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  • Public defence: 2024-02-29 13:15 Häggsalen, Uppsala
    Eliah Dawod, Ibrahim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. European XFEL, Holzkoppel 4, DE-22869 Schenefeld, Germany.
    Simulations of ultrafast photon-matter interactions for molecular imaging with X-ray lasers2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biological structure determination has had new avenues of investigation opened due to the introduction of X-ray free-electron lasers (XFELs). These X-ray lasers provide an extreme amount of photons on ultrafast timescales used to probe matter, and in particular biomolecules. The high intensity of the X-rays destroys the sample, though not before structural information has been acquired. The unique properties of the probe provide the unprecedented opportunity to study the un-crystallized form of biological macromolecules, small crystals of biomolecules and their dynamics. 

    In this work, we study processes in XFEL imaging experiments that could affect the achievable resolution of the protein structure in a diffraction experiment. Elastic scattering is the process which provides structural information and leaves the sample unperturbed. This interaction occurs far less often compared to damage inducing processes, such as photoabsorption, which leads to rapid ionization of the studied sample. By using density functional theory, we study the effect of ultrahigh charge states in small systems, such as amino acids and peptides, on the subsequent bond breaking and charge dynamics. Reproducible fragmentation patterns are studied in order to find features that could be understood in larger systems, such as proteins. 

    Biomolecules are dynamical systems, and the currently used pulse duration is not short enough to outrun the movement of the atoms. The diffraction patterns acquired in an experiment are therefore an incoherent sum of slightly different conformations of the same system. Water can help to reduce these structural variations, but the water molecules themselves will then be a source of noise. Using classical molecular dynamics, we study the optimal amount of water that should be used to achieve the highest resolution. 

    To simulate ultrafast molecular dynamics of larger systems such as proteins, we develop a hybrid Monte Carlo/molecular dynamics model. We utilize it to simulate the fragmentation dynamics of small proteins and investigate the possibility to extract structural information from the fragmentation patterns. For larger systems exposed to X-ray lasers, such as viruses and crystals, we develop a hybrid collisional-radiative and classical molecular dynamics approach. The method is used in several projects, both in theoretical studies and to support experiments conducted at XFEL facilities. In particular, we simulate the interaction of hexagonal ice with an X-ray laser, and show the structure makes a phase transition from the native crystal state to a plasma, while still partly retaining structural order. Furthermore, we note that the structural changes occur in an anisotropic manner, where different local structural configurations in ice decay on different time-scales. 

    Preliminary experimental results show this anisotropic dynamics in an X-ray pump-probe serial femtosecond X-ray crystallography experiment performed on  I3C crystals. The real space dynamics as a function of probe delay given by our theoretical model and the experiment both show good agreement, where the iodine atoms exhibit correlated motion. The model is also used to calculate the expected atomic displacement and ionization in a hemoglobin crystal, revealing the time and length scales of the dynamics in the protein during the experiment. 

    List of papers
    1. Femtosecond bond breaking and charge dynamics in ultracharged amino acids
    Open this publication in new window or tab >>Femtosecond bond breaking and charge dynamics in ultracharged amino acids
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    2019 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 151, no 14, article id 144307Article in journal (Refereed) Published
    Abstract [en]

    Historically, structure determination of nanocrystals, proteins, and macromolecules required the growth of high-quality crystals sufficiently large to diffract X-rays efficiently while withstanding radiation damage. The development of the X-ray free-electron laser has opened the path toward high resolution single particle imaging, and the extreme intensity of the X-rays ensures that enough diffraction statistics are collected before the sample is destroyed by radiation damage. Still, recovery of the structure is a challenge, in part due to the partial fragmentation of the sample during the diffraction event. In this study, we use first-principles based methods to study the impact of radiation induced ionization of six amino acids on the reconstruction process. In particular, we study the fragmentation and charge rearrangement to elucidate the time scales involved and the characteristic fragments occurring.

    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-395440 (URN)10.1063/1.5116814 (DOI)000500356200030 ()31615216 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), SNIC 2019/8-30Swedish National Infrastructure for Computing (SNIC), SNIC 2018/3-221Swedish Research Council, 637-2013-7303Swedish Research Council, 2013-3940Swedish Foundation for Strategic Research , ICA16-0037
    Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2024-01-09Bibliographically approved
    2. Imaging of femtosecond bond breaking and charge dynamics in ultracharged peptides
    Open this publication in new window or tab >>Imaging of femtosecond bond breaking and charge dynamics in ultracharged peptides
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    2022 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 24, no 3, p. 1532-1543Article in journal (Refereed) Published
    Abstract [en]

