somalian backgrounds in Stockholm, Göteborg, and Malmö. We find that an increased share of employed co-ethnics positively affects males’ employment prospects. We add to existing knowledge by showing that the effect of ethnic clustering on employment outcomes is conditional on the quality of ethnic networks – i.e., ethnic economic capital – and on the scale of measurement.

    Keywords
    neighbourhood effects, ethnic economic capital, employment, scale, Sweden
    National Category
    Human Geography
    Identifiers
    urn:nbn:se:uu:diva-378789 (URN)
    Available from: 2019-03-10 Created: 2019-03-10 Last updated: 2019-03-10
  • Public defence: 2019-04-29 13:00 Rudbecksalen, Uppsala
    Abramenkovs, Andris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Induction and repair of clustered DNA damage sites after exposure to ionizing radiation2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.

    The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.

    The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.

    In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.

    List of papers
    1. Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    Open this publication in new window or tab >>Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    2017 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, no 6, p. 597-604Article in journal (Refereed) Published
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

    Place, publisher, year, edition, pages
    RADIATION RESEARCH SOC, 2017
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:uu:diva-343567 (URN)10.1667/RR14693.1 (DOI)000416744600001 ()
    Funder
    Swedish Cancer SocietySwedish Radiation Safety Authority
    Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2019-03-08Bibliographically approved
    2. Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    Open this publication in new window or tab >>Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    2014 (English)In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 769, p. 1-10Article in journal (Refereed) Published
    Abstract [en]

    Efficient and correct repair of DNA double-strand break (DSB) is critical for cell survival. Defects in the DNA repair may lead to cell death, genomic instability and development of cancer. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is an essential component of the non-homologous end joining (NHEJ) which is the major DSB repair pathway in mammalian cells. In the present study, by using siRNA against DNA-PKcs in four human cell lines, we examined how low levels of DNA-PKcs affected cellular response to ionizing radiation. Decrease of DNA-PKcs levels by 80-95%, induced by siRNA treatment, lead to extreme radiosensitivity, similar to that seen in cells completely lacking DNA-PKcs and low levels of DNA-PKcs promoted cell accumulation in G2/M phase after irradiation and blocked progression of mitosis. Surprisingly, low levels of DNA-PKcs did not affect the repair capacity and the removal of 53BP1 or gamma-H2AX foci and rejoining of DSB appeared normal. This was in strong contrast to cells completely lacking DNA-PKcs and cells treated with the DNA-PKcs inhibitor NU7441, in which DSB repair were severely compromised. This suggests that there are different mechanisms by which loss of DNA-PKcs functions can sensitize cells to ionizing radiation. Further, foci of phosphorylated DNA-PKcs (T2609 and S2056) co-localized with DSB and this was independent of the amount of DNA-PKcs but foci of DNA-PKcs was only seen in siRNA-treated cells. Our study emphasizes on the critical role of DNA-PKcs for maintaining survival after radiation exposure which is uncoupled from its essential function in DSB repair. This could have implications for the development of therapeutic strategies aiming to radiosensitize tumors by affecting the DNA-PKcs function.

    Keywords
    DNA repair, DNA-PKcs, Ionizing radiation, DNA-PK deficiency, NU7441
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-237292 (URN)10.1016/j.mrfmmm.2014.06.004 (DOI)000343625700001 ()
    Available from: 2014-12-03 Created: 2014-12-01 Last updated: 2019-03-08Bibliographically approved
    3. The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    Open this publication in new window or tab >>The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

    Keywords
    Prostate cancer, ARv7, DNA damage, Ra-223, high-LET
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-378720 (URN)
    Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-03-08
    4. Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    Open this publication in new window or tab >>Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209594Article in journal (Refereed) Published
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-374120 (URN)10.1371/journal.pone.0209594 (DOI)000454621900032 ()30592737 (PubMedID)
    Funder
    Swedish Cancer Society, CAN2014/661Swedish Cancer Society, CAN2016/649Swedish Radiation Safety Authority, SSM2017-2374Swedish Radiation Safety Authority, SSM2018-2181
    Available from: 2019-01-23 Created: 2019-01-23 Last updated: 2019-03-08Bibliographically approved
  • Public defence: 2019-05-03 09:00 Enghoffsalen, Uppsala
    Sundbom, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Asthma and Sleep Disturbances: Associations to Comorbidities and Asthma Control2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis aimed to investigate the associations between asthma control, asthma-related comorbidity, and sleep. Insomnia symptoms with asthma are common, and have commonly been explained by poor asthma control and asthma symptoms during the night, which affect most asthmatics to some degree. The impact of asthma-related comorbidity, however, is not fully known. Further aims were to analyze the effects of asthma control and comorbidities on asthma-related quality of life, and to analyze the effects of co-existing asthma and obstructive sleep apnea on objective sleep quality. 

    Four different populations were investigated: the two large community-based cohorts GA2LEN (n=25,610) and LifeGene (n=23,875), a cohort of 369 young asthma patients (MIDAS), and a polysomnography study of 384 women (SHE).

    The GA2LEN study confirmed that insomnia symptoms remain a common problem among asthmatics. Poor asthma control and nasal congestion were important risk factors for insomnia symptoms. Smoking and obesity were other risk factors for insomnia symptoms among asthmatics.

    Asthma control, as assessed using the Asthma Control Test (ACT), was identified as the most important predictor of asthma-related quality of life in the MIDAS study. Combining the ACT score with data on insomnia, anxiety, and depression showed considerable additive effects of the conditions. 

    In the SHE study, co-existing asthma and OSA were associated with worse objective sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The group with both asthma and OSA had the highest levels of the markers of systemic inflammation CRP and IL-6.  

    Uncontrolled asthma was a risk factor for all insomnia symptoms in the LifeGene study. Asthma-related comorbidity had a great impact on sleep quality; in particular, the combination of uncontrolled asthma and any comorbidity was unfavorable. Chronic rhinosinusitis was a risk factor for both insomnia symptoms and uncontrolled asthma. 

    These findings have a high clinical relevance and underline the importance of structured evaluation of asthma control and attention to comorbidity in asthma care, as insomnia symptoms are common and affect quality of life. Optimizing asthma control is crucial for sleep quality, but treating asthma-related comorbidity must not be overlooked.

    List of papers
    1. Asthma symptoms and nasal congestion as independent risk factors for insomnia in a general population: Results from the GA 2 LEN survey
    Open this publication in new window or tab >>Asthma symptoms and nasal congestion as independent risk factors for insomnia in a general population: Results from the GA 2 LEN survey
    Show others...
    2013 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no 2, p. 213-219Article in journal (Refereed) Published
    Abstract [en]

    Background Asthma and rhinitis have been related to insomnia. The aim of this study was to further analyse the association between asthma, nasal symptoms and insomnia and to identify risk factors for sleep disturbance among patients with asthma, in a large population-based set of material. Method In 2008, a postal questionnaire was sent to a random sample of 45 000 adults in four Swedish cities. The questionnaire included questions on insomnia, asthma, rhinitis, weight, height, tobacco use and physical activity. Results Twenty-five thousand six hundred and ten subjects participated. Asthma was defined as either current medication for asthma or at least one attack of asthma during the last 12 months, and 1830 subjects (7.15%) were defined as asthmatics. The prevalence of insomnia symptoms was significantly higher among asthmatics than non-asthmatics (47.3% vs 37.2%, <0.0001). In the subgroup reporting both asthma and nasal congestion, 55.8% had insomnia symptoms compared with 35.3% in subjects without both asthma and nasal congestion. The risk of insomnia increased with the severity of asthma, and the adjusted OR for insomnia was 2.65 in asthmatics with three symptoms compared with asthmatics without symptoms. Nasal congestion (OR 1.50), obesity (OR 1.54) and smoking (OR 1.71) also increased the risk of insomnia. Conclusion Insomnia remains a common problem among asthmatics. Uncontrolled asthma and nasal congestion are important, treatable risk factors for insomnia. Lifestyle factors, such as smoking and obesity, are also risk factors for insomnia among asthmatics.

