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  • Baer, Lars-Anders
    Tolkning av ett förflutet2008In: För Sápmi i tiden, Stockholm: Nordiska museets förlag, 2008, p. 16-31Chapter in book (Other academic)
  • Urdaneta, Veronica
    et al.
    Hernandez, Sara B.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
    Casadesus, Josep
    Mutational and non mutational adaptation of Salmonella enterica to the gall bladder2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5203Article in journal (Refereed)
    Abstract [en]

    During systemic infection of susceptible hosts, Salmonella enterica colonizes the gall bladder, which contains lethal concentrations of bile salts. Recovery of Salmonella cells from the gall bladder of infected mice yields two types of isolates: (i) bile-resistant mutants; (ii) isolates that survive lethal selection without mutation. Bile-resistant mutants are recovered at frequencies high enough to suggest that increased mutation rates may occur in the gall bladder, thus providing a tentative example of stress-induced mutation in a natural environment. However, most bile-resistant mutants characterized in this study show defects in traits that are relevant for Salmonella colonization of the animal host. Mutation may thus permit short-term adaptation to the gall bladder at the expense of losing fitness for transmission to new hosts. In contrast, non mutational adaptation may have evolved as a fitness-preserving strategy. Failure of RpoS(-) mutants to colonize the gall bladder supports the involvement of the general stress response in non mutational adaptation.

  • Fugelstad, Anna
    et al.
    Karolinska Inst, Dept Clin Neurosci, Gotgatan 83E, SE-I1662 Stockholm, Sweden.
    Thiblin, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Johansson, Lars Age
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Ågren, Gunnar
    Former Natl Inst Publ Hlth, Gotgatan 83E, SE-17662 Stockholm, Sweden.
    Sidorchuk, Anna
    Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden.
    Opioid-related deaths and previous care for drug use and pain relief in Sweden2019In: Drug And Alcohol Dependence, ISSN 0376-8716, E-ISSN 1879-0046, Vol. 201, p. 253-259Article in journal (Refereed)
    Abstract [en]

    Aim: In 2006-2014, the rate of drug-related deaths, typically opioid poisonings, more than doubled in Sweden. Opioid prescriptions for pain control or opioid agonist therapy also increased. In this retrospective study, we compared death rates between individuals whose first recorded contact with prescribed opioids was for pain control and individuals that had received substance use disorder (SUD) treatment before their first recorded opioid prescription.

    Methods: We included 2834 forensically examined individuals (ages 15-64 years) that died of poisoning in Sweden in 2006-2014. For each death we acquired data on previous opioid prescriptions and SUD treatments. We compared three study groups: pain control (n = 788); a SUD treatment group (n = 1629); and a group with no prescription for pain control or SUD treatment (n = 417).

    Results: Overall fatal poisonings increased from 2.77 to 7.79 (per 100,000 individuals) from 2006 to 2014 (relative 181% increase). Fatal poisoning increased from 2006 to 2014 by 269% in the pain control group (0.64 to 2.36 per 100,000) and by 238% in the SUD treatment group (1.35 to 4.57 per 100,000). Heroin-related deaths remained constant; consequently, the increase was likely attributable to prescription opioids.

    Conclusion: A rapid increase in deaths attributable mainly to prescription opioids for pain control, was reported previously in the United States. Our study indicated that increased access to prescription opioids might contribute to higher death rates also in Sweden among patients seeking pain control and individuals with an established SUD; however, deaths related to prescription opioids mainly occurred among those with SUDs.

  • Zsoter, Ervin
    et al.
    European Ctr Medium Range Weather Forecasts, Reading, Berks, England;Univ Reading, Dept Geog & Environm Sci, Reading, Berks, England.
    Cloke, Hannah L.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL. Univ Reading, Dept Geog & Environm Sci, Reading, Berks, England;Univ Reading, Dept Meteorol, Reading, Berks, England;Ctr Nat Hazards & Disaster Sci, Uppsala, Sweden.
    Stephens, Elisabeth
    Univ Reading, Dept Geog & Environm Sci, Reading, Berks, England.
    de Rosnay, Patricia
    European Ctr Medium Range Weather Forecasts, Reading, Berks, England.
    Munoz-Sabater, Joaquin
    European Ctr Medium Range Weather Forecasts, Reading, Berks, England.
    Prudhomme, Christel
    European Ctr Medium Range Weather Forecasts, Reading, Berks, England.
    Pappenberger, Florian
    European Ctr Medium Range Weather Forecasts, Reading, Berks, England.
    How Well Do Operational Numerical Weather Prediction Configurations Represent Hydrology?2019In: Journal of Hydrometeorology, ISSN 1525-755X, E-ISSN 1525-7541, Vol. 20, no 8, p. 1533-1552Article in journal (Refereed)
    Abstract [en]

    Land surface models (LSMs) have traditionally been designed to focus on providing lower-boundary conditions to the atmosphere with less focus on hydrological processes. State-of-the-art application of LSMs includes a land data assimilation system (LDAS), which incorporates available land surface observations to provide an improved realism of surface conditions. While improved representations of the surface variables (such as soil moisture and snow depth) make LDAS an essential component of any numerical weather prediction (NWP) system, the related increments remove or add water, potentially having a negative impact on the simulated hydrological cycle by opening the water budget. This paper focuses on evaluating how well global NWP configurations are able to support hydrological applications, in addition to the traditional weather forecasting. River discharge simulations from two climatological reanalyses are compared: one "online" set, which includes land-atmosphere coupling and LDAS with an open water budget, and an "offline" set with a closed water budget and no LDAS. It was found that while the online version of the model largely improves temperature and snow depth conditions, it causes poorer representation of peak river flow, particularly in snowmelt-dominated areas in the high latitudes. Without addressing such issues there will never be confidence in using LSMs for hydrological forecasting applications across the globe. This type of analysis should be used to diagnose where improvements need to be made; considering the whole Earth system in the data assimilation and coupling developments is critical for moving toward the goal of holistic Earth system approaches.

  • Lindholm, Daniel
    et al.
    AstraZeneca R&D, Gothenburg, Sweden.
    Sarno, Giovanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Erlinge, David
    Lund Univ, Dept Cardiol, Lund, Sweden.
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hasvold, Lars Pal
    AstraZeneca, Dept Med, Sodertalje, Sweden.
    Janzon, Magnus
    Linkoping Univ, Dept Med & Hlth Sci, Dept Cardiol, Linkoping, Sweden.
    Jernberg, Tomas
    Karolinska Inst, Danderyd Univ Hosp, Dept Clin Sci, Stockholm, Sweden.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Combined association of key risk factors on ischaemic outcomes and bleeding in patients with myocardial infarction2019In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 105, no 15, p. 1175-1181Article in journal (Refereed)
    Abstract [en]

    Objective: In patients with myocardial infarction (MI), risk factors for bleeding and ischaemic events tend to overlap, but the combined effects of these factors have scarcely been studied in contemporary real-world settings. We aimed to assess the combined associations of established risk factors using nationwide registries.

    Methods: Using the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry, patients with invasively managed MI in 2006-2014 were included. Six factors were assessed in relation to cardiovascular death (CVD)/MI/stroke, and major bleeding: age >= 65, chronic kidney disease, diabetes, multivessel disease, prior bleeding and prior MI.

    Results: We studied 100 879 patients, of whom 20 831 (20.6%) experienced CVD/MI/stroke and 5939 (5.9%) major bleeding, during 3.6 years median follow-up. In adjusted Cox models, all factors were associated with CVD/MI/stroke, and all but prior MI were associated with major bleeding. The majority (53.5%) had >= 2 risk factors. With each added risk factor, there was a marked but gradual increase in incidence of the CVD/MI/stroke. This was seen also for major bleeding, but to a lesser extent, largely driven by prior bleeding as the strongest risk factor.

    Conclusions: The majority of patients with MI had two or more established risk factors. Increasing number of risk factors was associated with higher rate of ischaemic events. When excluding patients with prior major bleeding, bleeding incidence rate increased only minimally with increasing number of risk factors. The high ischaemic risk in those with multiple risk factors highlights an unmet need for additional preventive measures.

  • Agbo, Mathias Jr
    et al.
    Makuwira, Jonathan
    Malawi University of Science and Technology, Limbe, Malawi.
    Cruelty by design: how African cities discriminate against people with disabilities2019Report (Other academic)
    Abstract [en]

    Africa is currently home to some 78 million people with disabilities. Meanwhile, recent years have seen the size and populations of the continent’s major cities increasing at a startling rate. As a result, there is a pressing need to consider issues of urban design and accessibility, and how they affect people with disabilities.

  • Public defence: 2019-09-25 13:15 Planck, Linköping
    Kargén, Ulf
    Linköping University, Department of Computer and Information Science, Database and information techniques. Linköping University, Faculty of Science & Engineering.
    Scalable Dynamic Analysis of Binary Code2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In recent years, binary code analysis, i.e., applying program analysis directly at the machine code level, has become an increasingly important topic of study. This is driven to a large extent by the information security community, where security auditing of closed-source software and analysis of malware are important applications. Since most of the high-level semantics of the original source code are lost upon compilation to executable code, static analysis is intractable for, e.g., fine-grained information flow analysis of binary code. Dynamic analysis, however, does not suffer in the same way from reduced accuracy in the absence of high-level semantics, and is therefore also more readily applicable to binary code. Since fine-grained dynamic analysis often requires recording detailed information about every instruction execution, scalability can become a significant challenge. In this thesis, we address the scalability challenges of two powerful dynamic analysis methods whose widespread use has, so far, been impeded by their lack of scalability: dynamic slicing and instruction trace alignment. Dynamic slicing provides fine-grained information about dependencies between individual instructions, and can be used both as a powerful debugging aid and as a foundation for other dynamic analysis techniques. Instruction trace alignment provides a means for comparing executions of two similar programs and has important applications in, e.g., malware analysis, security auditing, and plagiarism detection. We also apply our work on scalable dynamic analysis in two novel approaches to improve fuzzing — a popular random testing technique that is widely used in industry to discover security vulnerabilities.