    X-ray free-electrons lasers have revolutionized the method of imaging biological macromolecules such as proteins, viruses and cells by opening the door to structural determination of both single particles and crystals at room temperature. By utilizing high intensity X-ray pulses on femtosecond timescales, the effects of radiation damage can be reduced. Achieving high resolution structures will likely require knowledge of how radiation damage affects the structure on an atomic scale, since the experimentally obtained electron densities will be reconstructed in the presence of radiation damage. Detailed understanding of the expected damage scenarios provides further information, in addition to guiding possible corrections that may need to be made to obtain a damage free reconstruction. In this work, we have quantified the effects of ionizing photon-matter interactions using first principles molecular dynamics. We utilize density functional theory to calculate bond breaking and charge dynamics in three ultracharged molecules and two different structural conformations that are important to the structural integrity of biological macromolecules, comparing to our previous studies on amino acids. The effects of the ultracharged states and subsequent bond breaking in real space are studied in reciprocal space using coherent diffractive imaging of an ensemble of aligned biomolecules in the gas phase.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry (RSC), 2022
    National Category
    Physical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-468649 (URN)10.1039/d1cp03419g (DOI)000733885500001 ()34939631 (PubMedID)
    Funder
    Swedish Research Council, 2018-05973Swedish Research Council, 2019-03935Swedish Research Council, 2018-00740Swedish Foundation for Strategic Research, ICA16-0037Swedish National Infrastructure for Computing (SNIC)
    Available from: 2022-02-28 Created: 2022-02-28 Last updated: 2024-01-09Bibliographically approved
    3. MolDStruct: modelling the dynamics and structure of matter exposed to ultrafast X-ray lasers with hybrid collisional-radiative/molecular dynamics
    Open this publication in new window or tab >>MolDStruct: modelling the dynamics and structure of matter exposed to ultrafast X-ray lasers with hybrid collisional-radiative/molecular dynamics
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We describe a method to compute photon-matter interaction and atomic dynamics with X-ray lasers using a hybrid code based on classical molecular dynamics and collisional-radiative calculations. The forces between the atoms are dynamically computed based on changes to their electronic occupations and the free electron cloud created due to the irradiation of photons in the X-ray spectrum. The rapid transition from neutral solid matter to dense plasma phase allows the use of screened potentials, which reduces the number of non-bonded interactions required to compute. In combination with parallelization through domain decomposition, large-scale molecular dynamics and ionization induced by X-ray lasers can be followed. This method is applicable for large enough samples (solids, liquids, proteins, viruses, atomic clusters and crystals) that when exposed to an X-ray laser pulse turn into a plasma in the first few femtoseconds of the interaction. We show several examples of the applicability of the method and we quantify the sizes that the method is suitable for. For large systems, we investigate non-thermal heating and scattering of bulk water, which we compare to previous experiments. We simulate molecular dynamics of a protein crystal induced by an X-ray pump, X-ray probe scheme, and find good agreement of the damage dynamics with experiments. For single particle imaging, we simulate ultrafast dynamics of a methane cluster exposed to a femtosecond X-ray laser. In the context of coherent diffractive imaging we study the fragmentation as given by an X-ray pump X-ray probe setup to understand the evolution of radiation damage.

    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-519450 (URN)
    Projects
    In thesis
    Funder
    Swedish Research Council, 2018- 00740, 2019-03935
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-09
    4. Anisotropic melting of ice induced by ultrafast non-thermal heating
    Open this publication in new window or tab >>Anisotropic melting of ice induced by ultrafast non-thermal heating
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Water and ice are routinely studied with X-rays to reveal their diverse structures and anomalous properties. We employ a hybrid collisional-radiative/molecular dynamics method to explore how femtosecond X-ray pulses interact with hexagonal ice. We find that ice makes a phase transition into a crystalline plasma where its initial structure is maintained up to tens of femtoseconds. The ultrafast melting process occurs anisotropically, where different geometric configurations of the structure melt on different time scales. The transient state and anisotropic melting of crystals can be captured by X-ray diffraction, which impacts any study of crystalline structures probed by femtosecond X-ray lasers.

    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-519477 (URN)
    Projects
    In thesis
    Funder
    Swedish Research Council, 2017-05128, 2018-00740, 2019-03935Carl Tryggers foundation , CTS 18:392The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-09
    5. Radiation damage in a hemoglobin crystal studied with an X-ray free-electron laser
    Open this publication in new window or tab >>Radiation damage in a hemoglobin crystal studied with an X-ray free-electron laser
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Radiation damage is a topic since the dawn of X-ray crystallography, and has gained new importance in the era of X-ray free-electron lasers (XFELs), due to their unprecedented brilliance and pulse duration. One of the driving questions has been how short the XFEL pulse has to be for the structural information to be ”damage free”. Here we compare data from Serial Femtosecond Crystallography (SFX) experiments conducted with a 3 fs and a 10 fs X-ray pulse. We conclude that even if the estimated displacement of atoms in the sample is an order of magnitude larger in the case of the 10 fs experiment, the displacement is still too small to affect the experimental data at a resolution relevant for structural determination.

    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-519591 (URN)
    Projects
    In thesis
    Funder
    Swedish Research Council, 2018-00740, 2019-03935
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-18
    6. Macromolecule classification using X-ray laser induced fragmentation simulated with hybrid Monte Carlo/Molecular Dynamics
    Open this publication in new window or tab >>Macromolecule classification using X-ray laser induced fragmentation simulated with hybrid Monte Carlo/Molecular Dynamics
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We have developed a hybrid Monte Carlo and classical molecular dynamics code to follow the ultrafast atomic dynamics in biological macromolecules induced by a femtosecond X-ray laser. Our model for fragmentation shows good qualitative agreement with ab-initio simulations of small molecules, while being computationally faster.  We applied the code for macromolecules and simulated the Coulomb explosion dynamics due to the fast ionization in six proteins with different physical properties. The trajectories of the ions are followed and projected onto a detector, where the particular pattern depends on the protein, providing a unique footprint. We utilize algorithms such as principal component analysis  and t-distributed stochastic neighbor embedding to classify the fragmentation pattern. The results show that the classification algorithms are able to separate the explosion patterns into distinct groups. We envision that this method could be used to provide additional class information, like particle mass or shape, in structural determination experiments using X-ray lasers.

    National Category
    Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-519565 (URN)
    Projects
    In thesis
    Funder
    Swedish Research Council, 2018-00740, 2019-03935, 2021-05988
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-09
    7. Structural Heterogeneity in Single Particle Imaging Using X-ray Lasers
    Open this publication in new window or tab >>Structural Heterogeneity in Single Particle Imaging Using X-ray Lasers
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    2020 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 11, no 15, p. 6077-6083Article in journal (Refereed) Published
    Abstract [en]

    One of the challenges facing single particle imaging with ultrafast X-ray pulses is the structural heterogeneity of the sample to be imaged. For the method to succeed with weakly scattering samples, the diffracted images from a large number of individual proteins need to be averaged. The more the individual proteins differ in structure, the lower the achievable resolution in the final reconstructed image. We use molecular dynamics to simulate two globular proteins in vacuum, fully desolvated as well as with two different solvation layers, at various temperatures. We calculate the diffraction patterns based on the simulations and evaluate the noise in the averaged patterns arising from the structural differences and the surrounding water. Our simulations show that the presence of a minimal water coverage with an average 3 Å thickness will stabilize the protein, reducing the noise associated with structural heterogeneity, whereas additional water will generate more background noise.