    Keywords
    asthma, epidemiology, rhinitis, sleep
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-194860 (URN)10.1111/all.12079 (DOI)000313727300010 ()
    Available from: 2013-02-20 Created: 2013-02-19 Last updated: 2019-03-13Bibliographically approved
    2. Effects of poor asthma control, insomnia, anxiety and depression on quality of life in young asthmatics
    Open this publication in new window or tab >>Effects of poor asthma control, insomnia, anxiety and depression on quality of life in young asthmatics
    Show others...
    2016 (English)In: Journal of Asthma, ISSN 0277-0903, E-ISSN 1532-4303, Vol. 53, no 4, p. 398-403Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Asthma-related quality of life has previously been shown to be associated with asthma control. The aims of the present study were to further analyze this correlation, identify other variables with impact on asthma-related quality of life, and investigate the covariance among these variables.

    METHODS: Information was retrieved from a cohort of 369 patients, aged 12-35, with physician-diagnosed asthma requiring anti-inflammatory treatment for at least 3 months per year. Questionnaire data [including the mini Asthma Quality of Life Questionnaire (mAQLQ), Asthma Control Test (ACT), and Hospital Anxiety and Depression Scale (HADS)], quality of sleep, lung function data and blood samples were analyzed. Linear regression models with the mAQLQ score as the dependent scalar variable were calculated.

    RESULTS: ACT was the single variable that had the highest explanatory value for the mAQLQ score (51.5%). High explanatory power was also observed for anxiety and depression (17.0%) and insomnia (14.1%). The population was divided into groups depending on presence of anxiety and depression, uncontrolled asthma, and insomnia. The group that reported none of these conditions had the highest mean mAQLQ score (6.3 units), whereas the group reporting all of these conditions had the lowest mAQLQ score (3.8 units).

    CONCLUSIONS: The ACT score was the single most important variable in predicting asthma-related quality of life. Combining the ACT score with the data on insomnia, anxiety and depression showed considerable additive effects of the conditions. Hence, we recommend the routine use of the ACT and careful attention to symptoms of insomnia, anxiety or depression in the clinical evaluation of asthma-related quality of life.

    Keywords
    Asthma; epidemiology; asthma control; ACT; mAQLQ; quality of life; sleep; HADS; anxiety; depression
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-270378 (URN)10.3109/02770903.2015.1126846 (DOI)000374991200009 ()26666333 (PubMedID)
    Funder
    VINNOVA
    Available from: 2015-12-27 Created: 2015-12-27 Last updated: 2019-03-13Bibliographically approved
    3. Effects of Coexisting Asthma and Obstructive Sleep Apnea on Sleep Architecture, Oxygen Saturation, and Systemic Inflammation in Women
    Open this publication in new window or tab >>Effects of Coexisting Asthma and Obstructive Sleep Apnea on Sleep Architecture, Oxygen Saturation, and Systemic Inflammation in Women
    2018 (English)In: Journal of Clinical Sleep Medicine (JCSM), ISSN 1550-9389, E-ISSN 1550-9397, Vol. 14, no 2, p. 253-259Article in journal (Refereed) Published
    Abstract [en]

    STUDY OBJECTIVES: Both asthma and obstructive sleep apnea (OSA) are strongly associated with poor sleep. Asthma and OSA also have several features in common, including airway obstruction, systemic inflammation, and an association with obesity. The aim was to analyze the effect of asthma, OSA, and the combination of asthma and OSA on objectively measured sleep quality and systemic inflammation.

    METHODS: Sleep and health in women is an ongoing community-based study in Uppsala, Sweden. Three hundred eighty-four women ages 20 to 70 years underwent overnight polysomnography and completed questionnaires on airway diseases and sleep complaints. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α were analyzed.

    RESULTS: = .04) than the group with OSA alone. The results were consistent after adjusting for age, body mass index, and smoking status. Asthma was independently associated with lower oxygen saturation, whereas OSA was not.

    CONCLUSIONS: Our data indicate that coexisting asthma and OSA are associated with poorer sleep quality and more profound nocturnal hypoxemia than either of the conditions alone. The results are similar to earlier findings related to OSA and chronic obstructive pulmonary disease, but they have not previously been described for asthma.

    Place, publisher, year, edition, pages
    American Academy of Sleep Medicine, 2018
    Keywords
    OSA, asthma, inflammation, polysomnography
    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-343517 (URN)10.5664/jcsm.6946 (DOI)000425136900013 ()29394961 (PubMedID)
    Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2019-03-13Bibliographically approved
    4. Insomnia symptoms and asthma control – interrelations and importance of comorbidities
    Open this publication in new window or tab >>Insomnia symptoms and asthma control – interrelations and importance of comorbidities
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background

     

    Insomnia symptoms are common with asthma. The aim of the study was to analyze the associations between insomnia symptoms and asthma control, asthma severity, and asthma-related comorbidity in a community-based population.

     

    Methods

    Adults (n=23,875, ages 18-45) from the community-based LifeGene study answered a questionnaire on insomnia symptoms, airway symptoms, asthma diagnosis, asthma medication, and asthma-related comorbidities (chronic rhinosinusitis, gastro-esophageal reflux, anxiety, depression, or obesity).

     

    Results

    Of the participants, 1,272 (5.3%) had asthma. The prevalence of any insomnia symptom was higher in participants with uncontrolled asthma (n=201) than with controlled or partially controlled asthma (32.2% vs. 19.9% and 20.1%, respectively, p<0.01). There was no significant difference in the prevalence of insomnia symptoms between subjects with controlled asthma and subjects without asthma. 

     

    Subjects with asthma and any asthma-related comorbidity reported more insomnia symptoms (29.0% vs. 22.4%, p<0.01) compared to asthmatics without comorbidity. Moreover, the prevalence was highest among subjects reporting both uncontrolled asthma and any asthma-related comorbidity (45.1%, p<0.01).

     

    Uncontrolled asthma remained significantly associated with insomnia symptoms (OR 1.72 (1.15-2.56)) after adjusting for age, sex, BMI, smoking history, comorbidities, physical activity, and educational level, while medication level was not. Among asthma-related comorbidities, chronic rhinosinusitis (OR 1.62 (1.20-2.19)), obesity (1.87 (1.07-3.25)), and depression (OR 1.85 (1.34-2.55)) were independently associated with insomnia symptoms. 

     

    Conclusion

     

    Uncontrolled asthma was significantly associated with insomnia symptoms, while controlled or partially controlled asthma was not. Asthma-related comorbidity is of great importance, and asthma control seems to be more important than asthma severity for sleep quality.