    To use dynamic slicing, detailed information about a program execution must first be recorded. Since the amount of information is often too large to fit in main memory, existing dynamic slicing methods apply various time-versus-space trade-offs to reduce memory requirements. However, these trade-offs result in very high time overheads, limiting the usefulness of dynamic slicing in practice. In this thesis, we show that the speed of dynamic slicing can be greatly improved by carefully designing data structures and algorithms to exploit temporal locality of programs. This allows avoidance of the expensive trade-offs used in earlier methods by accessing recorded runtime information directly from secondary storage without significant random-access overhead. In addition to being a standalone contribution, scalable dynamic slicing also forms integral parts of our contributions to fuzzing. Our first contribution uses dynamic slicing and binary code mutation to automatically turn an existing executable into a test generator. In our experiments, this new approach to fuzzing achieved about an order of magnitude better code coverage than traditional mutational fuzzing and found several bugs in popular Linux software. The second work on fuzzing presented in this thesis uses dynamic slicing to accelerate the state-of-the-art fuzzer AFL by focusing the fuzzing effort on previously unexplored parts of the input space.

    For the second dynamic analysis technique whose scalability we sought to improve — instruction trace alignment — we employed techniques used in speech recognition and information retrieval to design what is, to the best of our knowledge, the first general approach to aligning realistically long program traces. We show in our experiments that this method is capable of producing meaningful alignments even in the presence of significant syntactic differences stemming from, for example, the use of different compilers or optimization levels.

  • Adegun, Olumuyiwa
    The Nordic Africa Institute, Research Unit. Federal University of Technology, Akure, Akure, Nigeria ; University of the Witwatersrand, Johannesburg, South Africa.
    Community engagement key for upgrading informal settlements2019Report (Other academic)
    Abstract [en]

    Several African countries are tackling the issue of slums and informal settlements by building completely new housing developments. However, many residents view these new areas as less habitable because of poor social conditions. Drawing on three case studies, this policy note argues that community engagement is crucial when planning to replace informal settlements with modern housing in African cities.

  • Alerby, Eva
    et al.
    Luleå University of Technology, Department of Arts, Communication and Education, Education, Language, and Teaching.
    Hagström, Erica
    Luleå University of Technology, Department of Arts, Communication and Education, Education, Language, and Teaching.
    Förhandlingar, uppgivenhet och blåbärets area: en studie av gymnasieelevers upplevelser av skolan i Nacka kommun2019Report (Other academic)
  • Santoni, Giola
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Meinow, Bettina
    Karolinska Inst, Aging Res Ctr, Dept Neurobiol Care Sci & Soc, Tomtebodavagen 18A,Floor 10, S-17165 Solna, Sweden;Stockholm Univ, Stockholm, Sweden;Stockholm Gerontol Res Ctr, Stockholm, Sweden.
    Wimo, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Solna, Sweden.
    Marengoni, Alessandra
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden;Univ Brescia, Dept Clin & Expt Sci, Brescia, Italy.
    Fratiglioni, Laura
    Karolinska Inst, Aging Res Ctr, Dept Neurobiol Care Sci & Soc, Tomtebodavagen 18A,Floor 10, S-17165 Solna, Sweden;Stockholm Univ, Stockholm, Sweden;Stockholm Gerontol Res Ctr, Stockholm, Sweden.
    Calderon-Larranaga, Amaia
    Karolinska Inst, Aging Res Ctr, Dept Neurobiol Care Sci & Soc, Tomtebodavagen 18A,Floor 10, S-17165 Solna, Sweden;Stockholm Univ, Stockholm, Sweden.
    Using an Integrated Clinical and Functional Assessment Tool to Describe the Use of Social and Medical Care in an Urban Community-Dwelling Swedish Older Population2019In: Journal of the American Medical Directors Association, ISSN 1525-8610, E-ISSN 1538-9375, Vol. 20, no 8, p. 988-994Article in journal (Refereed)
    Abstract [en]

    Objectives: To describe the use of social and medical care services in a community-dwelling older population from Stockholm, Sweden, using an integrated clinical and functional assessment tool.

    Design: Study based on data from the longitudinal community-based Swedish National Study on Aging and Care in Kungsholmen.

    Setting and Participants: Random sample of people >65 years of age living in the community in central Stockholm between March 2001 and June 2004 (N = 2368).

    Measures: Health status was measured with a health assessment tool (HAT), which combines 5 indicators (gait speed, cognitive function, chronic multimorbidity, mild disability, severe disability) collected during Swedish National Study on Aging and Care in Kungsholmen clinical examinations. The amount of formal and informal social care was self-reported in hours per month and recorded by trained nurses at baseline and the 3-year follow-up for those >= 78 years of age at baseline. Data on hospital admissions, 30-day readmissions, days spent in the hospital, primary care visits, and specialist visits were obtained from Stockholm County Council registers (2001-2007).

    Results: At baseline, 10% of the sample received formal social care and 11% received informal care. Annually between baseline and the 3-year follow-up, 15% were admitted to the hospital, 5% were readmitted, 78% visited a specialist, and 89% visited primary care. Those with the best HAT scores received 0.02 hours/month of formal care; those with the worst, 34 h/mo. The corresponding numbers for other variables were 0.02 vs 73 h/mo of informal care, 2 vs 11 hospital admissions per 10 persons/year, 44 vs 226 hospital days per 10 persons/y, 0.4 vs 2 30-day readmissions per 10 persons/y, 37 vs 78 specialist visits per 10 persons/y, and 50 vs 327 primary care visits per 10 persons/y.

    Conclusions/Implications: Because of its high discriminative power, the easy-to-use HAT index could help decision makers to plan medical and social care services.

  • Westergren, Christina
    et al.
    The Nordic Museum.
    Silvén, Eva
    The Nordic Museum.
    Inledning2008In: För Sápmi i tiden, Stockholm: Nordiska museets förlag, 2008, p. 7-15Chapter in book (Other academic)
  • Public defence: 2019-09-13 09:15 B42, Uppsala
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Proteomics-informed analysis of drug disposition in the human liver and small intestine2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Orally administered drugs are absorbed in the intestine and generally metabolized in the liver. Therefore, understanding factors determining drug distribution and elimination in these tissues is important. This thesis aimed at using mass spectrometry (MS)-based proteomics and functional studies to better understand in vitro model systems used for drug clearance predictions. Further, it aimed at understanding the changes in drug disposition caused by obesity and gastric bypass surgery (GBP).

    The study was initiated by investigating factors influencing MS-based protein quantification by comparing results from different proteomics methods, and by studying protein distribution during subcellular fractionation. The largest variability in protein quantification was ascribed to insufficient enrichment from subcellular fractionation, most likely due to collection of the majority of the proteins in the initial fraction of the fractionation protocols.

    Proteomics and metabolic activity analyses were then used to investigate differences in intrinsic clearance from two commonly used in vitro systems, human liver microsomes and hepatocytes. For some compounds, the faster microsomal metabolism could be explained by a higher available unbound drug concentration and CYP content in the microsomes as compared to in the hepatocytes.

    Next, inter-individual protein expression variability in human liver and jejunum was explored. This showed that proteins covered a wide inter-individual variability spectrum, in which proteins with low variabilities were associated with essential cellular functions, while many proteins with high variabilities were disease-related.

    Further, the effects of obesity, GBP, and weight loss on the proteomes of human liver and jejunum were analyzed. After GBP and subsequent weight loss, patients showed lower levels of jejunal proteins involved in inflammatory response and drug metabolism.

    Finally, proteomics data from patients with and without obesity was combined with parameters from in vitro transport kinetics, and a mechanistic model to predict drug disposition was developed. The model successfully predicted rosuvastatin plasma concentrations in the patients.

    In conclusion, this thesis has provided insights into factors influencing protein quantification and function in vitro. Furthermore, this thesis demonstrates how proteomics contributes to improved understanding of inter-individual and physiological differences, and how it can be used for in vitro-in vivo scaling of drug clearance.

  • Jacob, Pierre
    et al.
    Harvard University, USA.
    Lindsten, Fredrik
    Uppsala universitet, Avdelningen för systemteknik, Sweden.
    Schön, Thomas B.
    Uppsala universitet, Avdelningen för systemteknik, Sweden.
    Retracted article: Smoothing with Couplings of Conditional Particle Filters2018In: Journal of the American Statistical Association, ISSN 0162-1459, E-ISSN 1537-274XArticle in journal (Refereed)
    Abstract [en]

    In state space models, smoothing refers to the task of estimating a latent stochastic process given noisy measurements related to the process. We propose an unbiased estimator of smoothing expectations. The lack-of-bias property has methodological benefits: independent estimators can be generated in parallel, and confidence intervals can be constructed from the central limit theorem to quantify the approximation error. To design unbiased estimators, we combine a generic debiasing technique for Markov chains, with a Markov chain Monte Carlo algorithm for smoothing. The resulting procedure is widely applicable and we show in numerical experiments that the removal of the bias comes at a manageable increase in variance. We establish the validity of the proposed estimators under mild assumptions. Numerical experiments are provided on toy models, including a setting of highly-informative observations, and for a realistic Lotka-Volterra model with an intractable transition density.

  • Bjønness, Kathrine
    et al.
    Jónsson, Kári
    Danielsson, Helena
    Gustafsson, Tomas
    Sander Poulsen, Tomas
    Forsberg, Tommi
    Keller, Nicole
    Stefani, Martina
    Skyrudsmoen, Lene
    F-gas methodologies and measurements in the Nordic Countries2019Other (Other (popular science, discussion, etc.))
    Abstract [en]

    This project report is a part of the NMR KOL project Nordic Policy Cluster for F-gases with the purpose of comparing the Nordic countries’ methodologies and regulations related to the use of F-gases.Fluorinated gases (F-gases, including HFCs, PFCs, SF6 and NF3) are a range of potent greenhouse gases that are used in a number of different applications and products for refrigeration, foams, aerosols, and technical installations.The report contains a survey and an overview of F-gas methodologies used for UNFCCC reporting, as well as an account of emissions and regulations in the Nordic countries.The objective with the analysis was to provide an overview of differences and similarities within the Nordic countries in relation to F-gases. The analysis shall enable harmonization of data collection, emission factors, choice of methods, and regulatory instruments.