    National Category
    Biophysics Atom and Molecular Physics and Optics
    Identifiers
    urn:nbn:se:uu:diva-416668 (URN)10.1021/acs.jpclett.0c01144 (DOI)000562064500038 ()32578996 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), SNIC 2019/8-30EU, Horizon 2020, 801406Swedish Research Council, 201800740Australian Research Council, DP190103027
    Available from: 2020-07-28 Created: 2020-07-28 Last updated: 2024-01-09Bibliographically approved
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    UUThesis_Eliah Dawod,I-2024
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  • Public defence: 2024-03-01 09:00 E-22, Visby
    Blyth, Samuel
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Natural Resources and Sustainable Development.
    Casting for Knowledge and Landing Understanding: Exploring the management of Swedish recreational fisheries as social-ecological systems2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The successful management of recreational fisheries must balance ecological, and social goals; select from and implement a range of management tools; operate under often complex governance structures; and contend with diverse human stakeholders’ expectations, desires, and actual behaviour in response to management activities. This complexity also means that there are many knowledge and research gaps regarding the information needed to meet the requirements of specific fisheries. This thesis explores Swedish recreational fisheries as social-ecological systems to help close these gaps, and improve their future management.

    The sea trout (Salmo trutta) fishery around the island of Gotland provides context for investigating the human and ecological dimensions of catch-and-release (C&R), and stock level connections between angler expectations, catches, and spawning returns. This case study first identifies key motivations to retain or release sea trout of legal size, and factors anglers think are important for successful C&R. Then determines which angler-related, fish-related, or environmental factors impact stress levels and injuries for sea trout. Further, it identifies the potential for small changes in anglers harvest preferences to significantly impact mortality rates for an important segment of the spawning population. Taken together these outcomes identify knowledge and behavioural gaps that influence the successful application of C&R in this fishery, and that could affect the achievement of fishery management goals.

    Several opportunities to improve the transfer of information between stakeholder groups in Swedish recreational fisheries are illuminated through an assessment of how best practices for C&R are communicated to anglers, and an evaluation of potential biases generated when collecting data through angler surveys. Communication from freshwater fishery managers to fishing license buyers is deficient in the quality and quantity of information on best practices for C&R. In addition, this is notably poorer for certain fisheries and target species that have very high rates of C&R. In the opposite direction, the collection of information from anglers is also challenging, as common sampling techniques and the grouping of survey responses in recreational fisheries can introduce significant biases that impact how data can be interpreted. These include psychological dimensions of fishing experiences that connect angler motivations and behaviours to fishery management structures.

    This thesis contributes to the knowledge and discussion about sustainably managing recreational fisheries, but the methods to apply this information to existing governance structures and induce positive behavioural change in diverse populations of anglers require further development.

    List of papers
    1. To eat or not to eat, coastal sea trout anglers' motivations and perceptions of best practices for catch and release
    Open this publication in new window or tab >>To eat or not to eat, coastal sea trout anglers' motivations and perceptions of best practices for catch and release
    2022 (English)In: Fisheries Research, ISSN 0165-7836, E-ISSN 1872-6763, Vol. 254, article id 106412Article in journal (Refereed) Published
    Abstract [en]

    The wide variety of perspectives and actions of individual anglers contribute greatly to success or failure when adopting and implementing fisheries management tools. Catch-and-release (C&R) is one such tool where success is influenced by both variation in human factors, but also species and fishery specific characteristics. In this study, an intercept survey of 94 sea trout anglers in a C&R dominated fishery on the Swedish island of Gotland investigated motivations to release or retain catches, self-assessment of anglers' own ability to release fish, and their rating of the importance of various factors influencing the successful outcomes of C&R. Retention of catches was most strongly motivated by situations where anglers deemed the fish unlikely to survive, however more than half of anglers acknowledged being unaware of delayed mortality in released fish. The spawning status of an individual fish was the primary motivation for release, particularly among anglers that prefer to keep at least some of their catches. The roles of water temperature, using single, and barbless hooks were scored as significantly less important than other components contributing to the success of a release. Anglers that gave a favourable rating to their ability to release sea trout also gave greater importance to various factors influencing the success of release, reported higher catch per unit effort, and released a greater proportion of their catches. These findings are discussed in the context of bridging knowledge and behavioural gaps around best practices for C&R in this fishery.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    Keywords
    Catch-and-release, Recreational fisheries, Salmo trutta, Human dimensions, Angling
    National Category
    Ecology Fish and Wildlife Management
    Identifiers
    urn:nbn:se:uu:diva-487109 (URN)10.1016/j.fishres.2022.106412 (DOI)000861667900005 ()
    Funder
    Swedish Research Council Formas, 2016-00227
    Available from: 2022-10-25 Created: 2022-10-25 Last updated: 2024-01-12Bibliographically approved
    2. After the spawn and on the hook: Sea trout Salmo trutta biophysical responses to different components of catch and release in a coastal fishery
    Open this publication in new window or tab >>After the spawn and on the hook: Sea trout Salmo trutta biophysical responses to different components of catch and release in a coastal fishery
    2022 (English)In: Journal of Fish Biology, ISSN 0022-1112, E-ISSN 1095-8649, Vol. 101, no 3, p. 464-477Article in journal (Refereed) Published
    Abstract [en]