    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-379139 (URN)
    Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-13
  • Public defence: 2019-05-03 09:15 B21, Uppsala
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    With 10 million new infections yearly, tuberculosis has a major impact on the human well-being of the world. Most patients have infections susceptible to a first-line treatment with a treatment success rate of 80%, a number that can potentially be improved by optimising the first-line treatment. Besides susceptible disease, each year half a million patients are infected by tuberculosis with resistance to first-line treatment where only 50% of patients get cured. Thus, new drugs against resistant tuberculosis are desperately needed but given the inefficiency of developing new anti-tuberculosis drugs, enough new drugs will not reach patients in time. The aim of this thesis was to develop pharmacometric models to optimise the development and use of current and future drugs for treating tuberculosis.

    A population pharmacokinetic model for rifampicin, the most prominent first-line drug, was developed and later used for developing exposure-response models followed by clinical trial simulations. The developed exposure-response models were based on liquid culture data and were expanded to describe the relationship between liquid culture results and a new biomarker, the molecular bacterial load assay which is a quicker alternative to liquid culture and is also contamination-free.

    The in vitro-derived semi-mechanistic Multistate Tuberculosis Pharmacometric (MTP) model was applied to clinical rifampicin and clofazimine colony forming unit datasets. This novel application of the MTP model allowed detection of statistically significant exposure-response relationships between rifampicin and clofazimine for the specific killing of non-multiplying, persister bacteria. Furthermore, the MTP model was compared to conventional statistical analyses for detecting drug effects in Phase IIa. If designing and analysing Phase IIa using the MTP model, the required sample size for detecting drug effects can be lowered. An improved design and analysis of pre-clinical treatment outcome assessments was developed which increased the information gain compared to a conventional design yet kept the animal use at a minimum. Lastly, a therapeutic drug monitoring approach was suggested based on updated targets for rifampicin, a framework easily expandable to second-line drugs.

    In conclusion this thesis presents the development of pharmacometric models which will streamline both the development and use of drugs against tuberculosis.

    List of papers
    1. A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses
    Open this publication in new window or tab >>A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses
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    2018 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 4, p. 674-683Article in journal (Refereed) Published
    Abstract [en]

    Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis–Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure–response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.

    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-342737 (URN)10.1002/cpt.778 (DOI)000427114900030 ()28653479 (PubMedID)
    Funder
    Swedish Research Council, 115337EU, FP7, Seventh Framework Programme
    Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2019-03-15Bibliographically approved
    2. Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations
    Open this publication in new window or tab >>Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations
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    2018 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 218, no 6, p. 991-999Article in journal (Refereed) Published
    Abstract [en]

    Background. The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.

    Methods. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.

    Results. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days.

    Conclusions. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.

    Keywords
    Pharmacodynamics, tuberculosis, pharmacokinetics, patients, time to positivity, early bactericidal activity, models, bactericidal effect, Mycobacterium tuberculosis
    National Category
    Infectious Medicine Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-362631 (URN)10.1093/infdis/jiy242 (DOI)000441792600017 ()29718390 (PubMedID)
    Funder
    Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme
    Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2019-03-15Bibliographically approved
    3. Model-based relationship between the molecular bacterial load assay and time-to-positivity in liquid culture
    Open this publication in new window or tab >>Model-based relationship between the molecular bacterial load assay and time-to-positivity in liquid culture
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The molecular bacterial load (MBL) assay is a new tuberculosis biomarker, a substantially faster, contamination-free alternative to the current standard assay of time-to-positivity (TTP) in liquid culture. The MBL-TTP relationship has not been thoroughly studied. We aimed to develop a semi-mechanistic model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients with joint MBL and TTP observations collected for 12 weeks. Treatment consisted of isoniazid, pyrazinamide and ethambutol in standard doses together with rifampicin 10 or 35 mg/kg. The developed MBL-TTP model was semi-mechanistic, including several linked sub-models; a sputum sub-model describing decline of bacterial load in sputum,  a mycobacterial growth model describing growth in liquid culture and a hazard model translating bacterial growth in liquid culture to the probability of a positive TTP signal. Additional components for contaminated and negative TTP samples were included in the final model. The model gave good fit to the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampicin (p=0.002). In conclusion, a semi-mechanistic combined model for MBL and TTP was developed that described the MBL-TTP relationship. The MBL-TTP model can distinguish regimen efficacy in clinical trials, as a full MBL-TTP model or each sub-model used separately. Secondly, the model can be used to predict biomarker response for MBL given TTP data or vice versa in historical or future trials.

    Keywords
    Pharmacometrics, Pharmacodynamics, Modelling, Biomarker, Tuberculosis
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-379314 (URN)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15
    4. The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
    Open this publication in new window or tab >>The Potential for Treatment Shortening With Higher Rifampicin Doses: Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
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    2018 (English)In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 67, no 1, p. 34-41Article in journal (Refereed) Published
    Abstract [en]

    Background. Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L.h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS INC, 2018
    Keywords
    high-dose rifampicin, pharmacometrics, PK-PD, exposure-response, sputum culture conversion
    National Category
    Infectious Medicine Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-361283 (URN)10.1093/cid/ciy026 (DOI)000438446600010 ()29917079 (PubMedID)
    Available from: 2018-09-27 Created: 2018-09-27 Last updated: 2019-03-15Bibliographically approved
    5. Application of the Multistate Tuberculosis Pharmacometric Model in Patients With Rifampicin-Treated Pulmonary Tuberculosis
    Open this publication in new window or tab >>Application of the Multistate Tuberculosis Pharmacometric Model in Patients With Rifampicin-Treated Pulmonary Tuberculosis
    2016 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, no 5, p. 264-273Article in journal (Refereed) Published
    Abstract [en]

    This is the first clinical implementation of the Multistate Tuberculosis Pharmacometric (MTP) model describing fast-, slow-, and nonmultiplying bacterial states of Mycobacterium tuberculosis. Colony forming unit data from 19 patients treated with rifampicin were analyzed. A previously developed rifampicin population pharmacokinetic (PK) model was linked to the MTP model previously developed using in vitro data. Drug effect was implemented as exposure-response relationships tested at several effect sites, both alone and in combination. All MTP model parameters were fixed to in vitro estimates except B-max. Drug effect was described by an on/off effect inhibiting growth of fast-multiplying bacteria in addition to linear increase of the stimulation of the death rate of slow-and nonmultiplying bacteria with increasing drug exposure. Clinical trial simulations predicted well three retrospective clinical trials using the final model that confirmed the potential utility of the MTP model in antitubercular drug development.

    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-303399 (URN)10.1002/psp4.12079 (DOI)000381566700004 ()27299939 (PubMedID)
    Available from: 2016-09-19 Created: 2016-09-19 Last updated: 2019-03-15Bibliographically approved
    6. Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
    Open this publication in new window or tab >>Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CFZ) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of CFZ and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis we characterized statistically significant exposure-response relationships for both drugs that could explain the original findings of increase in colony forming units (CFU) with CFZ treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make right decisions for advancement to further development. We propose that this quantitative semi-mechanistic approach provides a rational framework for analysing Phase IIa EBA studies, and can accelerate anti-TB drug development.

    Keywords
    Pharmacometrics, Pharmacodynamics, Pharmacokinetics, Biomarker, Tuberculosis
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-379356 (URN)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15
    7. Improved power for TB Phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods
    Open this publication in new window or tab >>Improved power for TB Phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods
    2017 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 8, p. 2311-2319Article in journal (Refereed) Published
    Abstract [en]

    Background: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process.

    Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic-pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials.

    Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-dailymonotherapy at four different doses per drug and a reference (10mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono-and bi-exponential models and a pharmacokinetic-pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level.

    Results: For the pharmacokinetic-pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, > 1250, 315, > 1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively.