  • Ericsson, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Advanced Neutron Spectroscopy in Fusion Research2019In: Journal of fusion energy, ISSN 0164-0313, E-ISSN 1572-9591, Vol. 38, no 3-4, p. 330-355Article in journal (Refereed)
    Abstract [en]

    This paper presents a review of the current state-of-the-art neutron spectroscopy in fusion research. The focus is on the fundamental nuclear physics and measurement principles. A brief introduction to relevant nuclear physics concepts is given and also a summary of the basic properties of neutron emission from a fusion plasma. Compact monitors/spectrometers like diamond, CLYC and the liquid scintillator are discussed. A longer section describes in some detail the more advanced, designed systems like those based on the thin-foil proton recoil and time-of-flight techniques. Examples of spectroscopy systems installed at JET and planned for ITER are given.

  • Wigren, Anna
    et al.
    Uppsala universitet, Avdelningen för systemteknik, Sweden.
    Murray, Lawrence
    Uppsala universitet, Avdelningen för systemteknik, Sweden.
    Lindsten, Fredrik
    Uppsala universitet, Avdelningen för systemteknik, Sweden.
    Improving the particle filter in high dimensions using conjugate artificial process noise2018Conference paper (Refereed)
    Abstract [en]

    The particle filter is one of the most successful methods for state inference and identification of general non-linear and non-Gaussian models. However, standard particle filters suffer from degeneracy of the particle weights, in particular for high-dimensional problems. We propose a method for improving the performance of the particle filter for certain challenging state space models, with implications for high-dimensional inference. First we approximate the model by adding artificial process noise in an additional state update, then we design a proposal that combines the standard and the locally optimal proposal. This results in a bias-variance trade-off, where adding more noise reduces the variance of the estimate but increases the model bias. The performance of the proposed method is empirically evaluated on a linear-Gaussian state space model and on the non-linear Lorenz'96 model. For both models we observe a significant improvement in performance over the standard particle filter.

  • Cecconello, Marco
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Applied Nuclear Physics.
    Liquid Scintillators Neutron Response Function: A Tutorial2019In: Journal of fusion energy, ISSN 0164-0313, E-ISSN 1572-9591, Vol. 38, no 3-4, p. 356-375Article in journal (Refereed)
    Abstract [en]

    This tutorial is devoted to the understanding of the different components that are present in the neutron light output pulse height distribution of liquid scintillators in fusion relevant energy ranges. The basic mechanisms for the generation of the scintillation light are briefly discussed. The different elastic collision processed between the incident neutrons and the hydrogen and carbon atoms are described in terms of probability density functions and the overall response function as their convolution. The results from this analytical approach is then compared with those obtained from simplified and full Monte Carlo simulations. Edge effect, finite energy resolution, light output and transport and competing physical processes between neutron and carbon and hydrogen atoms and their impact on the response functions are discussed. Although the analytical treatment here presented allows only for a qualitative comparison with full Monte Carlo simulations it enables an understanding of the main features present in the response function and therefore provides the ground for the interpretation of more complex response functions such those measured in fusion plasmas. Although the main part of this tutorial is focused on the response function to mono-energetic 2.45 MeV neutrons a brief discussion is presented in case of broad neutron energy spectra and how these can be used to infer the underlying properties of fusion plasmas via the application of a forward modelling method.

  • Calafat, Francisco M.
    et al.
    Natl Oceanog Ctr, Joseph Proudman Bldg,6 Brownlow St, Liverpool L3 5DA, Merseyside, England.
    Wahl, Thomas
    Univ Cent Florida, Natl Ctr Integrated Coastal Res, 12800 Pegasus Dr,Suite 211, Orlando, FL 32816 USA;Univ Cent Florida, Dept Civil Environm & Construct Engn, USA.
    Lindsten, Fredrik
    Uppsala universitet, Reglerteknik.
    Williams, Joanne
    Natl Oceanog Ctr, England.
    Frajka-Williams, Eleanor
    Univ Southampton, Ocean & Earth Sci, European Way, England.
    Coherent modulation of the sea-level annual cycle in the United States by Atlantic Rossby waves2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2571Article in journal (Refereed)
    Abstract [en]

    Changes in the sea-level annual cycle (SLAC) can have profound impacts on coastal areas, including increased flooding risk and ecosystem alteration, yet little is known about the magnitude and drivers of such changes. Here we show, using novel Bayesian methods, that there are significant decadal fluctuations in the amplitude of the SLAC along the United States Gulf and Southeast coasts, including an extreme event in 2008-2009 that is likely (probability = 68%) unprecedented in the tide-gauge record. Such fluctuations are coherent along the coast but decoupled from deep-ocean changes. Through the use of numerical and analytical ocean models, we show that the primary driver of these fluctuations involves incident Rossby waves that generate fast western-boundary waves. These Rossby waves project onto the basin-wide upper mid-ocean transport (top 1000 m) leading to a link with the SLAC, wherein larger SLAC amplitudes coincide with enhanced transport variability.

  • Åkerstedt, Torbjorn
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Schwarz, Johanna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden;Stockholm Univ, Stress Res Inst, Stockholm, Sweden.
    Gruber, Georg
    Siesta Grp, Vienna, Austria.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Short sleep-poor sleep?: A polysomnographic study in a large population-based sample of women2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 28, no 4, article id e12812Article in journal (Refereed)
    Abstract [en]

    There is a lack of studies on the association between total sleep time (TST) and other polysomnographical parameters. A key question is whether a short sleep is an expression of habitual short sleep, or whether it reflects temporary impairment. The purpose of the present study was to investigate the association between TST and amount of sleep stages and sleep continuity measures, in a large population-based sample of women (n = 385), sleeping at home in a normal daily life setting. The results show that sleep efficiency, N1 (min), N2 (min), REM (min), REM% and proportion of long sleep segments, increased with increasing TST, whereas the number of awakenings/hr, the number of arousals/hr, N1% and REM intensity decreased. In addition, longer sleep was more associated with TST being perceived as of "usual" duration and with better subjective sleep quality. TST was not associated with habitual reported sleep duration. It was concluded that short TST of a recorded sleep in a real-life context may be an indicator of poor objective sleep quality for that particular sleep episode. Because individuals clearly perceived this reduction, it appears that self-reports of poor sleep quality often may be seen as indicators of poor sleep quality. It is also concluded that PSG-recorded sleep duration does not reflect habitual reported sleep duration in the present real-life context.

  • Alvarez, Laura
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid- Consejo Superior de Investigaciones Científicas, Madrid, Spain.
    Sanchez-Hevia, Dione
    Sanchez, Mercedes
    Berenguer, Jose
    A new family of nitrate/nitrite transporters involved in denitrification2019In: International Microbiology, ISSN 1139-6709, E-ISSN 1618-1905, Vol. 22, no 1, p. 19-28Article in journal (Refereed)
    Abstract [en]

    Denitrifying bacteria carry out nitrate and nitrite respiration inside and outside the cell, respectively. In Thermus thermophilus, nitrate and nitrite transport processes are carried out by major facilitator superfamily (MFS) transporters. The sequence of the nar operon of nitrate-only respiring strains of T. thermophilus includes two tandemly organized MFS transporter genes (narK and narT) of the NarK1 and NarK2 families. Both can function as nitrate/nitrite antiporters, but NarK has been proposed as more specific for nitrate whereas NarT more specific for nitrite. In some nitrate- and nitrite-respiring strains of the same species, a single MFS transporter (NarO) belonging to a different MFS subfamily appears. To analyze the role of this single MFS in the same genetic context, we transferred the two types of nar operon to the aerobic strain HB27, and further included in both of them the ability to respire nitrite. The new denitrifying strains HB27dn, with two MFS, and HB27dp, with a single one, were used to isolate mutants devoid of transporters. Through in trans complementation experiments, we demonstrate that the NarO single MFS works efficiently in the transport of both nitrate and nitrite.

  • Singh, S. S.
    et al.
    Univ Cambridge, Dept Engn, Trumpington St, Cambridge CB2 1PZ, England.
    Lindsten, Fredrik
    Uppsala universitet, Reglerteknik, Sweden.
    Moulines, E.
    Ecole Polytech, Ctr Math Appl, Route Saclay, F-91128 Palaiseau, France.
    Blocking strategies and stability of particle Gibbs samplers2017In: Biometrika, ISSN 0006-3444, E-ISSN 1464-3510, Vol. 104, no 4, p. 953-969Article in journal (Refereed)
    Abstract [en]

    Sampling from the posterior probability distribution of the latent states of a hidden Markov model is nontrivial even in the context of Markov chain Monte Carlo. To address this, Andrieu et al. (2010) proposed a way of using a particle filter to construct a Markov kernel that leaves the posterior distribution invariant. Recent theoretical results have established the uniform ergodicity of this Markov kernel and shown that the mixing rate does not deteriorate provided the number of particles grows at least linearly with the number of latent states. However, this gives rise to a cost per application of the kernel that is quadratic in the number of latent states, which can be prohibitive for long observation sequences. Using blocking strategies, we devise samplers that have a stable mixing rate for a cost per iteration that is linear in the number of latent states and which are easily parallelizable.