    This study investigated the biophysical responses of sea run brown trout Salmo trutta to catch-and-release in the coastal fishery around Gotland, Sweden. It used information recorded on individual angled S. trutta (n = 162), including fight time, handling time, total air exposure time, injury, bleeding, fish length, body condition, spawning status, water temperature, hook location and difficulty of hook removal. Reflex action mortality predictors (equilibrium, operculum beats, tail grab response, body flex response and vestibular-ocular response), tests of blood glucose and lactate, and observation of hooking injury were used to measure the relative impact of the angling event on the fish's physical state and stress experienced. The results of this study suggest low rates of post-release mortality and generally limited stress responses to angling events, and relatively high post-release survival supported by the recapture of many tagged S. trutta. However, a number of scenarios were identified in which stress responses are likely to be compounded and where anglers should take additional action to reduce sublethal physiological disturbances and the risk of delayed mortality. Particular care should be taken to limit cumulative total air exposure to <10 s, and to reduce handling time and risk of additional injury in angling events with extended fight times, when water temperatures >10 degrees C, or where S. trutta show evidence of being physically compromised by injury or having recently spawned. The results also indicate the importance of using appropriately sized single hooks rather than larger treble hooks to reduce hooking injury and handling time during unhooking.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2022
    Keywords
    angler behaviour, angling, catch-and-release, fish impairment, recreational fisheries, stakeholder collaboration
    National Category
    Fish and Aquacultural Science Ecology
    Identifiers
    urn:nbn:se:uu:diva-493284 (URN)10.1111/jfb.15108 (DOI)000816845500001 ()35598067 (PubMedID)
    Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2024-01-12Bibliographically approved
    3. Imagination, reality, and reproduction: Comparing the expectations of coastal sea trout anglers with real catches, and sea trout spawning activity
    Open this publication in new window or tab >>Imagination, reality, and reproduction: Comparing the expectations of coastal sea trout anglers with real catches, and sea trout spawning activity
    (English)Manuscript (preprint) (Other academic)
    National Category
    Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-520541 (URN)
    Available from: 2024-01-12 Created: 2024-01-12 Last updated: 2024-01-12
    4. Informing obligations: Best practice information for catch‐and‐release in Swedish local recreational fisheries management
    Open this publication in new window or tab >>Informing obligations: Best practice information for catch‐and‐release in Swedish local recreational fisheries management
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    2023 (English)In: Fisheries Management and Ecology, ISSN 0969-997X, E-ISSN 1365-2400, Vol. 30, no 3, p. 310-322Article in journal (Refereed) Published
    Abstract [en]

    Catch-and-release (C&R) is a popular management tool that can support sustainable development of recreational fisheries, if anglers adopt scientifically informed “best practices.” However, although the role of best practices is widely established in the academic literature, this knowledge is not always disseminated to anglers. In this paper, we investigated if and to what extent local management organizations provided best practice information to anglers. Based on a sample of 331 Swedish organizations, we reviewed the websites through which these organizations sold fishing licenses. Our review demonstrated widespread use of C&R as a management tool yet a general lack of best practice information. Among the small fraction of organizations that mentioned best practices, most mentioned only a single practice, with little consistency among practices that received attention. In addition, best practice information was particularly lacking for pike (Esox Lucius) and perch (Perca fluviatilis), which are by far the most landed and released species nationally. We discovered major knowledge deficiencies that provide insights about where and how to focus efforts for improving best practice information, in the context of local recreational fisheries management.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2023
    Keywords
    C&R science, hierarchical clustering, inland waters, institutional grammar, local management, mandatory C&R
    National Category
    Other Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-507503 (URN)10.1111/fme.12622 (DOI)000961359800001 ()
    Funder
    Swedish Research Council Formas, 2016-00227Swedish Research Council, 2016-00227
    Available from: 2023-07-06 Created: 2023-07-06 Last updated: 2024-01-12Bibliographically approved
    5. Beyond asking the right questions: Accounting for biases in a recreational fishery survey
    Open this publication in new window or tab >>Beyond asking the right questions: Accounting for biases in a recreational fishery survey
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    selection bias, survey research, human dimensions, fishing motivation, fishing satisfaction, multispecies fishery
    National Category
    Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-520533 (URN)
    Available from: 2024-01-12 Created: 2024-01-12 Last updated: 2024-01-12
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  • Public defence: 2024-03-01 09:00 Heinz-Otto Kreiss Föreläsningssal, Uppsala
    Ravensburg, Anna L.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
    Order and interfaces in epitaxial heterostructures: Structure and magnetism2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work in this dissertation is devoted to investigating order and interfaces in epitaxial heterostructures. To achieve that the software tool box GenL was developed for simulating and fitting x-ray diffraction patterns from epitaxial thin films, which is used to access structural information on the length scales of interfaces and atomic bonds. Employing GenL, it is shown that a small lattice mismatch between substrate and epitaxial layer is not the sole origin of high crystal quality, as demonstrated for nearly strain-free epitaxial growth of tungsten on sapphire with a lattice mismatch of up to 19.4 %. Furthermore, it is discussed that electronic states at the substrate/film interface can have substantial significance for the crystal structure of an epitaxial layer. For instance, despite a nearly mismatch-free interface of body-centered cubic iron on spinel, the presence of a boundary-induced interface layer with tetragonally distorted crystal structure is discovered, which has a profound impact on the magnetic properties. Finally, when creating multilayered structures, not only the interface states but the total structure is found to influence the physical properties, which is demonstrated for the interlayer exchange coupling in [Fe/MgO]N superlattices.

    List of papers
    1. GENL: An extensible fitting program for Laue oscillations
    Open this publication in new window or tab >>GENL: An extensible fitting program for Laue oscillations
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    GENL is a flexible program that can be used to simulate and/or fit x-ray diffraction data from epitaxial thin films exhibiting Laue oscillations. It utilizes differential evolution within a genetic algorithm for the fitting of data and is based on the kinematic theory of diffraction. Effects of polarization, absorption, the Lorentz factor, as well as instrumental resolution and vibrations are taken into account. Useful parameters that can be extracted after fitting include: atomic interplanar spacings, number of coherently scattering atomic planes, strain profiles along the film thickness, and crystal roughness. The program has been developed in MATLAB and employs a graphical user interface. The deployment strategy is twofold whereby the software can either be obtained in source code form and executed within the MATLAB environment, or as a pre-compiled binary for those who prefer not to run it within MATLAB. Finally, GENL can easily be extended to simulate multilayered film systems, superlattices, and films with atomic steps. The program is released under the GNU General Public Licence. 