    Conclusions: A model-based design and analysis using a pharmacokinetic-pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.

    National Category
    Infectious Medicine Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-332928 (URN)10.1093/jac/dkx129 (DOI)000406155400021 ()28520930 (PubMedID)
    Funder
    Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, FP7/2007-2013
    Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2019-03-15Bibliographically approved
    8. Improving treatment outcome assessment in a mouse tuberculosis model
    Open this publication in new window or tab >>Improving treatment outcome assessment in a mouse tuberculosis model
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    2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5714Article in journal (Refereed) Published
    Abstract [en]

    Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (R(p)ZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal E-max model in favor over linear or conventional E-max models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and R(p)ZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2018
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-352487 (URN)10.1038/s41598-018-24067-x (DOI)000429405000014 ()29632372 (PubMedID)
    Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2019-03-15Bibliographically approved
    9. Individualised dosing algorithm and personalised treatment of rifampicin for tuberculosis
    Open this publication in new window or tab >>Individualised dosing algorithm and personalised treatment of rifampicin for tuberculosis
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Aims: To propose new Bayesian TDM targets well-suited for high-dose rifampicin and to apply them using a TDM coupled with Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin’s auto-induction, saturable pharmacokinetics and high inter-occasion variability. Methods: Rifampicin Bayesian TDM targets were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin’s pharmacokinetics i.e. highest plasma concentration during 24 hours (Cmax) and area under the plasma concentration-time curve during 24 hours (AUC0-24h). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC. Results: The suggested Bayesian TDM target was a steady state AUC0-24h of 181-214 h×mg/L. The observed MICs ranged from 0.016-0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000 mg (mode 1800 mg, n=24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h-only target. Conclusions: A new up-to-date Bayesian TDM target well-suited for high-dose rifampicin was derived. The TDM coupled with Bayesian forecasting approach allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.

    Keywords
    Therapeutic drug monitoring, Pharmacokinetics, Modelling and simulation, Pharmacometrics, Population pharmacokinetics
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-379357 (URN)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15
  • Public defence: 2019-05-03 09:15 Rudbecksalen, Uppsala
    Gudmundsson, Sanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Up to 8% of all live-born children are affected with a congenital disorder. Some are Mendelian disorders of known etiology, but many are of undetermined genetic cause and mechanism, limiting diagnosis and treatment. This project aims to investigate the underlying causes of unresolved Mendelian disorders, and especially syndromes associated with intellectual disability, by using cutting-edge sequencing techniques and molecular tools in a translational setting that intends to directly benefit affected families.

    In Paper I, we report the first keratitis-ichthyosis-deafness syndrome patient presenting with reversion of disease phenotype, a phenomenon known as revertant mosaicism. Third-generation sequencing and a cell assay were used to pin-point the mechanism of the somatic variants giving rise to healthy looking skin in the patient. In Paper II, we describe a novel approach to investigate parental origin, gonadal mosaicism, and estimate recurrence risk of disease in two families. Third-generation sequencing was used for haplotype phasing and detection of low-frequency variants in paternal sperm. The recurrence risk in future offspring in the families affected with Noonan syndrome and Treacher Collins syndrome was determined to be 40% and <0.1% respectively. In Paper III, we describe a novel variant in a patient affected with Cornelia de Lange Syndrome, primarily associated with intellectual disability. The affected gene is linked to an extremely rare form of the syndrome, with limited cases described in the literature, usually associated with mild symptoms. Investigation of rare intellectual disability syndromes was continued in Paper IV, by clinical and genetic characterization of six affected males with a likely pathogenic variant in the TAF1 gene. By creating the first TAF1 orthologue knockout we revealed that taf1 is essential for life and that lack of functional taf1 during embryonic development in zebrafish primarily impacts expression of genes in pathways associated with neurodevelopment. 

    By progressive translational research, using state-of-the-art methodology, this project has illuminated the implication of revertant and gonadal mosaicism in disease (Papers I-II), as well as two extremely rare intellectual disability syndromes (Papers III-IV). In total, five families affected with five different disorders have gained clinical and genetic diagnosis and/or further understanding of prognosis and recurrence risk. The study has led to improved understanding of disease etiology and basic developmental processes, enabling development of new therapies and improved care of future patients.

    List of papers
    1. Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
    Open this publication in new window or tab >>Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
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    2017 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 6, p. 1070-1077Article in journal (Refereed) Published
    Abstract [en]

    Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS, 2017
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-324349 (URN)10.1093/hmg/ddx017 (DOI)000400911000004 ()28158657 (PubMedID)
    Funder
    Swedish Research Council, K2013-57X-22309-3
    Available from: 2017-06-15 Created: 2017-06-15 Last updated: 2019-03-17Bibliographically approved
    2. A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
    Open this publication in new window or tab >>A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
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    2017 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, no 11, p. 1146-1154Article in journal (Refereed) Published
    Abstract [en]

    Objective

    De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

    Methods

    We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

    Results

    In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

    Conclusions

    Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-342916 (URN)10.1002/pd.5156 (DOI)000415897200012 ()28921562 (PubMedID)
    Funder
    Swedish Society for Medical Research (SSMF)
    Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-03-17Bibliographically approved
    3. A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.
    Open this publication in new window or tab >>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature.
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    2018 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, article id S1769-7212(18)30189-7Article in journal (Refereed) Epub ahead of print
    Abstract [en]

    Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

    Keywords
    Cohesin complex, Cohesin protein, Cohesinopathy, Cornelia de Lange syndrome type 4, RAD21 cohesin complex component
    National Category
    Genetics Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-379362 (URN)10.1016/j.ejmg.2018.08.007 (DOI)30125677 (PubMedID)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-17
    4. TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish
    Open this publication in new window or tab >>TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1’s molecular function remains elusive. In this study, we present a five-generation family affected with X-linked intellectual disability, co-segregating with a TAF1 c.3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while carrier females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment during early embryogenesis by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial role of human TAF1 during early embryogenesis can be inferred from the model, demonstrating that an intact taf1 is essential for life from early embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment of genes in pathways associated with neurodevelopmental processes. In conclusion, we suggest that TAF1 is essential for life and that functional TAF1 is vital for early neurogenesis.

    Keywords
    taf1, intellectual disability, zebrafish
    National Category
    Medical and Health Sciences Genetics
    Research subject
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-379358 (URN)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-17
  • Public defence: 2019-05-03 13:00 Sal IV, Uppsala
    Juvrud, Joshua
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    The perception of actions and interactions: And the importance of context2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The perception of actions and interactions is a dynamic process linked with perceptual processes, the internal and external states of the individual, prior experiences, and the immediate environment. Given these differential contexts, it is very likely there are differences in how infants perceive, interpret, and respond to actions. The present thesis took a developmental and individual differences approach to understanding action perception and processing in infancy. The overarching aim was to understand the development of action perception and how individual differences contribute to the perception and processing of actions. More specifically, individual differences included the capacity to which variations in a child’s context can affect the development of action perception. Study I demonstrated that, like adults, infants could differentiate between physically possible and physically impossible apparent motion paths, as evidenced by pupil dilation. This perception may be related to the context of whether the motion was performed by a human figure or an object. Study II found that in the context of a more complex social interaction, infants differentiated between appropriate and inappropriate responses to a giving action. Furthermore, infants’ individual differences in perceiving a giving action were related to their own giving behaviors later in childhood, suggesting possible specialized mechanisms. Study III took an integrative perspective on context and demonstrated the joint impact of internal and external emotional contexts for infants’ subsequent selective attention during visual search. Infants’ visual attention was affected by previous exposure to a facial emotion and by the mothers’ negative affect. The results of these three studies demonstrate that given differential environmental contexts and experiences, there are differences in how individuals perceive and interpret actions and interactions. Together, this thesis proposes an integrative role of context in perception and demonstrates that perception can never be truly decontextualized.