  • Public defence: 2019-09-13 10:00 E1405
    Kallin, Sara
    Jönköping University, School of Health and Welfare, HHJ, Dep. of Rehabilitation.
    Deformation of human soft tissues: Experimental and numerical aspects2019Licentiate thesis, monograph (Other academic)
  • Aaboud, M.
    et al.
    Asimakopoulou, Eleni M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Bokan, Petar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellajosyula, Venugopal
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Gradin, P. O. Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Isacson, Max
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Mårtensson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Sales De Bruin, Pedro H.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Searches for third-generation scalar leptoquarks in √s = 13 TeV pp collisions with the ATLAS detector2019In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, no 6, article id 144Article in journal (Refereed)
    Abstract [en]

    Limits are set on the pair production of scalar leptoquarks, where all possible decays of the leptoquark into a quark (t, b) and a lepton (, ) of the third generation are considered. The limits are presented as a function of the leptoquark mass and the branching ratio into charged leptons for up-type (LQ<sub ) and down-type (/t) leptoquarks. Many results are reinterpretations of previously published ATLAS searches. In all cases, LHC proton-proton collision data at a centre-of-mass energy of = 13 TeV recorded by the ATLAS detector in 2015 and 2016 are used, corresponding to an integrated luminosity of 36.1 fb(-1). Masses below 800 GeV are excluded for both LQu and LQd independently of the branching ratio, with masses below about 1 TeV being excluded for the limiting cases of branching ratios equal to zero or unity.

  • Public defence: 2019-09-16 09:00 sal FB42 AlbaNova universitetscentrum, Stockholm
    Mohamed El Hassan, Ashraf
    Stockholm University, Faculty of Science, Department of Physics.
    Multiparty Quantum Communication and fs-laser Written Integrated Optics Circuits2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Quantum information science, the rapidly developing interdisciplinary field,  gives power to the information and communications technologies (ICT) by  providing secure communication, precision measurements, ultra-powerful simulation and ultimately computation. It is well known that photons are an ideal candidate for encoding the quantum bit, or "qubit", in quantum information and specially for quantum communication. This thesis consists of two main parts. In the first part, realization of quantum security tasks using optical fibers has been implemented. Bell tests are a cornerstone of quantum key distribution and are necessary for device-independent security. Device-independent Bell inequality test must be performed with care to avoid loopholes. Time-energy entanglement has a distinct advantage over polarization as it is easier transmitted over longer distances, therefore, it may be preferable as a quantum resource to perform reliable key distribution. Novel multi-party communication protocols: secret sharing, detectable Byzantine agreement, clock synchronization, and reduction of communication complexity, all these quantum protocols has been realized without compromising on detection efficiency or generating extremely complex many-particle entangled states. These protocols are realized in an optical fiber setup with sequential phase modulation on single photons. In recent years there has been great interest in fabricating ICT optical setups in low scale in glass chips, which would replace the bulk setups on tables used today. In the second part of the thesis, realization of photonic waveguides in glass has been implemented. Using femtosecond laser inscription of waveguides in glass, photonic quantum technologies and integrated optical circuits are becoming more and more important in miniaturization of optical circuits written in different glass samples for the quantum optics and quantum information processing. These platforms offer stability over the time-scales required for multi-photon coincidence based measurements. The study and optimization the different building blocks for integrated photonic quantum circuits, for instance the directional coupler and Mach-Zehnder interferometer is very important. The principal goal is to develop a method for design, fabrication and characterization of integrated optics circuits for further applications in quantum information. Incorporation of photon sources, detectors, and circuits integrating waveguides technology can be used to produce integrated photonics devices.

  • Zambrano, Jesus
    et al.
    Malardalen Univ, Sch Business Soc & Engn, POB 883, S-72123 Vasteras, Sweden.
    Samuelsson, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. IVL Swedish Environm Res Inst, POB 210, S-10031 Stockholm, Sweden.
    Carlsson, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control.
    Machine learning techniques for monitoring the sludge profile in a secondary settler tank2019In: Applied water science, ISSN 2190-5487, E-ISSN 2190-5495, Vol. 9, no 6, article id 146Article in journal (Refereed)
    Abstract [en]

    The aim of this paper is to evaluate and compare the performance of two machine learning methods, Gaussian process regression (GPR) and Gaussian mixture models (GMMs), as two possible methods for monitoring the sludge profile in a secondary settler tank (SST). In GPR, the prediction of the response variable is given as a Gaussian probability density function, whereas in the GMM the probability density function is built as a weighted sum of Gaussian distributions. In both approaches, a residual is calculated and a fault detection criterion is implemented via a recursive decision rule. As case study, GMM and GPR were tested using real data from a sensor measuring the suspended solids concentration as a function of the SST level in a wastewater treatment plant in Bromma, Sweden. Results suggest that GMM gives a faster response but is also more sensitive than GPR to changes during normal conditions.

  • Public defence: 2019-09-13 13:00 Room E22, VisbyNorberg, Monica
    Engagerat ledarskap för att skapa förutsättningar för allas delaktighet: Utgångspunkter i kvalitetsarbetet2019Doctoral thesis, monograph (Other academic)
    Abstract [en]

    According to increased demands on continuous improvements for organizations, they choose different strategies for improvements such as the use of systematic quality systems to structure the progresses in the business. However, studies have shown that improvement projects often fail due to the leadership and commitment within the organization. Research points out weak or missing techniques and tools connected to committed leadership and let everybody be committed, two important principles in systematic quality systems like Total Quality Management, in Sweden mentioned as the cornerstone model.

    Based on six different studies, this doctoral thesis deepens the knowledge about managers’ prerequisites to use leadership, which can enable commitment to an organization’s quality work in a Swedish context. First, five smaller studies were conducted, mainly focused on diversity, inclusion, and leadership in different kinds of organizations. The results from these five studies created a foundation for the sixth and main study, a case study within an organization dealing with Fast-Moving Consumer Goods. The case study included observations, both non-participation and participation, interviews with CEO, the management group, employees, but included also group measurement and document studies during a year with follow-up interviews.

    In conclusion, the doctoral thesis results have contributed to the development of techniques and tools connected to how a committed leadership can give prerequisites to let everybody be committed. The results have also given the possibility to complement the model Principles-Practices-Tools (PAV) with additional principles, concrete techniques and tools

  • Svärd, Magnus
    et al.
    Dept. of Mathematics, University of Bergen, Bergen, Norway.
    Nordström, Jan
    Linköping University, Department of Mathematics, Computational Mathematics. Linköping University, Faculty of Science & Engineering.
    On the convergence rates of energy-stable finite-difference schemes2019In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 397, article id 108819Article in journal (Refereed)
    Abstract [en]

    We consider constant-coefficient initial-boundary value problems, with a first or second derivative in time and a highest spatial derivative of order q, and their semi-discrete finite difference approximations. With an internal truncation error of order p≥1, and a boundary error of order r≥0, we prove that the convergence rate is: min⁡(p,r+q). The assumptions needed for these results to hold are: i) The continuous problem is linear and well-posed (with a smooth solution). ii) The numerical scheme is consistent, nullspace consistent, nullspace invariant, and energy stable. These assumptions are often satisfied for Summation-By-Parts schemes.

  • Vyakaranam, Achyut Ram
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma2019In: Cancers, ISSN 2072-6694, Vol. 11, no 6, article id 847Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

  • Tabar, Laszlo
    et al.
    Dean, Peter B.
    Chen, Tony Hsiu-Hsi
    Yen, Amy Ming-Fang
    Chen, Sam Li-Sheng
    Fann, Jean Ching-Yuan
    Chiu, Sherry Yueh-Hsia
    Ku, May Mei-Sheng
    Wu, Wendy Yi-Ying
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Hsu, Chen-Yang
    Chen, Yu-Ching
    Beckmann, Kerri
    Smith, Robert A.
    Duffy, Stephen W.
    The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening2019In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 125, no 4, p. 515-523Article in journal (Refereed)
    Abstract [en]

    Background: Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate? Methods: To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease-specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39-year period (1977-2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958-1976). All patients received stage-specific therapy according to the latest national guidelines, irrespective of the mode of detection. Results: The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34-0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44-0.63) compared with the corresponding risks for nonparticipants. Conclusions: Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.

  • Liu, Haoyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Cai, Demin
    Univ Calif Davis, Dept Biochem & Mol Med, Sacramento, CA 95817 USA.
    Ahl, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nyman, Margareta
    Lund Univ, Dept Food Technol Engn & Nutr, S-22100 Lund, Sweden.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Dietary Fiber in Bilberry Ameliorates Pre-Obesity Events in Rats by Regulating Lipid Depot, Cecal Short-Chain Fatty Acid Formation and Microbiota Composition2019In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 6, article id 1350Article in journal (Refereed)
    Abstract [en]

    Obesity is linked to non-alcoholic fatty liver disease and risk factors associated to metabolic syndrome. Bilberry (Vaccinium myrtillus) that contains easily fermentable fiber may strengthen the intestinal barrier function, attenuate inflammation and modulate gut microbiota composition, thereby prevent obesity development. In the current study, liver lipid metabolism, fat depot, cecal and serum short-chain fatty acids (SCFAs) and gut microbiome were evaluated in rats fed bilberries in a high-fat (HFD + BB) or low-fat (LFD + BB) setting for 8 weeks and compared with diets containing equal amount of fiber resistant to fermentation (cellulose, HFD and LFD). HFD fed rats did not obtain an obese phenotype but underwent pre-obesity events including increased liver index, lipid accumulation and increased serum cholesterol levels. This was linked to shifts of cecal bacterial community and reduction of major SCFAs. Bilberry inclusion improved liver metabolism and serum lipid levels. Bilberry inclusion under either LFD or HFD, maintained microbiota homeostasis, stimulated interscapular-brown adipose tissue depot associated with increased mRNA expression of uncoupling protein-1; enhanced SCFAs in the cecum and circulation; and promoted butyric acid and butyrate-producing bacteria. These findings suggest that bilberry may serve as a preventative dietary measure to optimize microbiome and associated lipid metabolism during or prior to HFD.

  • Gustafsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Lämås, Kristina
    Umeå University, Faculty of Medicine, Department of Nursing.
    Isaksson, Ulf
    Umeå University, Faculty of Medicine, Department of Nursing. Umeå University, Arctic Research Centre at Umeå University.
    Sandman, Per-Olof
    Umeå University, Faculty of Medicine, Department of Nursing. Department of Neurobiology, Care Sciences and Society, Division of Nursing, Karolinska Institutet, Stockholm, Sweden.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Constipation and laxative use among people living in nursing homes in 2007 and 20132019In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 19, article id 38Article in journal (Refereed)
    Abstract [en]

    Background: Constipation is a common condition among older people, particularly among people living in nursing homes, and the use of drugs such as opioids is one of many factors that contribute to its high prevalence. The aim of this study was to compare the prevalence of constipation and the use of laxatives between 2007 and 2013, to analyze constipation and laxative use among people who are prescribed opioids, and to identify factors associated with constipation. Methods: In 2007 and 2013, two surveys were performed in the county of Vasterbotten in Northern Sweden, comprising all those living in nursing homes. The Multi-Dimensional Dementia Assessment Scale was used to collect data regarding laxative, opioid and anticholinergic drug use, functioning in activities of daily living (ADL), cognition and symptoms of constipation. A comparison was made between 2820 people from 2007 and 1902 people from 2013. Results: The prevalence of symptoms of constipation among people living in nursing homes increased from 36% in 2007 to 40% in 2013. After controlling for age, sex, ADL, cognitive impairment and use of opioid and anticholinergic drugs, this difference was found to be statistically significant. When controlled for demographic changes, there was a statistically significant difference in the regular use of laxatives between the respective years, from 46% in 2007 to 59% in 2013. People prescribed opioids and anticholinergic drugs were at increased risk of constipation, while people with a higher ADL score were at decreased risk. Further, among people prescribed opioids and rated as constipated, 35% in 2007 and 20% in 2013 were not prescribed laxatives for regular use, a difference that was found to be statistically significant. Conclusions: The prevalence of symptoms of constipation increased between 2007 and 2013. Although there was a decrease between the years, there were still a number of people being prescribed with opioids and rated as constipated who were not treated with laxatives. This study therefore indicates that constipation remains a significant problem among people in nursing homes and also indicates that those prescribed opioids could benefit from an increased awareness of the risk of constipation and treatment, if required.

  • Public defence: 2019-09-27 10:15 Alan Turing, Linköping
    Mengist, Alachew
    Linköping University, Department of Computer and Information Science, Software and Systems.
    Methods and Tools for Efficient Model-Based Development of Cyber-Physical Systems with Emphasis on Model and Tool Integration2019Licentiate thesis, monograph (Other academic)
    Abstract [en]

    Model-based tools and methods are playing important roles in the design and analysis of cyber-physical systems before building and testing physical prototypes. The development of increasingly complex CPSs requires the use of multiple tools for different phases of the development lifecycle, which in turn depends on the ability of the supporting tools to interoperate. However, currently no vendor provides comprehensive end-to-end systems engineering tool support across the entire product lifecycle, and no mature solution currently exists for integrating different system modeling and simulation languages, tools and algorithms in the CPSs design process. Thus, modeling and simulation tools are still used separately in industry.

    The unique challenges in integration of CPSs are a result of the increasing heterogeneity of components and their interactions, increasing size of systems, and essential design requirements from various stakeholders. The corresponding system development involves several specialists in different domains, often using different modeling languages and tools. In order to address the challenges of CPSs and facilitate design of system architecture and design integration of different models, significant progress needs to be made towards model-based integration of multiple design tools, languages, and algorithms into a single integrated modeling and simulation environment.

    In this thesis we present the need for methods and tools with the aim of developing techniques for numerically stable co-simulation, advanced simulation model analysis, simulation-based optimization, and traceability capability, and making them more accessible to the model-based cyber physical product development process, leading to more efficient simulation. In particular, the contributions of this thesis are as follows: 1) development of a model-based dynamic optimization approach by integrating optimization into the model development process; 2) development of a graphical co-modeling editor and co-simulation framework for modeling, connecting, and unified system simulation of several different modeling tools using the TLM technique; 3) development of a tool-supported method for multidisciplinary collaborative modeling and traceability support throughout the development process for CPSs; 4) development of an advanced simulation modeling analysis tool for more efficient simulation.

  • Fors, Carina
    et al.
    Swedish National Road and Transport Research Institute, Traffic and road users, Human Factors in the Transport System.
    Johansen, Trond Cato
    Ramböll.
    Nordic certification system for roadmarking materials: Version 6:20192019Report (Other academic)
    Abstract [en]

    A Nordic certification system for road marking materials was introduced in 2015. The system is basedon documented performance measurements of material samples applied on test fields on public roads.The certification system includes both flat (type I) and structured/profiled (type II) markings, antiskidmaterials (materials with enhanced friction), temporary markings (Denmark only) and inlaid markings(Norway only). From 2019, the certification system will also include materials for hand applicationand materials with enhanced durability for illuminated high-traffic urban areas.

    Material tests are carried out at two test sites: one in Norway and one in Denmark. The tests fields aresituated on public roads and the tested materials are thus exposed to real traffic conditions and toweather conditions representative for the Nordic countries. The materials are followed up byperformance measurements during one or two years. The certification includes requirements oncoefficient of retroreflected luminance RL under dry and wet conditions, luminance coefficient underdiffuse illumination Qd, friction and colour coordinates. The number of wheel passages is measured atthe test sites annually. The certification system includes material identification, which allows forfuture material sampling and analysis.

    The certification system is based on the European standards EN 1824 Road marking materials – Roadtrials, EN 1436 Road marking materials – Road marking performance for road users, and EN 12802Road marking materials – Laboratory methods for identification.

    The report describes the certification system and how it is applied in the Nordic countries. Proceduresand methods that are used for application of materials and performance measurements are specified.

  • Färgforum 2019: hållbarhet : rapport2019Report (Other academic)
    Abstract [sv]

    Färgforum 2019 arrangerades 11–12 april 2019 av Riksantikvarieämbetet i samarbete med Sundsvalls kommun, Göteborgs universitet, Hantverkslaboratoriet, Statens fastighetsverk och Byggnadsvårdsföreningen. Konferensen hölls i stadshuset i Sundsvall. Rapporten sammanfattar de presentationer som hölls under konferensen och har sammanställts av Färgforums projektgrupp på Riksantikvarieämbetet.

  • Malm Lindberg, Ingrid
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology, Studies in Faith and Ideologies.
    The Thought Experimenting Qualities of Kierkegaard's Fear and Trembling2019In: Religions, ISSN 2077-1444, E-ISSN 2077-1444, Vol. 10, no 6, article id 391Article in journal (Refereed)
    Abstract [en]

    In this article, I examine the possible thought experimenting qualities of SOren Kierkegaard's novel Fear and Trembling and in which way (if any) it can be explanatory. Kierkegaard's preference for pseudonyms, indirect communication, Socratic interrogation, and performativity are identified as features that provide the narrative with its thought experimenting quality. It is also proposed that this literary fiction functions as a Socratic-theological thought experiment due to its influences from both philosophy and theology. In addition, I suggest three functional levels of the fictional narrative that, in different ways, influence its possible explanatory force. As a theoretical background for the investigation, two accounts of literary cognitivism are explored: Noel Carroll's Argument Account and Catherine Elgin's Exemplification Account. In relation to Carroll's proposal, I conclude that Fear and Trembling develops a philosophical argumentation that is dependent on the reader's own existential contribution. In relation to Elgin's thought, the relation between truth and explanatory force is acknowledged. At the end of the article, I argue that it is more accurate to see the explanatory force of Fear and Trembling in relation to its exploratory function.

  • Cavanagh, Jorunn Pauline
    et al.
    Askarian, Fatemeh
    Pain, Maria
    Bruun, Jack-Ansgar
    Urbarova, Ilona
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schmidt, Frank
    Johannessen, Mona
    Proteome profiling of secreted and membrane vesicle associated proteins of an invasive and a commensal Staphylococcus haemolyticus isolate2019In: Data in Brief, E-ISSN 2352-3409, Vol. 22, p. 914-919Article in journal (Refereed)
    Abstract [en]

    Bacterial membrane vesicles (MVs) mediate bacterial virulence by enabling secretion and long distance delivery of bacterial effector molecules. Staphylococcus haemolyticus has now been demonstrated to produce membrane vesicles (MVs). The protein content of S. haemolyticus MVs was identified by Mass spectrometry and compared to proteins identified in the total secretome. This information is presented in this data article. Further background and interpretation of the data can be found in the article: Comparative exoproteome profiling of an invasive and a commensal S. haemolyticus isolate (Cavanagh et al., in press). Data are available via Proteome Xchange with identifier PXD010389.

  • Procházka, Vladimir
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Theoretical Physics.
    Boundary gauge and gravitational anomalies from Ward identities2019In: Journal of High Energy Physics (JHEP), ISSN 1126-6708, E-ISSN 1029-8479, no 7, article id 047Article in journal (Refereed)
    Abstract [en]

    We consider the two-point functions of conserved bulk currents and energymomentum tensor in a boundary CFT defined on R_(1,2). Starting from the consistent forms of boundary gauge and gravitational anomalies we derive their respective contributions to the correlation functions in the form of anomalous Ward identities. Using the recently developed momentum space formalism we find an anomalous solution to each of these identities depending on a single undetermined form-factor. We study the solution in two different kinematic limits corresponding to small and large momentum p(n), perpendicular to the boundary. We find that the anomalous term interpolates between a non-local form resembling the standard anomaly-induced term in a two-dimensional CFT at small pn and Chern-Simons contact terms at large pn. Using this we derive some consistency conditions regarding the dependence of these anomalies on the boundary conditions and discuss possible cancellation mechanisms. These ideas are then demonstrated on the explicit example of free, massless three-dimensional fermion. In particular we manage to obtain the respective anomalies via a diagrammatic momentum space computation and expose the well- known relation between bulk parity anomaly and boundary gauge anomalies.