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-520681 (URN)10.48550/arXiv.2310.13539 (DOI)
    Available from: 2024-01-14 Created: 2024-01-14 Last updated: 2024-01-15
    2. Influence of misfit strain on the physical properties of Fe thin films
    Open this publication in new window or tab >>Influence of misfit strain on the physical properties of Fe thin films
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    2022 (English)In: Thin Solid Films, ISSN 0040-6090, E-ISSN 1879-2731, Vol. 761, article id 139494Article in journal (Refereed) Published
    Abstract [en]

    We investigate the growth of thin Fe layers on MgAl2O4 (001) and MgO (001) substrates using dc magnetron sputtering. The crystal quality of Fe layers deposited on MgAl2O4 is found to be substantially higher as compared to Fe grown on MgO substrates. The effects of the crystal quality on the magnetic and electric transport properties are discussed. 

    Place, publisher, year, edition, pages
    Elsevier, 2022
    National Category
    Condensed Matter Physics
    Research subject
    Physics
    Identifiers
    urn:nbn:se:uu:diva-473435 (URN)10.48550/arXiv.2204.02286 (DOI)000867640600006 ()
    Funder
    Swedish Research Council, 2019-03581Swedish Research Council, 2019-05379Swedish Energy Agency, 2020-005212
    Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2024-01-15Bibliographically approved
    3. Boundary-induced phase in epitaxial iron layers
    Open this publication in new window or tab >>Boundary-induced phase in epitaxial iron layers
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We report the discovery of a boundary-induced body-centered tetragonal (bct) iron phase in thin films deposited on MgAl2O4 (001) substrates. We present evidence for this phase using detailed x-ray analysis and ab-initio density functional theory calculations. A lower magnetic moment and a rotation of the easy magnetisation direction are observed, as compared to body-centered cubic (bcc) iron. Our findings expand the range of known crystal and magnetic phases of iron, providing valuable insights for the development of heterostructure devices using ultra-thin iron layers. 

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-520682 (URN)
    Available from: 2024-01-14 Created: 2024-01-14 Last updated: 2024-01-15
    4. Epitaxy enhancement in oxide/tungsten heterostructures by harnessing the interface adhesion
    Open this publication in new window or tab >>Epitaxy enhancement in oxide/tungsten heterostructures by harnessing the interface adhesion
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    2024 (English)In: Applied Physics A: Materials Science & Processing, ISSN 0947-8396, E-ISSN 1432-0630, Vol. 130, no 2, article id 74Article in journal (Refereed) Published
    Abstract [en]

    The conditions whereby epitaxy is achieved are commonly believed to be mostly governed by misfit strain. We report on a systematic investigation of growth and interface structure of single crystalline tungsten thin films on two different metal oxide substrates, Al2O3 (11‾20) and MgO (001). We demonstrate that despite a significant mismatch, enhanced crystal quality is observed for tungsten grown on the sapphire substrates. This is promoted by stronger adhesion and chemical bonding with sapphire compared to magnesium oxide, along with the restructuring of the tungsten layers close to the interface. The latter is supported by ab initio calculations using density functional theory. Finally, we demonstrate the growth of magnetic heterostructures consisting of high-quality tungsten layers in combination with ferromagnetic CoFe layers, which are relevant for spintronic applications.

    Place, publisher, year, edition, pages
    Springer, 2024
    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-520683 (URN)10.1007/s00339-023-07212-w (DOI)001137900100005 ()
    Funder
    Swedish Research Council, 2019-03581Swedish Research Council, 2021-0465Swedish Energy Agency, 2020-005212Olle Engkvists stiftelse, 217-0023National Academic Infrastructure for Supercomputing in Sweden (NAISS)Swedish Research Council, 2022-06725
    Available from: 2024-01-14 Created: 2024-01-14 Last updated: 2024-01-31Bibliographically approved
    5. The effect of iron layer thickness on the interlayer exchange coupling in Fe/MgO (001) superlattices
    Open this publication in new window or tab >>The effect of iron layer thickness on the interlayer exchange coupling in Fe/MgO (001) superlattices
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We describe the effect of the Fe layer thickness on the antiferromagnetic interlayer exchange coupling in [Fe/MgO]N superlattices. An increase in coupling strength with increasing Fe layer thickness is observed, which highlights the need of including the extension of both the layers when discussing the interlayer exchange coupling in superlattices.

    National Category
    Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-520684 (URN)
    Available from: 2024-01-14 Created: 2024-01-14 Last updated: 2024-01-15
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  • Public defence: 2024-03-01 09:15 Häggsalen - Ångströmlaboratory, Uppsala
    Osinger, Barbara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry.
    Investigation of compositionally complex refractory metal based thin films2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The search for new and improved materials has led to the discovery and establishment of compositionally complex or high-entropy materials. The work in this thesis is focused on the investigation of new compositionally complex materials based on the refractory metals of groups 4-6. The materials in this work were synthesised using non-reactive dc magnetron sputtering and three material systems have been studied: HfNbTiVZr-C, CrTiTaWNb-C and Nb-Mo-C. In the context of compositionally complex materials, this thesis aims to contribute specifically to questions regarding (i) the prediction of phase formation and stability (ii) the chemical interaction between atoms (iii) the correlation between the material properties and compositional complexity. 

    The prediction of phase formation and stability using calculated phase diagram (CALPHAD) methods was studied in the HfNbTiVZr-C system. The findings suggest that CALPHAD methods are promising predictive tools, although kinetic effects during synthesis need to be taken into consideration. Furthermore, theoretical, and experimental evidence of charge transfer effects was demonstrated within the HfNbTiVZr-C system. The results of ab initio materials simulations and X-ray Photoelectron Spectroscopy (XPS) measurements highlight the importance of understanding and considering the local chemical environment and chemical interactions in compositionally complex materials.

    The approach of metal alloying according to the valence electron concentration (VEC) to tune the mechanical properties was studied in the Nb-Mo-C system. The findings show the importance of microstructural effects on the mechanical properties in the studied thin film materials, which can overshadow the compositional or VEC variations. 