    List of papers
    1. Context dependent perception of apparent motion in 12-month-old infants and adults
    Open this publication in new window or tab >>Context dependent perception of apparent motion in 12-month-old infants and adults
    (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Other academic) Submitted
    Abstract [en]

    The current study examines if 12-month-old infants and adults perceptions of apparent motion stimuli are context dependent by measuring sensitivity to possible and impossible apparent motion performed by a human figure.  In Study 1, infants and adults viewed an apparent motion stimulus comprising of an arm moving from one side of a leg to the other. Results showed that both infants and adults reacted with larger pupil dilation when observing an impossible apparent motion, that is, larger pupil dilation when it appears that a hand passed through the leg as opposed to moving around the leg. Study 2 found no such effect when 12-month-old infants observed an object control stimulus with perceptually similar properties. These findings suggest that apparent motion perception is context dependent and that the constraints of the human body and human actions are taken into account when perceiving rapidly changing static images as fluid motion.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-379488 (URN)
    Available from: 2019-03-17 Created: 2019-03-17 Last updated: 2019-03-17
    2. Longitudinal Continuity in Understanding and Production of Giving-Related Behavior From Infancy to Childhood
    Open this publication in new window or tab >>Longitudinal Continuity in Understanding and Production of Giving-Related Behavior From Infancy to Childhood
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    2019 (English)In: Child Development, ISSN 0009-3920, E-ISSN 1467-8624, Vol. 90, no 2, p. e182-e191Article in journal (Refereed) Published
    Abstract [en]

    Infants have an early understanding of giving (the transfer of an item by one agent to another), but little is known about individual differences in these abilities or their developmental outcomes. Here, 9-month-olds (N = 59) showing clearer neural processing (Event-related potential, ERP) of a give-me gesture also evidenced a stronger reaction (pupil dilation) to an inappropriate response to a give-me gesture, and at 2 years were more likely to give in response to a give-me gesture. None of the differences in understanding and production of giving-related behaviors were associated with other sociocognitive variables investigated: language, gaze-following, and nongiving helping. The early developmental continuity in understanding and production of giving behavior is consistent with the great importance of giving for humans throughout the life span.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-370001 (URN)10.1111/cdev.13131 (DOI)000460664900001 ()30102423 (PubMedID)
    Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2019-04-11Bibliographically approved
    3. How infants view the world: The functional role of emotional context and maternal affect
    Open this publication in new window or tab >>How infants view the world: The functional role of emotional context and maternal affect
    (English)In: Developmental Science, ISSN 1363-755X, E-ISSN 1467-7687Article in journal (Other academic) Submitted
    Abstract [en]

    Individual differences in their emotional context may differentially impact infants’ ability to selectively encode and learn from their environment. The current study takes an integrative approach in considering three emotional contexts that have independently been found to modulate infants’ allocation of selective attention: maternal negative affect, infant temperament, and an emotional face prime (the mother and a stranger’s face). The study looked at the effects of that these contexts had on 9-month-old infants’ performance on a subsequent eye-tracking visual search task. Results revealed that infants were faster to find the target after viewing their mother’s angry face or a fearful face, regardless of familiarity. When the mother reported high negative affect, infants’ visual search performance was increasingly impacted by a fearful face, resulting in significantly faster visual search times. The findings demonstrate that both immediate emotional face prime and the mother’s negative affect have the capacity to influence what infants attend to and consequently influence their processing of information in their environment.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-379489 (URN)
    Available from: 2019-03-17 Created: 2019-03-17 Last updated: 2019-03-17
  • Public defence: 2019-05-03 14:15 Häggsalen, Uppsala
    Fang, Hailiang
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Structural Studies of Mn-X (X=Al, Bi): Permanent Magnetic Materials without Rare Earth Metals2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    How to generate and use electricity in a more efficient way is a major challenge for humankind. In this context, permanent magnets play an important role within a very broad range of electric power applications. The strongest magnets used today are mainly based on alloys that contain rare-earth metals, which are neither economical nor sustainable. The search for new alternative alloys with satisfactory magnetic properties is the major motivation for the investigations summarized in this thesis. Interesting candidates for alternative rare-earth free alloys were selected with τ-MnAl as the basis. Theoretical studies suggest that such alloys may show good magnetic properties after chemical modifications to optimize them. Another compound with promising magnetic properties is MnBi, included in this study.

    MnAl-Z (Z= C, B, Ga as doping elements) and MnBi compounds were synthesized through carefully devised high-temperature methods, followed by various milling and annealing steps. The structural phase analysis of the samples was based on X-ray and neutron diffraction. A systematic microstructural investigation was also performed for selected samples. The phase transitions of MnAl and MnBi during heating and cooling at different rates were studied by in situ X-ray diffraction from a synchrotron source. The magnetic properties were characterized by various methods.

    By strict control of experimental parameters, the metastable τ-MnAl was found to be directly obtainable using a "drop synthesis” process. A cooling rate of 10 K/min yielded an almost pure ferromagnetic τ-MnAl phase. A microstructural characterization of similarly synthesized MnAl-C samples revealed the presence of phase segregation, a Mn-rich region and an Al-rich grain boundary phase.

    A cryomilling process was employed which decreased the particle size of the MnAl-C sample. Neutron diffraction data disclosed accompanying amorphous features, related to changes in Mn and Al atom occupancies during the milling process. A flash heating procedure regenerated the structural ordering between Mn and Al in the structure, where the initial magnetic properties were recovered.

    The MnBi compound was synthesized by a self-flux method in order to isolate single crystals. As for τ-MnAl, in situ diffraction studies were applied for following phase transitions and the magnetic properties were studied.

    List of papers
    1. Directly obtained tau-phase MnAl, a high performance magnetic material for permanent magnets
    Open this publication in new window or tab >>Directly obtained tau-phase MnAl, a high performance magnetic material for permanent magnets
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    2016 (English)In: Journal of Solid State Chemistry, ISSN 0022-4596, E-ISSN 1095-726X, Vol. 237, p. 300-306Article in journal (Refereed) Published
    Abstract [en]

    The metastable tetragonal iota-phase has been directly obtained from casting Mn0.54Al0.46 and (Mn0.55Al0.45)(100)C-2 using the drop synthesis method. The as-casted samples were ball milled to decrease the particle size and relaxed at 500 degrees C for 1 h. The phase composition, crystallographic parameters, magnetic properties and microstructure were systematically studied. The results reveal that the iota-phase could be directly obtained from drop synthesis. The highest M-s of 117 emu/g was achieved in the (Mn0.55Al0.45)(100)C-2 where the iota-phase was stabilized by doping with carbon. Carbon doping increased the c/a ratio of the tau-phase as it occupies specific interstitial positions (1/2, 1/2, 0) in the structure. Furthermore, ball milling increases the coercivity (H-c) at the expense of a decrease in magnetic saturation (M-s). The increase in coercivity is explained by a decrease of grain size in conjunction with domain wall pinning due to defects introduced during the ball milling process.