  • Zorgati, Habiba
    et al.
    ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore;Natl Univ Singapore, Dept Biochem, Singapore 117596, Singapore.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore.
    Ren, Weitong
    Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Dept Phys, Natl Lab Solid State Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
    Sim, Adelene Y. L.
    ASTAR, Bioinformat Inst, Singapore 138671, Singapore.
    Gettemans, Jan
    Univ Ghent, Fac Med & Hlth Sci, Dept Biomol Med, Nanobody Lab, B-9000 Ghent, Belgium.
    Grimes, Jonathan M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England;Diamond Light Source Ltd, Didcot OX11 ODE, Oxon, England.
    Li, Wenfei
    Nanjing Univ, Collaborat Innovat Ctr Adv Microstruct, Dept Phys, Natl Lab Solid State Microstruct, Nanjing 210093, Jiangsu, Peoples R China.
    Robinson, Robert C.
    ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore;Vidyasirimedhi Inst Sci & Technol, Sch Biomol Sci & Engn, Rayong 21210, Thailand;Okayama Univ, Res Inst Interdisciplinary Sci, Okayama 7008530, Japan.
    The role of gelsolin domain 3 in familial amyloidosis (Finnish type)2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 28, p. 13958-13963Article in journal (Refereed)
    Abstract [en]

    In the disease familial amyloidosis, Finnish type (FAF), also known as AGeI amyloidosis (AGeI), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.

  • Wänström, Johan
    Linköping University, Department for Studies of Social Change and Culture, Centre for Municipality Studies – CKS. Linköping University, Faculty of Arts and Sciences.
    Motsatta ideal i den politiska styrningen av mindre kommuner: Mot en ny(gammal) kommunal politikerroll?2019Report (Other academic)
    Abstract [sv]

    Under senare år har det förts en diskussion om hur Sveriges kommuner ska styras. Tillitsdelegationen och dess uppdragsgivare (regeringen) vill till exempel se mindre målstyrning och framförallt mindre uppföljning och hårt ansvarsutkrävande till förmån för en politisk styrning som präglas mer av dialog och tillit. Mycket av den tidigare forskningen om målstyrning har genomförts på kommuner som är större än den svenska mediankommunen, det vill säga kommuner som har mer än 16 000 invånare. Den här studien gör istället nedslag i tre kommuner som alla har mindre än 16 000 invånare.

    Syftet med den här studien är att beskriva och analysera de olika ideal som präglar ledande politikers och tjänstepersoners reflektioner kring hur den politiska styrningen i mindre kommuner bör organiseras och utföras. Genom djupintervjuer med 14 ledande politiker och tjänstepersoner framkom två övergripande modeller för den politiska styrningen – modeller som i sin tur präglas av två övergripande ideal: närhet och distans.

    Vissa av respondenterna framhävde betydelsen av att ett större avstånd mellan styrande politiker och oppositionspolitiker för att på så sätt skapa förutsättningar för mer av majoritets- och framförallt konkurrensdemokrati. De förespråkade också ett större avstånd mellan politiker och tjänstemän där politikerna fokuserar på att styra genom mål och andra former av övergripande riktlinjer. Andra respondenter framhävde betydelsen av att olika aktörer – såväl politiker, tjänstepersoner som lokala medborgare, företag och föreningar – verkar i ett nära samspel där samförstånd snarare än konflikt eftersträvas. När förespråkare för mer distanserade relationer framhäver vikten av platsoberoende akademiskt förankrad kunskap (vilken framförallt förväntas finnas i den professionaliserade förvaltningen) framhäver de som förespråkar ett nära samspel ofta betydelsen av den lokalt förankrade kunskapen som finns och växer fram i samspelet mellan olika aktörer. När de som förespråkar mer distanserade relationer framhäver vikten av tilliten till övergripande principer och system, framhäver de som förespråkar ett nära samspel tilliten mellan enskilda individer.

    Det faktum att Sveriges kommuner ser olika ut i relation till en rad olika parametrar, såsom till exempel befolkningsmässig och geografisk storlek, gör att man har olika förutsättningar att genomföra någon form av universell styrmodell. Den här studien påvisar därutöver att såväl politiker som tjänstpersoner i olika kommuner sätter olika värde till olika ideal kopplade till den politiska styrningen – ideal som ofta behöver balanseras mot varandra.

  • Zisopoulos, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics. CERN, CH-1211 Geneva, Switzerland.
    Papaphilippou, Y.
    CERN, CH-1211 Geneva, Switzerland.
    Laskar, J.
    IMCCE, Observ Paris, 77 Ave Denfert Rochereau, F-75014 Paris, France.
    Refined betatron tune measurements by mixing beam position data2019In: PHYSICAL REVIEW ACCELERATORS AND BEAMS, E-ISSN 2469-9888, Vol. 22, no 7, article id 071002Article in journal (Refereed)
    Abstract [en]

    The measurement of the betatron tunes in a circular accelerator is of paramount importance due to their impact on beam dynamics. The resolution of the these measurements, when using turn-by-turn (TBT) data from beam position monitors, is greatly limited by the available number of turns in the signal. Because of decoherence from finite chromaticity and/ or amplitude detuning, the transverse betatron oscillations appear to be damped in the TBT signal. On the other hand, an adequate number of samples is needed, if precise and accurate tune measurements are desired. In this paper, a method is presented that allows for very precise tune measurements within a very small number of turns. The theoretical foundation of this method is presented with results from numerical and tracking simulations and experimental TBT data which are recorded at electron and proton circular accelerators.

  • Public defence: 2019-09-24 13:00 Belladonna, Linköping
    Bratengeier, Cornelia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.

    In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?

    We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.

    In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.

  • Tammimies, Kristiina
    et al.
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Li, Danyang
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Rabkina, Ielyzaveta
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Stamouli, Sofia
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Becker, Martin
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Nicolaou, Veronika
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden.
    Berggren, Steve
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden;Stockholm Hlth Serv, Child & Adolescent Psychiat, Stockholm, Sweden.
    Coco, Christina
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden;Stockholm Hlth Serv, Child & Adolescent Psychiat, Stockholm, Sweden.
    Falkmer, Torbjörn
    Curtin Univ, Sch Occupat Therapy Social Work & Speech Pathol, Curtin Autism Res Grp, Bentley, WA, Australia;Linkoping Univ, Dept Med & Hlth Sci, Pain & Rehabil Ctr, Linkoping, Sweden.
    Jonsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden;Stockholm Hlth Serv, Child & Adolescent Psychiat, Stockholm, Sweden.
    Choque-Olsson, Nora
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden;Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden.
    Bölte, Sven
    Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Psychiat Res, Ctr Neurodev Disorders KIND,Div Neuropsychiat, Solna, Sweden;Stockholm Hlth Serv, Child & Adolescent Psychiat, Stockholm, Sweden;Curtin Univ, Sch Occupat Therapy Social Work & Speech Pathol, Curtin Autism Res Grp, Bentley, WA, Australia.
    Association between Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9810Article in journal (Refereed)
    Abstract [en]

    Challenges in social communication and interaction are core features of autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest and heterogeneous effects. One of the major genetic risk factors in ASD is rare copy number variation (CNV). However, limited information exists whether CNV profiles could be used to aid intervention decisions. Here, we analyzed the rare genic CNV carrier status for 207 children, of which 105 received SSGT and 102 standard care as part of a randomized clinical trial for SSGT. We found that being a carrier of rare genic CNV did not have an impact on the SSGT outcome measured by the parent-report Social Responsiveness Scale (SRS). However, when stratifying by pathogenicity and size of the CNVs, we identified that carriers of clinically significant and large genic CNVs (> 500 kb) showed inferior SRS outcomes at post-intervention (P = 0.047 and P = 0.036, respectively) and follow-up (P = 0.008 and P = 0.072, respectively) when adjusting for standard care effects. Our study provides preliminary evidence that carriers of clinically significant and large genic CNVs might not benefit as much from SSGT as non-carriers. Our results indicate that genetic information might help guide the modifications of interventions in ASD.

  • Carlsson, Johanna
    et al.
    Egertsdotter, Ulrika
    Ganeteg, Ulrika
    Svennerstam, Henrik
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Nitrogen utilization during germination of somatic embryos of Norway spruce: revealing the importance of supplied glutamine for nitrogen metabolism2019In: Trees, ISSN 0931-1890, E-ISSN 1432-2285, Vol. 33, no 2, p. 383-394Article in journal (Refereed)
    Abstract [en]

    Key messageThis paper shows that germinating Norway spruce somatic embryos are dependent on the carbon and nitrogen supplied in the medium, and that supplied glutamine accounts for 50 % of assimilated nitrogen during germination.AbstractThe female megagametophyte, which provides the zygotic embryo with nitrogen (N), carbon (C) and energy during germination, is not present in Norway spruce (Picea abies) mature somatic embryos. Therefore, somatic embryos presumably rely on nutrients supplied in the germination medium in addition to their storage compounds accumulated during maturation. However, to what extent stored versus supplied compounds contribute to a somatic embryo germination is unclear. In this 24-day study, we addressed the above question by monitoring the biomass changes and the N and C budget during somatic embryo germination, under low-intensity red light. We found that the C and N storage reserves, accumulated during the maturation phase, were not sufficient to support the growth of the germinating somatic embryos, rather they were dependent on the medium components. In addition, in a previous study it has been found that glutamine (Gln) supplied in the medium was crucial for maintaining the primary amino acid (AA) metabolism and growth of the proliferating embryogenic cultures of Norway spruce (Carlsson et al., PLoS One 12(8):e0181785, 2017). Therefore, we hypothesised that Gln would be required as a significant source of N also during somatic embryo germination. By tracing the uptake of isotopically labelled N-sources from the medium and further into primary N assimilation, we found that Gln was the preferred source of N for the germinating somatic embryos, accounting for 50% of assimilated N. As the amounts of both arginine (Arg) and Gln were increased in the germinating somatic embryos, it also suggested that germination in low-intensity red light promoted N storage, similar to what has been observed in the zygotic embryo maturation in conifers (King, Gifford, Plant Physiol 113:1125-1135, 1997).