    The response to Xe heavy-ion irradiation was studied in the CrTiTaWNb-C system using in situ irradiation experiments. This work presents a comparison between three different compositions: a TaW-rich alloy and carbide thin film as well as a near-equimolar carbide film. The findings indicate that both microstructure and chemical homogeneity play important roles when it comes to radiation damage tolerance in compositional complex materials.

    This thesis demonstrates the elaborate and multifaceted nature of compositionally complex materials. Whether it comes to the fundamental understanding or the effective implementation of a materials design tool, many factors need to be taken into consideration, including chemical interactions between the constituent elements and microstructural effects.

    List of papers
    1. Investigation of the phase formation in magnetron sputtered hard multicomponent (HfNbTiVZr)C coatings
    Open this publication in new window or tab >>Investigation of the phase formation in magnetron sputtered hard multicomponent (HfNbTiVZr)C coatings
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    2022 (English)In: Materials & design, ISSN 0264-1275, E-ISSN 1873-4197, Vol. 221, article id 111002Article in journal (Refereed) Published
    Abstract [en]

    Multicomponent carbides have gained interest especially for ultra-high temperature applications, due to their ceramic hardness, good oxidation resistance and enhanced strength. In this study the phase forma-tion, stability and mechanical properties of (HfNbTiVZr)C multicomponent carbide coatings were inves-tigated. Phase stability was predicted by the CALPHAD (CALculation of PHAse Diagrams) methods. This revealed that the multicomponent solid solution phase is only stable at elevated temperatures, namely above 2400 degrees C. At lower temperatures a phase mixture was predicted, with a particular tendency for V to segregate. Magnetron sputtered thin films deposited at 300 degrees C exhibited a single NaCl-type multicom-ponent carbide phase, which attributes to the kinetic stabilisation of simple structures during thin film growth. Films deposited at 700 degrees C, or exposed to UHV annealing at 1000 degrees C, however, revealed the decom-position of the single-phase multicomponent carbide by partial elemental segregation and formation of additional phases. Thus, confirming the CALPHAD predictions. These results underscore the importance of explicitly considering temperature when discussing the stability of multicomponent carbide materials, as well as the applicability of CALPHAD methods for predicting phase formation and driving forces in these materials. The latter being crucial for designing materials, such as carbides, that are used in appli-cations at elevated temperatures.

    Place, publisher, year, edition, pages
    ElsevierElsevier BV, 2022
    Keywords
    High entropy ceramics, Multi -principal element carbide, Multicomponent carbide, Physical vapour deposition (PVD), CALPHAD
    National Category
    Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-482676 (URN)10.1016/j.matdes.2022.111002 (DOI)000839257000004 ()
    Funder
    Swedish Research Council, 2018-04834Swedish Research CouncilSwedish Research Council, 2017-00646_9Swedish Foundation for Strategic Research, RIF14-0053
    Available from: 2022-09-07 Created: 2022-09-07 Last updated: 2024-01-15Bibliographically approved
    2. Experimental and theoretical evidence of charge transfer in multi-component alloys: how chemical interactions reduce atomic size mismatch
    Open this publication in new window or tab >>Experimental and theoretical evidence of charge transfer in multi-component alloys: how chemical interactions reduce atomic size mismatch
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    2021 (English)In: Materials Chemistry Frontiers, E-ISSN 2052-1537, Vol. 5, no 15, p. 5746-5759Article in journal (Refereed) Published
    Abstract [en]

    Ab initio simulations of a multi-component alloy using density functional theory (DFT) were combined with experiments on thin films of the same material using X-ray photoelectron spectroscopy (XPS) to study the connection between the electronic and atomic structures of multi-component alloys. The DFT simulations were performed on an equimolar HfNbTiVZr multi-component alloy. Structure and charge transfer were evaluated using relaxed, non-relaxed, as well as elemental reference structures. The use of a fixed sphere size model allowed quantification of charge transfer, and separation into different contributions. The charge transfer was generally found to follow electronegativity trends and results in a reduced size mismatch between the elements, and thus causes a considerable reduction of the lattice distortions compared to a traditional assumption based on tabulated atomic radii. A calculation of the average deviation from the average radius (i.e. the so-called δ-parameter) based on the atomic Voronoi volumes gave a reduction of δ from ca. 6% (using the volumes in elemental reference phases) to ca. 2% (using the volumes in the relaxed multi-component alloy phase). The reliability of the theoretical results was confirmed by XPS measurements of a Hf22Nb19Ti18V19Zr21 thin film deposited by sputter deposition. The experimentally observed core level binding energy shifts (CLS), as well as peak broadening due to a range of chemical surroundings, for each element showed good agreement with the calculated DFT values. The single solid solution phase of the sample was confirmed by X-ray diffraction (XRD) and transmission electron microscopy (TEM) including energy dispersive spectroscopy (EDS) with nm-resolution. These observations show that the HfNbTiVZr solid solution phase is non-ideal, and that chemical bonding plays an important part in the structure formation, and presumably also in the properties. Our conclusions should be transferable to other multi-component alloy systems, as well as some other multi-component material systems, and open up interesting possibilities for the design of material properties via the electronic structure and controlled charge transfer between selected metallic elements in the materials.