    Keywords
    Permanent magnets, Rare-earth free, High temperature synthesis, Diffraction, Magnetic measurements
    National Category
    Chemical Sciences Physical Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-294651 (URN)10.1016/j.jssc.2016.02.031 (DOI)000373661100041 ()
    Funder
    Swedish Energy AgencySweGRIDS - Swedish Centre for Smart Grids and Energy Storage
    Available from: 2016-06-02 Created: 2016-05-26 Last updated: 2019-03-13Bibliographically approved
    2. Insights into formation and stability of tau-MnAlZ(x) (Z = C and B)
    Open this publication in new window or tab >>Insights into formation and stability of tau-MnAlZ(x) (Z = C and B)
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    2017 (English)In: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 692, p. 198-203Article in journal (Refereed) Published
    Abstract [en]

    The tau-phase MnAl alloys are promising candidate for rare earth free permanent magnets. In this study, In order to better understand the MnAl epsilon ->tau phase transition mechanism in a continuous cooling process and metastable MnAl tau-phase high temperature stability, Mn0.54Al0.46, Mn0.55Al0.45C0.02 and Mn0.55Al0.45B0.02 alloys were systematically studied by in situ synchrotron X-ray powder diffraction (SR-XRD). The relationship between tau-phase formation tendency and different cooling rates of Mn0.55Al0.45C0.02 was investigated. Besides, the high temperature stabilities of undoped tau-MnAl and carbon/boron doped tau-MnAl were studied. Differential thermal analysis (DTA) was also employed to study the phase transformation as well. The research results show that a high cooling rate of 600 degrees C/min leads to a 50/50 wt% mixture of epsilon- and tau-phase; almost pure tau-phase was obtained when cooled at a moderate cooling rate of 10 degrees C/min; while for a slow cooling rate of 2 degrees C/min, the tau-phase partially decomposed into beta and gamma(2) phases. No intermediate epsilon'-phase was observed during the epsilon ->tau phase transition during the experiments. For the boron and carbon doped tau-MnAl, the 800 degrees C high temperature stability experiments reveal that C stabilizes the tau-MnAl while doped B destabilises the tetragonal structure and it decomposes into beta- and gamma(2)-phases.

    Keywords
    Phase transition, Thermal analysis, In situ, Powder diffraction, Phase stability, Permanent magnet
    National Category
    Metallurgy and Metallic Materials
    Identifiers
    urn:nbn:se:uu:diva-308613 (URN)10.1016/j.jallcom.2016.09.047 (DOI)000386231200025 ()
    Funder
    Swedish Energy AgencySweGRIDS - Swedish Centre for Smart Grids and Energy Storage
    Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2019-03-13Bibliographically approved
    3. Structural, microstructural and magnetic evolution in cryo milled carbon doped MnAl
    Open this publication in new window or tab >>Structural, microstructural and magnetic evolution in cryo milled carbon doped MnAl
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    2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 2525Article in journal (Refereed) Published
    Abstract [en]

    The low cost, rare earth free τ-phase of MnAl has high potential to partially replace bonded Nd2Fe14B rare earth permanent magnets. However, the τ-phase is metastable and it is experimentally difficult to obtain powders suitable for the permanent magnet alignment process, which requires the fine powders to have an appropriate microstructure and high τ-phase purity. In this work, a new method to make high purity τ-phase fne powders is presented. A high purity τ-phase Mn0.55Al0.45C0.02 alloy was synthesized by the drop synthesis method. The drop synthesized material was subjected to cryo milling and followed by a fash heating process. The crystal structure and microstructure of the drop synthesized, cryo milled and flash heated samples were studied by X-ray in situ powder diffraction, scanning electron microscopy, X-ray energy dispersive spectroscopy and electron backscatter diffraction. Magnetic properties and magnetic structure of the drop synthesized, cryo milled, flash heated samples were characterized by magnetometry and neutron powder diffraction, respectively. The results reveal that the 2 and 4hours cryo milled and flash heated samples both exhibit high τ-phase purity and micron-sized round particle shapes. Moreover, the fash heated samples display high saturation magnetization as well as increased coercivity.

    National Category
    Materials Chemistry Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-341024 (URN)10.1038/s41598-018-20606-8 (DOI)000424189500012 ()29410462 (PubMedID)
    Funder
    Swedish Energy AgencySweGRIDS - Swedish Centre for Smart Grids and Energy StorageSwedish Research Council
    Available from: 2018-02-06 Created: 2018-02-06 Last updated: 2019-03-13Bibliographically approved
    4. Measured and calculated properties of B-doped τ-phase MnAl: A rare earth free permanent magnet
    Open this publication in new window or tab >>Measured and calculated properties of B-doped τ-phase MnAl: A rare earth free permanent magnet
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    2019 (English)In: Journal of Magnetism and Magnetic Materials, Vol. 474, p. 591-598Article in journal (Refereed) Published
    Abstract [en]

    The metastable tetragonal τ-phase MnAl has been doped interstitially with B through a drop synthesis method creating the (Mn0.55Al0.45)B0.02 compound. The as-casted samples were annealed, quenched and thereafter ball-milled and relaxed in order to decrease grain size and reduce the number of crystallographic defects. The Curie temperature of the quenched sample was estimated to 655 K. The magnetization, coercivity and anisotropy were analyzed with respect to flash-milling time, relaxation time and temperature. The results show that (Mn0.55Al0.45)B0.02 could be directly obtained from drop synthesis. The highest measured saturation magnetization of 393 kA/m (measured at ±1440kA/m) was achieved with a relaxation process after 1.5h milling, giving a theoretical maximum energy product of 48 kJ/m3. The highest value of the coercivity was 355 kA/m achieved by flash-milling for 10 h. However, the high coercivity was achieved at an expense of low saturation magnetization.

    Keywords
    Permanent magnets; Rare-Earth-free; Diffraction; Magnetometry; Computational modeling
    National Category
    Condensed Matter Physics
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-368265 (URN)10.1016/j.jmmm.2018.11.006 (DOI)000459494600086 ()
    Funder
    Swedish Energy AgencySweGRIDS - Swedish Centre for Smart Grids and Energy Storage
    Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2019-03-21Bibliographically approved
    5. Insights into phase transitions and magnetism of MnBi crystals synthesized from self-flux
    Open this publication in new window or tab >>Insights into phase transitions and magnetism of MnBi crystals synthesized from self-flux
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    2019 (English)In: Journal of Alloys and Compounds, ISSN 0925-8388, E-ISSN 1873-4669, Vol. 781, p. 308-314Article in journal (Refereed) Published
    Abstract [en]

    To effectively synthesize high purity ferromagnetic low temperature phase (LTP) MnBi with optimal microstructure is still a challenge that needs to be overcome for the system to reach its full potential. Here, the phase transitions and magnetic properties of MnBi crystals are reported. The phase transition between the low and high temperature structure of MnBi was systematically investigated at different heating/cooling rates using in situ synchrotron radiation X-ray diffraction. The material crystallizes in a layered hexagonal structure giving a platelike microstructure. The magnetic characterization of the crystals reveal that the saturation magnetization varies from 645 kA/m at 50 K to 546 kA/m at 300 K. Magnetization measurements also show that the sample upon heating becomes non-magnetic and transforms to the high temperature phase (HTP) at similar to 640 K, and that it regains ferromagnetic properties and transforms back to the LTP at similar to 610 K upon subsequent cooling.