  • Avenel, Christophe
    et al.
    CADESS Med AB, Uppsala, Sweden.
    Tolf, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Carlbom, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. CADESS Med AB, Uppsala, Sweden.
    Glandular Segmentation of Prostate Cancer: An Illustration of How the Choice of Histopathological Stain Is One Key to Success for Computational Pathology2019In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 7, article id 125Article in journal (Refereed)
    Abstract [en]

    Digital pathology offers the potential for computer-aided diagnosis, significantly reducing the pathologists' workload and paving the way for accurate prognostication with reduced inter-and intra-observer variations. But successful computer-based analysis requires careful tissue preparation and image acquisition to keep color and intensity variations to a minimum. While the human eye may recognize prostate glands with significant color and intensity variations, a computer algorithm may fail under such conditions. Since malignancy grading of prostate tissue according to Gleason or to the International Society of Urological Pathology (ISUP) grading system is based on architectural growth patterns of prostatic carcinoma, automatic methods must rely on accurate identification of the prostate glands. But due to poor color differentiation between stroma and epithelium from the common stain hematoxylin-eosin, no method is yet able to segment all types of glands, making automatic prognostication hard to attain. We address the effect of tissue preparation on glandular segmentation with an alternative stain, Picrosirius red-hematoxylin, which clearly delineates the stromal boundaries, and couple this stain with a color decomposition that removes intensity variation. In this paper we propose a segmentation algorithm that uses image analysis techniques based on mathematical morphology and that can successfully determine the glandular boundaries. Accurate determination of the stromal and glandular morphology enables the identification of the architectural pattern that determine the malignancy grade and classify each gland into its appropriate Gleason grade or ISUP Grade Group. Segmentation of prostate tissue with the new stain and decomposition method has been successfully tested on more than 11000 objects including well-formed glands (Gleason grade 3), cribriform and fine caliber glands (grade 4), and single cells (grade 5) glands.

  • Public defence: 2019-09-20 10:15 ACAS, Linköping
    Larsson, L. Viktor
    Linköping University, Department of Management and Engineering, Fluid and Mechatronic Systems. Linköping University, Faculty of Science & Engineering.
    Control of Hybrid Hydromechanical Transmissions2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with control aspects of complex hybrid hydromechanical transmissions for heavy mobile working machines. Control problems are identified and solved to facilitate the implementation and use of these systems.

    Fuel prices and environmental concerns have increased the interest in hybrid hydromechanical transmissions for heavy mobile working machines. Hybridisation, the introduction of a secondary energy source in the transmission, offers attractive improvements in terms of both fuel efficiency and performance. These improvements are, in turn, enabled by software control. A complex transmission architecture has several components that need to interact in a stable manner. In addition, optimal utilisation of the added energy source is required to maximise fuel savings. Meanwhile, there is a strong trend towards automation, where many of the operator’s difficult control tasks need to be managed by computers. Sophisticated control strategies are therefore needed, along with a deeper understanding of dynamic properties.

    Previous research on the control of hybrid hydromechanical transmissions has primarily focussed on on-road applications. The working conditions of heavy working machines place different requirements on the transmission, which is also reflected in the control strategy.

    This thesis highlights the importance of fast response of the variable displacement pump/motors used in hybrid hydromechanical transmissions. Their central position in the interface between hydraulics and mechanics makes their dynamic performance a limiting factor both for the stability of the transmission control loops and in the realisation of smooth mode shifts in multiplemode transmissions. Dynamic models and control strategies for displacement actuators are derived and validated in simulation and experiments. A linear model for dynamic analysis of a general hybrid hydromechanical transmission for heavy working machines is derived and a powertrain control strategy based on decoupled control is proposed. The strategy is verified in simulations and experiments in hardware-in-the-loop simulations, and may be used in a working machine with or without a human operator.

  • Dahal, Prabin
    et al.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Simpson, Julie Anne
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostatist, Melbourne, Vic, Australia.
    Abdulla, Salim
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Achan, Jane
    MRC Unit, Banjul, Gambia.
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan.
    Agarwal, Aarti
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Allan, Richard
    Mentor Initiat, Fajara, Gambia.
    Anvikar, Anupkumar R.
    Natl Inst Malaria Res, Sector 8, Dwarka, New Delhi 110077, India.
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda.
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Awab, Ghulam Rahim
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Minist Publ Hlth, Islam Republ Afghanistan, Kabul, Afghanistan.
    Bassat, Quique
    Ctr Investigacao Saude Manhica CISM, Maputo, Mozambique;Univ Barcelona, Hosp Clin, ISGlobal, Barcelona, Spain;ICREA, Pg Lluis Companys 23, Barcelona 08010, Spain.
    Bjorkman, Anders
    Karolinska Inst, Depatment Microbiol Tumour & Cell Biol, Stockholm, Sweden.
    Bompart, Francois
    Sanofi Access Med, Gentilly, France.
    Borrmann, Steffen
    Kenya Med Res Inst Kilifi, Kilifi, Kenya;Wellcome Trust Res Programme, Kilifi, Kenya;Heidelberg Univ, Sch Med, Dept Infect Dis, Heidelberg, Germany.
    Bousema, Teun
    Radboud Inst Hlth Sci, Radboudumc Nijmegen, Nijmegen, Netherlands;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.
    Broek, Ingrid
    Centrum Infectieziektebestrijding, Epidemioloog Epidemiol Surveillance RIVM, Bilthoven, Netherlands.
    Bukirwa, Hasifa
    African Field Epidemiol Network, Kampala, Uganda.
    Carrara, Verena I.
    Shoklo Malaria Res Unit, Mae Sot, Bangkok, Thailand;Mahidol Oxford Univ Res Unit, Bangkok, Thailand.
    Corsi, Marco
    Private Consultancy Drug Dev Trop Dis, Sigma Tau SpA Ind Farmaceutiche Riunite, Pomezia, Rome, Italy.
    Cot, Michel
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    D'Alessandro, Umberto
    MRC Unit, Fajara, Gambia;London Sch Hyg & Trop Med, London, England.
    Davis, Timothy M. E.
    Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
    de Wit, Marit
    Med Sans Frontieres Operat Ctr Amsterdam, Geneva, Switzerland.
    Deloron, Philippe
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Dimbu, Pedro Rafael
    Natl Malaria Control Program, Luanda, Angola.
    Djalle, Djibrine
    Inst Pasteur, BP 923, Bangui, Cent Afr Republ.
    Djimde, Abdoulaye
    Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Doumbo, Ogobara K.
    Univ Sci Techn & Technol Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med & Odonto Stomatol, Bamako, Mali.
    Drakeley, Chris J.
    London Sch Hyg & Trop Med, Dept Infect & Immun, London, England.
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland.
    Edstein, Michael D.
    Australian Army Malaria Inst, Brisbane, Qld, Australia.
    Espie, Emmanuelle
    R&D Ctr, GSK Vaccines, Clin & Epidemiol Dept, Epicentre, Ave Fleming 20,1300 Wavre,8 Rue St Sabin, F-75011 Paris, France.
    Faiz, Abul
    Malaria Res Grp, Chittagong, Bangladesh;Dev Care Fdn, Dhaka, Bangladesh.
    Falade, Catherine
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Med, Ctr Global Hlth, Oxford, England.
    Faucher, Jean-Francois
    Besancon Univ Med Ctr, Dept Infect Dis, Mother & Child Hlth Trop Res Unit, Inst Rech Dev IRD, Besancon, France.
    Faye, Babacar
    Univ Cheikh Anta Diop, Fac Med, Dept Med Parasitol, Dakar, Senegal.
    Fortes, Filomeno de Jesus
    Natl Malaria Control Program, Luanda, Angola.
    Gadalla, Nahla B.
    Sudanese Amer Med Assoc, Fairfax, VA USA.
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Med Parasitol, Fac Med, Dakar, Senegal.
    Gil, J. Pedro
    Karolinska Inst, Div Pharmacogenet, Dept Physiol & Pharmacol, Drug Resistance Unit, Stockholm, Sweden;Univ Lisbon, Ctr Biodivers Funct & Integrat Gen, Fac Ciencias, Lisbon, Portugal.
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England.
    Grivoyannis, Anastasia
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA.
    Hamed, Kamal
    Basilea Pharmaceut Int Ltd, Basel, Switzerland;Novartis Pharmaceut, E Hanover, NJ USA.
    Hien, Tran Tinh
    Oxford Univ Clin Res Unit OUCRU, Ctr Trop Med, Wellcome Trust Major Overseas Program MOP, Oxford, England.
    Hughes, David
    Novartis Int AG, Basel, Switzerland.
    Humphreys, Georgina
    Wellcome Trust Res Labs, London, England;World Wide Antimalarial Resistance Network WWARN, London, England.
    Hwang, Jimee
    US Centers Dis Control & Prevent, Div Parasit Dis & Malaria, US Presidents Malaria Initiat Malaria Branch, Atlanta, GA USA;Univ Calif San Francisco, San Francisco, CA 94143 USA;Global Hlth Grp, San Francisco, CA 94143 USA.
    Ibrahim, Maman Laminou
    Ctr Rech Med & Saniataire CERMES, Niamey, Niger.
    Janssens, Bart
    Medecins Sans Frontieres, Phnom Penh, Belgium.
    Jullien, Vincent
    Univ Paris 05, Assistance Publique Hop Paris, Serv Pharmacol Clin, Paris, France;Grp Hosp Cochin Saint Vincent Paul, Inserm U663, WWARN, Paris, France.
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kamugisha, Erasmus
    Weill Bugando Univ Coll Hlth Sci, Mwanza, Tanzania.
    Karema, Corine
    Minist Hlth, Natl Malaria Control Program TRAC Plus, Kigali, Rwanda.
    Karunajeewa, Harin A.
    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia.
    Kiechel, Jean R.
    Drugs Neglected Dis initiat, Geneva, Switzerland.
    Kironde, Fred
    Islam Univ Uganda, Habib Med Sch, Kampala, Uganda.
    Kofoed, Poul-Erik
    Bandim Hlth Project, Indepth Network, Apartado 861, Bissau, Guinea Bissau;Lillebaelt Hosp, Hlth Serv Res Unit, Vejle, Denmark;IRS Univ Southern Denmark, Vejle, Denmark;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark.
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany;Ctr Recherches Medic Lambarene, Lambarene, Gabon.
    Lameyre, Valerie
    Sanofi Access Med, Gentilly, France.
    Lee, Sue J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Marsh, Kevin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Wellcome Trust Res Programme, Kilifi, Kenya;Kenya Govt Med Res Ctr, Kilifi, Kenya.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Mayxay, Mayfong
    Mahosot Hosp, Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, Microbiol Lab, Viangchan, Laos.
    Menan, Herve
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire;Univ Hlth Sci, Minist Hlth, Fac Postgraduate Studies, Viangchan, Laos.
    Mens, Petra
    Acad Med Ctr, Med Microbiol Parasitol, Amsterdam, Netherlands.
    Mutabingwa, Theonest K.
    Hubert Kairuki Mem Univ, Dar Es Salaam, Tanzania;London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London, England.
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Fac Med, Parasitol & Mycol Lab, Dakar, Senegal.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden.
    Noedl, Harald
    Med Univ Vienna, Vienna, Austria.
    Nosten, Francois
    Univ Oxford, Nuffield Dept Med Res Bldg, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Offianan, Andre Toure
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire.
    Oguike, Mary
    London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England.
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, Kisumu, Kenya;US Army Med Res Unit, Kisumu, Kenya.
    Olliaro, Piero
    UNICEF, UNDP, World Bank, WHO TDR, Geneva, Switzerland.
    Ouedraogo, Jean Bosco
    Inst Rech Sci Sante, Direct Regionale Ouest, Bobo Dioulasso, Burkina Faso;Ctr Muraz Bobo Dioulasso, Non Transmissible Dis Dept, Bobo Dioulasso, Burkina Faso.
    Piola, Patrice
    Inst Pasteur Cambodge, Phnom Penh, Cambodia.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Plucinski, Mateusz M.
    US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, US Presidents Malaria Initiat, Atlanta, GA USA;Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA.
    Pratt, Oliver James
    Minist Hlth & Social Welf, Natl Malaria Control Program, Monrovia, Liberia.
    Premji, Zulfikarali
    Muhimbili Univ Coll Hlth Sci, Dar Es Salaam, Tanzania.
    Ramharter, Michael
    Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany.
    Rogier, Christophe
    Div Expertise & Def Hlth strategy, Cent Directorate, French Mil Hlth Serv, Paris, France;IRBA, Bretigny Sur Orge, France;URMITE, UMR 6236, Marseille, France.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Sawa, Patrick
    Human Hlth Div, Int Ctr Insect Physiol & Ecol, Mbita, Kenya.
    Schramm, Birgit
    Epicentre, Paris, France.
    Sibley, Carol
    WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Sinou, Veronique
    Aix Marseille Univ, INSERM, SSA, IRBA,MCT, Marseille, France.
    Sirima, Sodiomon
    GRAS, 06 BP 10248, Ouagadougou 06, Burkina Faso.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Oxford, England.
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda;London Sch Hyg & Trop Med, Dept Clin Res, London, England.
    Sutanto, Inge
    Univ Indonesia, Dept Parasitol, Fac Med, 6 Salemba Raya, Jakarta 10430, Indonesia.
    Talisuna, Ambrose Otau
    WHO, Reg Off Afr, Brazzaville, Rep Congo;Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Tarning, Joel
    WorldWide Antimalarial Resistance Network, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Taylor, Walter R. J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand.
    Temu, Emmanuel
    MENTOR Initiat, Crawley, England.
    Thriemer, Kamala L.
    Charles Darwin Univ, Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.
    Thuy, Nhien Nguyen
    Oxford Univ Clin Res Unit OUCRU, Wellcome Trust Major Overseas Program MOP, Ctr Trop Med, Oxford, England.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch & Presidents Malaria Initiat, Atlanta, GA USA.
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC C1, Solna, Sweden;Danderyd Hosp, Dept Infect Dis, Danderyd, Sweden.
    van Herp, Michel
    Operat Ctr Brussels, Med Sans Frontieres, Brussels, Belgium;Univ Amsterdam, Acad Med Ctr, Div Infect Dis, Ctr Trop Med & Travel Med, Amsterdam, Netherlands.
    van Vugt, Michele
    Whitty, Christopher
    London Sch Hyg & Trop Med, Dept Infect & Trop Dis, Malaria Partnership, London, England.
    William, Yavo
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire.
    Winnips, Cornelis
    NovartisInternat AG, Basel, Switzerland.
    Zongo, Issaka
    Inst Rech Sci Sante, Direct Regionale lOuest, Bobo Dioulasso, Burkina Faso.
    Guerin, Philippe
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Price, Ric N.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Menzies Sch Hlth Res Charles Darwin Univ, Darwin, NT, Australia;Churchill Hosp, Ctr Clin Vaccinol & Trop Med, Oxford, England.
    Stepniewska, Kasia
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis2019In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, article id 225Article in journal (Refereed)
    Abstract [en]

    Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.

    Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.

    Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.

    Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.

  • Hughes, Patrick William
    Max Planck Institute for Plant Breeding Research, Germany.
    Between semelparity and iteroparity: Empirical evidence for a continuum of modes of parity2017In: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 7, no 20, p. 8232-8261Article in journal (Refereed)
    Abstract [en]

    The number of times an organism reproduces (i.e., its mode of parity) is a fundamental life‐history character, and evolutionary and ecological models that compare the relative fitnesses of different modes of parity are common in life‐history theory and theoretical biology. Despite the success of mathematical models designed to compare intrinsic rates of increase (i.e., density‐independent growth rates) between annual‐semelparous and perennial‐iteroparous reproductive schedules, there is widespread evidence that variation in reproductive allocation among semelparous and iteroparous organisms alike is continuous. This study reviews the ecological and molecular evidence for the continuity and plasticity of modes of parity—that is, the idea that annual‐semelparous and perennial‐iteroparous life histories are better understood as endpoints along a continuum of possible strategies. I conclude that parity should be understood as a continuum of different modes of parity, which differ by the degree to which they disperse or concentrate reproductive effort in time. I further argue that there are three main implications of this conclusion: (1) that seasonality should not be conflated with parity; (2) that mathematical models purporting to explain the general evolution of semelparous life histories from iteroparous ones (or vice versa) should not assume that organisms can only display either an annual‐semelparous life history or a perennial‐iteroparous one; and (3) that evolutionary ecologists should base explanations of how different life‐history strategies evolve on the physiological or molecular basis of traits underlying different modes of parity.

  • Hughes, P. William
    Max Planck Institute for Plant Breeding Research, Germany; University of Cologne, Germany.
    Minimal-Risk Seed Heteromorphism: Proportions of Seed Morphs for Optimal Risk-Averse Heteromorphic Strategies2018In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 9, article id 1412Article in journal (Refereed)
    Abstract [en]

    Seed heteromorphism is the reproductive strategy characterized by the simultaneous production of multiple seed types. While comparing heteromorphic to monomorphic strategies is mathematically simple, there is no explicit test for assessing which ratio of seed morphs minimizes fitness variance, and hence offers a basis for comparing different heteromorphic strategies. Such a test may be particularly valuable when more than two distinct morphs are present, since many strategies may have equivalent geometric fitnesses. As noted by Gillespie (1974), in these cases avoiding rare but evolutionarily important instances of severe reductions in fitness involves the minimization of variation in fitness—i.e., risk. Here I compute the optimal proportions of two or more seed morphs for heteromorphic strategies that either: (1) minimize total fitness variance; or (2) maximize the fitness-risk ratio—i.e., the “extra” fitness accrued per unit of “extra” fitness variance. This work thereby provides a testable null hypothesis to estimate the optimal frequencies of seed morphs when multiple heteromorphic strategies have evolved in environments with severe fitness risks. Moreover, it also permits the calculation of expected seed morph frequencies when more than two seed morphs are produced.

  • Hughes, P. William
    et al.
    Max Planck Institute for Plant Breeding Research, Germany.
    Simons, Andrew M.
    Microsatellite evidence for obligate autogamy, but abundant genetic variation in the herbaceous monocarp Lobelia inflata (Campanulaceae)2015In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 28, no 11, p. 2068-2077Article in journal (Refereed)
    Abstract [en]

    Although high levels of self‐fertilization (>85%) are not uncommon in nature, organisms reproducing entirely through selfing are extremely rare. Predominant selfers are expected to have low genetic diversity because genetic variation is distributed among rather than within lineages and is readily lost through genetic drift. We examined genetic diversity at 22 microsatellite loci in 105 individuals from a population of the semelparous herb Lobelia inflata L. and found (i) no evidence of heterozygosity through outcrossing, yet (ii) high rates of genetic polymorphism (2–4 alleles per locus). Furthermore, this genetic variation among lineages was associated with phenotypic traits (e.g. flower colour, size at first flower). Coupled with previous work characterizing the fitness consequences of reproductive timing, our results suggest that temporal genotype‐by‐environment interaction may maintain genetic variation and, because genetic variation occurs only among lineages, this simple system offers a unique opportunity for future tests of this mechanism.

  • Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kumar, Chanchal
    AstraZeneca, R&D BioPharmaceut, Translat Sci & Expt Med, Early Cardiovasc Renal & Metab, Gothenburg, Sweden;Karolinska Inst, AstraZeneca Integrated CardioMetab Ctr KI AZ ICMC, Dept Med, Huddinge, Sweden.
    Skrtic, Stanko
    AstraZeneca AB, Pharmaceut Technol & Dev, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9653Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.