    Place, publisher, year, edition, pages
    Royal Society of ChemistryRoyal Society of Chemistry (RSC), 2021
    National Category
    Materials Chemistry Condensed Matter Physics
    Identifiers
    urn:nbn:se:uu:diva-468314 (URN)10.1039/d1qm00380a (DOI)000664149100001 ()
    Funder
    Swedish Research Council, 2018-04834Swedish Research Council, 2019-05403Swedish Research Council, 2018-05973Swedish Research Council, 2019-05487Knut and Alice Wallenberg Foundation, KAW-2018.0194Swedish Foundation for Strategic Research , FFL 15-0290Swedish National Infrastructure for Computing (SNIC)
    Available from: 2022-02-25 Created: 2022-02-25 Last updated: 2024-01-15Bibliographically approved
    3. Charge transfer effects in (HfNbTiVZr)C – shown by ab-initio calculations and X-ray photoelectron spectroscopy
    Open this publication in new window or tab >>Charge transfer effects in (HfNbTiVZr)C – shown by ab-initio calculations and X-ray photoelectron spectroscopy
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    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    Considering charge transfer effects and the variability of the bonding between elements with different electronegativity opens up a deeper understanding of the electronic structure and as a result many of the properties in high entropy related materials. This study investigates the importance of the diverse bonding and chemical environments when discussing multicomponent carbide materials. A combination of ab initio calculations and X-ray photoelectron spectroscopy (XPS) was used to investigate the electronic structure of multicomponent thin films based on the (HfNbTiVZr)C system. The charge transfer was quantified theoretically using relaxed and non-relaxed multicomponent as well as binary carbide reference structures, employing a fixed sphere model. High-resolution XPS spectra from (HfNbTiVZr)C magnetron sputtered thin films displayed core level binding energy shifts and broadening effects as a result of the complex chemical environment. Charge transfer effects and a changed electronic structure in the multicomponent material, compared with the reference binary carbides, are observed both experimentally and in the DFT simulations. The observed effects loosely follow electronegativity considerations, leading to a deviation from an ideal solid solution structure assuming non-distinguishable chemically equivalent environments. 

    Keywords
    DFT, Magnetron sputtering, Multicomponent carbide, X-ray Photoelectron spectroscopy, Charge transfer
    National Category
    Materials Chemistry
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-517270 (URN)
    Available from: 2024-01-09 Created: 2024-01-09 Last updated: 2024-01-19
    4. Structural and mechanical properties of magnetron sputtered (NbxMo1-x)C thin films
    Open this publication in new window or tab >>Structural and mechanical properties of magnetron sputtered (NbxMo1-x)C thin films
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    (English)In: Article in journal (Other academic) Submitted
    Abstract [en]

    While transition metal carbides (TMCs) exhibit favourable mechanical properties, alloying according to the valence electron concentration (VEC) has the potential to further enhance the properties of these hard but inherently brittle materials. This study investigates the influence of alloying on the microstructure and mechanical properties of (NbxMo1-x)C carbide films, including binary references and ternary compositions with varying metal ratios (x between 0.35 and 0.52). Furthermore, the influence of various substrate materials is studied by comparing films deposited on Al2O3, MgO and SiO2. All films exhibit a NaCl-type carbide structure and X-ray photoelectron spectroscopy revealed the presence of small amounts of an additional amorphous carbon (a-C) phase. Hardness values around 20 ± 2 GPa were obtained for the films on Al2O3 and MgO, whereas a reduced hardness of 11 ± 1 GPa was observed for the films on SiO2 which is attributed to larger crystallite size and more polycrystalline structure. Overall no clear trend as a function of composition can be noted, indicating that microstructure effects dominate the mechanical properties in this study overshadowing the effect of varying the metal content.

    Keywords
    Magnetron sputtering, Ceramic coating, Transition metal carbides, Mechanical properties
    National Category
    Materials Chemistry
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-517298 (URN)
    Available from: 2024-01-09 Created: 2024-01-09 Last updated: 2024-01-12
    5. From high-entropy alloys to high-entropy ceramics: The radiation-resistant highly concentrated refractory carbide (CrNbTaTiW)C
    Open this publication in new window or tab >>From high-entropy alloys to high-entropy ceramics: The radiation-resistant highly concentrated refractory carbide (CrNbTaTiW)C
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    2023 (English)In: Acta Materialia, ISSN 1359-6454, E-ISSN 1873-2453, Vol. 250, article id 118856Article in journal (Refereed) Published
    Abstract [en]

    High-entropy materials represent the state-of-the-art on the alloy design strategy for future applications in extreme environments. Recent data indicates that high-entropy alloys (HEAs) exhibit outstanding radiation resistance in face of existing diluted alloy counterparts due to suppressed damage formation and evolution. An extension of the HEA concept is presented in this paper towards the synthesis and characterization of novel high-entropy ceramics as emergent materials for application in environments where energetic particle irradiation is a major concern. A novel carbide within the quinary refractory system CrNbTaTiW has been synthesized using magnetron-sputtering. The material exhibited nanocrystalline grains, single-phase crystal structure and C content around 50 at.%. Heavy-ion irradiation with in-situ Transmission Electron Microscopy was used to assess the irradiation response of the new high-entropy carbide (HEC) at 573 K and a comparison with the HEA within the system is made. No displacement damage effects appear within the microstructures of both HEA and HEC up to a dose of 10 displacements-per-atom. Surprisingly, the HEC has not amorphized under the investigated conditions. Xe was implanted in both materials and bubbles nucleated, but smaller sizes compared with conventional nuclear materials shedding light they are potential candidates for use in nuclear energy.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    High-entropy ceramics, High-entropy alloys, Nanocrystalline materials, Radiation damage, Extreme environments
    National Category
    Materials Engineering
    Identifiers
    urn:nbn:se:uu:diva-499313 (URN)10.1016/j.actamat.2023.118856 (DOI)000958714700001 ()
    Funder
    EU, European Research Council, 757961Swedish Research Council, 2017-00646_9Swedish Research Council, 2019_00191Swedish Foundation for Strategic Research, RIF14-0053
    Available from: 2023-03-27 Created: 2023-03-27 Last updated: 2024-01-11Bibliographically approved
    6. Probing the high entropy concept through the irradiation response of near-equimolar (CrTiTaWNb)C ceramic coatings
    Open this publication in new window or tab >>Probing the high entropy concept through the irradiation response of near-equimolar (CrTiTaWNb)C ceramic coatings
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    High-entropy ceramics, Coatings, radiation damage, extreme environments
    National Category
    Materials Chemistry
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-517271 (URN)
    Available from: 2024-01-07 Created: 2024-01-07 Last updated: 2024-01-11
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  • Public defence: 2024-03-01 09:15 H:son Holmdahl-salen, Uppsala
    Okhiria, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Articulation and velopharyngeal function in patients with cleft lip and/or palate: Outcome predictors2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cleft lip and/or palate is the most common congenital craniofacial malformation, requiring multidisciplinary treatment, including surgery and often speech therapy. Palatal surgery restores the anatomical barrier between the oral and nasal cavities as well as the palatal function needed for normal speech.