    Place, publisher, year, edition, pages
    ELSEVIER SCIENCE SA, 2019
    Keywords
    In situ synchrotron radiation X-ray diffraction, Phase transitions, Rare earth free permanent magnet, MnBi, Single crystals
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-378612 (URN)10.1016/j.jallcom.2018.12.146 (DOI)000457845900034 ()
    Funder
    Swedish Energy AgencySwedish Foundation for Strategic Research
    Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-13Bibliographically approved
    6. One step towards MnAl-based permanent magnets: Differences in magnetic, and microstructural properties from an intermediate annealing step during synthesis
    Open this publication in new window or tab >>One step towards MnAl-based permanent magnets: Differences in magnetic, and microstructural properties from an intermediate annealing step during synthesis
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    2018 (English)In: Journal of Solid State Chemistry, ISSN 0022-4596, E-ISSN 1095-726XArticle in journal (Refereed) Submitted
    Abstract [en]

    The influence of an additional annealing step during synthesis on the preparation of MnAl based permanent magnet alloys has been investigated. Bulk samples of Mn55Al45C2 alloys were synthesized using induction heating through drop synthesis from 1400 °C. Samples produced using cooling directly from 1400 °C (from the melt), and from 1400 °C to an intermediate annealing step at 1200 °C for ~ 30 min before cooling were compared with respect to differences in phase purity, microstructure and magnetic properties. We found that the phase purity was significantly enhanced using the route with an intermediate annealing step at 1200 °C. From XRD the phase purity of the tau-phase was improved from ~ 91 wt% for the sample cooled directly from 1400 °C to ~ 95.1 - 99.5 wt% for the sample exposed to an intermediate annealing step before cooling. Additionally, EBSD, and SEM with EDS indicates a clear difference in the phase composition and differences in the distribution of the magnetic tau phase and the non-magnetic epsilon-, beta-, and gamma-phases. Magnetic properties also indicate, an improvement in saturation magnetization for the sample exposed to the extra annealing step during synthesis. Our results suggest that an intermediate annealing step in the production of MnAl based alloys will provide a simple way of achieving better phase purity and magnetic properties in the bulk alloy.

    Keywords
    permanent magnet, rare earth free, microstructure
    National Category
    Natural Sciences Engineering and Technology Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-368283 (URN)
    Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2019-03-13Bibliographically approved
  • Public defence: 2019-05-07 09:00 Sal IX, Uppsala
    Hagerman, Heidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Working Life Among First-Line Managers and Their Subordinates in Elderly Care: an Empowerment Perspective2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim: The aim of this thesis was to study the working life of first-line managers and their subordinates in elderly care from an empowerment perspective. Methods: Paper I and II used a qualitative approach, and semi-structured interviews were conducted with 14 male and 14 female first-line managers. Data were analyzed using qualitative content analysis. Paper III and IV used a quantitative approach with a longitudinal, correlational and multilevel design. 78 first-line managers and 1398 subordinates filled in the questionnaire at T1 and 56 first-line managers and 769 subordinates at T2. Data were analyzed using descriptive statistics, multivariate analyses (III & IV) and multilevel modelling (IV). Results: In Paper I and II, the first-line managers reported having a challenging and complex work situation. Although the first-line managers sometimes expressed a need for better access to structural empowerment in terms of information, resources and support, they experienced psychological empowerment in their work. In Paper III, the results indicated that the more access the first-line managers had to structural empowerment over time, the more likely they were to feel psychologically empowered over time, resulting in lower ratings of their stress symptoms and higher ratings of their own self-rated leadership-management performance over time. Another finding in Paper III was the influence the number of subordinates per first-line manager had on the first-line managers’ ratings of structural empowerment and the subordinates’ ratings of structural empowerment and stress symptoms. In Paper IV, the results indicate that the more access the first-line managers had to structural empowerment at T1, the more access the subordinates had to structural empowerment at T2, and the higher the subordinates rated their first-line manager’s leadership-management performance at T2, when controlling for psychological empowerment. Conclusions: The working life of first-line managers in elderly care is complex and challenging, and they seem to need better access to structural empowerment (Paper I-IV). However, although deficiencies in access to structural empowerment were reported, the first-line managers experienced their work as a positive challenge (Paper 1) and felt that, though the work was not easy, it was worth it (Paper II).

    List of papers
    1. Male first-line managers' experiences of the work situation in elderly care: an empowerment perspective
    Open this publication in new window or tab >>Male first-line managers' experiences of the work situation in elderly care: an empowerment perspective
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    2015 (English)In: Journal of Nursing Management, ISSN 0966-0429, E-ISSN 1365-2834, Vol. 23, no 6, p. 695-704Article in journal (Refereed) Published
    Abstract [en]

    AIM: To describe male first-line managers' experiences of their work situation in elderly care.

    BACKGROUND: First-line managers' work is challenging. However, less attention has been paid to male managers' work situation in health care. Knowledge is needed to empower male managers.

    METHOD: Fourteen male first-line managers were interviewed. The interview text was subjected to qualitative content analysis.

    RESULT: Work situations were described as complex and challenging; challenges were the driving force. They talked about 'Being on one's own but not feeling left alone', 'Having freedom within set boundaries', 'Feeling a sense of satisfaction and stimulation', 'Feeling a sense of frustration' and 'Having a feeling of dejection and resignation'.

    CONCLUSION: Although the male managers report deficiencies in the support structure, they largely experience their work as a positive challenge.

    IMPLICATIONS FOR NURSING MANAGEMENT: To meet increasing challenges, male first-line managers need better access to supportive structural conditions. Better access to resources is needed in particular, allowing managers to be more visible for staff and to work with development and quality issues instead of administrative tasks. Regarding organisational changes and the scrutiny of management and the media, they lack and thus need support and information from superiors.

    National Category
    Nursing
    Identifiers
    urn:nbn:se:uu:diva-244392 (URN)10.1111/jonm.12197 (DOI)000360840300002 ()24283766 (PubMedID)
    Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2019-03-15Bibliographically approved
    2. How do female first-line managers in elderly care experience their work situation? – an interview study
    Open this publication in new window or tab >>How do female first-line managers in elderly care experience their work situation? – an interview study
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Nursing
    Research subject
    Caring Sciences
    Identifiers
    urn:nbn:se:uu:diva-378707 (URN)
    Funder
    AFA Insurance
    Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2019-03-15
    3. A longitudinal study of working life among first-line managers in the care of older adults
    Open this publication in new window or tab >>A longitudinal study of working life among first-line managers in the care of older adults
    Show others...
    2016 (English)In: Applied Nursing Research, ISSN 0897-1897, E-ISSN 1532-8201, Vol. 32, p. 7-13Article in journal (Refereed) Published
    Abstract [en]

    Aim: To study whether the number of subordinates plays a role in first-line managers' and subordinates' ratings of empowerment, stress symptoms, and leadership-management performance. The aim was also to study relationships between managers' empowerment and stress symptoms and leadership-management performance. Methods: A longitudinal and correlational design was used. All first-line managers (n = 98) and their subordinates (n = 2085) working in the care of older adults in five municipalities were approached. Results: With fewer (<= 30) subordinates per manager, there were higher ratings of structural empowerment among managers and subordinates and lower stress symptoms among subordinates, than with >= 31 subordinates. Furthermore, structural empowerment was related to the managers' stress symptoms and leadership management performance, mediated through psychological empowerment Moreover, structural empowerment can control/adjust for large numbers of subordinates in relation to stress symptoms. Conclusion: The higher FLMs rated their access to empowerment, the lower stress symptoms and higher leadership-management performance they rated over time.

    Keywords
    First-line manager, Leadership-management performance, Number of subordinates, Stress symptoms, Structural and psychological empowerment
    National Category
    Nursing
    Identifiers
    urn:nbn:se:uu:diva-310763 (URN)10.1016/j.apnr.2016.03.003 (DOI)000388057100002 ()27969055 (PubMedID)
    Funder
    AFA Insurance
    Available from: 2016-12-19 Created: 2016-12-19 Last updated: 2019-03-15Bibliographically approved
    4. Empowerment and performance of managers and subordinates in elderly care: A longitudinal and multilevel study
    Open this publication in new window or tab >>Empowerment and performance of managers and subordinates in elderly care: A longitudinal and multilevel study
    Show others...
    2017 (English)In: Journal of Nursing Management, ISSN 0966-0429, E-ISSN 1365-2834, Vol. 25, no 8, p. 647-656Article in journal (Refereed) Published
    Abstract [en]

    AIM: To investigate relationships between first-line managers' ratings of structural and psychological empowerment, and the subordinates' ratings of structural empowerment, as well as their ratings of the managers' leadership-management performance.

    BACKGROUND: Work situations in elderly care are complex. To date, few studies have used a longitudinal, correlational and multilevel design to study the working life of subordinates and managers.

    METHOD: In five Swedish municipalities, questionnaires were answered twice during 2010-12 by 56 first-line managers and 769 subordinates working in nursing homes or home-help services.

    RESULTS: First-line managers' empowerment at Time 1 partially predicted subordinate's structural empowerment and ratings of their managers' leadership-management performance at Time 2. Changes over time partially revealed that the more access managers had to structural empowerment, i.e. increase over time, the higher the ratings were for structural empowerment and managerial leadership-management performance among subordinates.

    CONCLUSIONS: Findings strengthen research and theoretical suggestions linking first-line managers' structural empowerment to their subordinates' structural empowerment and ratings of their manager's leadership-management performance.

    IMPLICATIONS FOR NURSING MANAGEMENT: Managers with high access to structural empowerment are more likely to provide subordinates access to structural empowerment.

    Keywords
    first-line manager, leadership-management performance, linear mixed model, structural and psychological empowerment, subordinate
    National Category
    Nursing
    Identifiers
    urn:nbn:se:uu:diva-331770 (URN)10.1111/jonm.12504 (DOI)000414511300009 ()28714218 (PubMedID)
    Funder
    AFA Insurance
    Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2019-03-15Bibliographically approved
  • Public defence: 2019-05-08 09:00 TLS, Carolina Rediviva Library, Uppsala
    Ayyalasomayajula, Kalyan Ram
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Learning based segmentation and generation methods for handwritten document images2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computerized analysis of handwritten documents is an active research area in image analysis and computer vision. The goal is to create tools that can be available for use at university libraries and for researchers in the humanities. Working with large collections of handwritten documents is very time consuming and many old books and letters remain unread for centuries. Efficient computerized methods could help researchers in history, philology and computer linguistics to cost-effectively conduct a whole new type of research based on large collections of documents. The thesis makes a contribution to this area through the development of methods based on machine learning. The passage of time degrades historical documents. Humidity, stains, heat, mold and natural aging of the materials for hundreds of years make the documents increasingly difficult to interpret. The first half of the dissertation is therefore focused on cleaning the visual information in these documents by image segmentation methods based on energy minimization and machine learning. However, machine learning algorithms learn by imitating what is expected of them. One prerequisite for these methods to work is that ground truth is available. This causes a problem for historical documents because there is a shortage of experts who can help to interpret and interpret them. The second part of the thesis is therefore about automatically creating synthetic documents that are similar to handwritten historical documents. Because they are generated from a known text, they have a given facet. The visual content of the generated historical documents includes variation in the writing style and also imitates degradation factors to make the images realistic. When machine learning is trained on synthetic images of handwritten text, with a known facet, in many cases they can even give an even better result for real historical documents.

    List of papers
    1. Document binarization using topological clustering guided Laplacian Energy Segmentation
    Open this publication in new window or tab >>Document binarization using topological clustering guided Laplacian Energy Segmentation
    2014 (English)In: Proceedings International Conference on Frontiers in Handwriting Recognition (ICFHR), 2014, 2014, p. 523-528Conference paper, Published paper (Refereed)
    Abstract [en]

    The current approach for text binarization proposesa clustering algorithm as a preprocessing stage toan energy-based segmentation method. It uses a clusteringalgorithm to obtain a coarse estimate of the background (BG)and foreground (FG) pixels. These estimates are used as a priorfor the source and sink points of a graph cut implementation,which is used to efficiently find the minimum energy solution ofan objective function to separate the BG and FG. The binaryimage thus obtained is used to refine the edge map that guidesthe graph cut algorithm. A final binary image is obtained byonce again performing the graph cut guided by the refinededges on a Laplacian of the image.

    Series
    Frontiers in Handwriting Recognition, ISSN 2167-6445 ; 14
    Keywords
    Image Processing; Classification; Machine Learning; Graph-theoretic methods.
    National Category
    Computer Systems Signal Processing
    Research subject
    Computer Science
    Identifiers
    urn:nbn:se:uu:diva-238316 (URN)10.1109/ICFHR.2014.94 (DOI)978-1-4799-4335-7 (ISBN)
    Conference
    International Conference on Frontiers in Handwriting Recognition (ICFHR),September 1-4, 2014, Crete, Greece.
    Funder
    Swedish Research Council, 2012-5743
    Available from: 2014-12-11 Created: 2014-12-11 Last updated: 2019-03-19Bibliographically approved
    2. Historical document binarization combining semantic labeling and graph cuts
    Open this publication in new window or tab >>Historical document binarization combining semantic labeling and graph cuts
    2017 (English)In: Image Analysis: Part I, Springer, 2017, p. 386-396Conference paper, Published paper (Refereed)
    Abstract [en]

    Most data mining applications on collections of historical documents require binarization of the digitized images as a pre-processing step. Historical documents are often subjected to degradations such as parchment aging, smudges and bleed through from the other side. The text is sometimes printed, but more often handwritten. Mathematical modeling of appearance of the text, background and all kinds of degradations, is challenging. In the current work we try to tackle binarization as pixel classification problem. We first apply semantic segmentation, using fully convolutional neural networks. In order to improve the sharpness of the result, we then apply a graph cut algorithm. The labels from the semantic segmentation are used as approximate estimates of the text and background, with the probability map of background used for pruning the edges in the graph cut. The results obtained show significant improvement over the state of the art approach.

    Place, publisher, year, edition, pages
    Springer, 2017
    Series
    Lecture Notes in Computer Science, ISSN 0302-9743 ; 10269
    National Category
    Computer Vision and Robotics (Autonomous Systems)
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-335335 (URN)10.1007/978-3-319-59126-1_32 (DOI)000454359300032 ()978-3-319-59125-4 (ISBN)
    Conference
    SCIA 2017, June 12–14, Tromsø, Norway
    Funder
    Swedish Research Council, 2012-5743Riksbankens Jubileumsfond, NHS14-2068:1
    Available from: 2017-05-19 Created: 2017-12-04 Last updated: 2019-03-19Bibliographically approved
    3. PDNet: Semantic segmentation integrated with a primal-dual network for document binarization
    Open this publication in new window or tab >>PDNet: Semantic segmentation integrated with a primal-dual network for document binarization