    The present thesis aimed to investigate factors thought to impact surgical and speech outcomes. These factors include the timing of surgery, surgical technique, the surgeon's experience, cleft type, and cleft width.

    Study I investigated the impact of cleft type and width on velopharyngeal function (VPF) and secondary surgery rates from ages three to 16. Cleft width was associated with increased surgery rates and signs of velopharyngeal insufficiency (VPI) at ages three and five. Contrary to some previous studies, surgery rates and speech outcomes were not associated with cleft type at any age.

    Study II examined VPF and articulation development between ages five and ten in children adopted from China compared to Swedish-born children. Adoptees had palatoplasty later and had more severe articulation difficulties at both ages. The number of adoptees and non-adoptees with VPI was similar, but fewer adoptees had competent VPF.

    Study III explored different types of intra-velar veloplasty and the impact of cleft width and surgeon experience on outcomes in 5-year-old children. Radical muscle dissection was not superior to intra-velar veloplasty reinforced by the palatopharyngeal muscle. Cleft width had a more significant impact on secondary surgery rates and VPF than did surgical technique—neither affected articulation proficiency.

    Study IV examined the association between cleft type and width and surgical and speech outcomes, especially articulation, in 5-year-old children. Cleft width, not type, indicated articulation proficiency. The same errors occurred across all cleft types. Neither cleft type nor width was significantly associated with secondary surgery rates or VPF.

    The present thesis highlights the importance of considering various factors when predicting secondary palatal surgery rates and speech outcomes. Cleft width significantly affects secondary surgery rates, VPF, and articulation proficiency, while cleft type and surgical technique do not. Adopted children are at higher risk of persistent articulation errors, which may partly be due to their later palatoplasty. 

    List of papers
    1. Greater Palatal Cleft Width Predicts an Increased Risk for Unfavorable Outcomes in Cleft Palate Repair.
    Open this publication in new window or tab >>Greater Palatal Cleft Width Predicts an Increased Risk for Unfavorable Outcomes in Cleft Palate Repair.
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    2022 (English)In: The Cleft Palate-Craniofacial Journal, ISSN 1055-6656, E-ISSN 1545-1569, Vol. 59, no 8, p. 1030-1037Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate the impact of cleft width and cleft type on the need for secondary surgery and velopharyngeal competence from a longitudinal perspective.

    DESIGN: Retrospective, longitudinal study.

    SETTING: A single multidisciplinary craniofacial team at a university hospital.

    PATIENTS: Consecutive patients with unilateral or bilateral cleft lip and palate and cleft palate only (n = 313) born from 1984 to 2002, treated with 2-stage palatal surgery, were reviewed. A total of 213 patients were included.

    MAIN OUTCOME MEASURES: The impact of initial cleft width and cleft type on secondary surgery. Assessment of hypernasality, audible nasal emission, and glottal articulation from routine follow-ups from 3 to 16 years of age. The assessments were compared with reassessments of 10% of the recordings.

    RESULTS: Cleft width, but not cleft type, predicted the need for secondary surgery, either due to palatal dehiscence or velopharyngeal insufficiency. The distribution of cleft width between the scale steps on a 4-point scale for hypernasality and audible nasal emission differed significantly at 5 years of age but not at any other age. Presence of glottal articulation differed significantly at 3 and 5 years of age. No differences between cleft types were seen at any age for any speech variable.

    CONCLUSIONS: Cleft width emerged as a predictor of the need for secondary surgery as well as more deviance in speech variables related to velopharyngeal competence during the preschool years. Cleft type was not related to the need for secondary surgery nor speech outcome at any age.

    Place, publisher, year, edition, pages
    Sage, 2022
    Keywords
    cleft type, cleft width, nasality, secondary surgery, speech production, velopharyngeal competence, velopharyngeal function
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-459538 (URN)10.1177/10556656211029537 (DOI)000705465500001 ()34259078 (PubMedID)
    Available from: 2021-11-25 Created: 2021-11-25 Last updated: 2024-01-23Bibliographically approved
    2. Longitudinal data on speech outcomes in internationally adopted children compared with non‐adopted children with cleft lip and palate
    Open this publication in new window or tab >>Longitudinal data on speech outcomes in internationally adopted children compared with non‐adopted children with cleft lip and palate
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    2023 (English)In: International journal of language and communication disorders, ISSN 1368-2822, E-ISSN 1460-6984, Vol. 58, no 5, p. 1440-1453Article in journal (Refereed) Published
    Abstract [en]

    Background: At the beginning of the 21st century, international adoptions of children with cleft lip and/or palate increased dramatically in Sweden. Many children arrived partially or totally unoperated, despite being at an age when palatoplasty has usually been performed. To date, the speech development of internationally adopted (IA) children has been described up to age 7–8 years, but later development remains unstudied.

    Aims: To investigate speech development between ages 5 and 10 years in children born with cleft lip and palate (CLP) adopted from China and to compare them with non-adopted (NA) children with CLP. A secondary aim was to compare the frequencies of secondary palatal surgery and number of visits to a speech and language pathologist (SLP) between the groups.

    Methods & Procedures: In a longitudinal study, 23 IA children from China were included and matched with 23 NA children born in Sweden. Experienced SLPs blindly reassessed audio recordings from routine follow-ups at ages 5 and 10 years. Velopharyngeal function (VPF) was assessed with the composite score for velopharyngeal competence (VPC-Sum) for single words and rated on a three-point scale (VPC-Rate) in sentence repetition. Target sounds in words and sentences were phonetically transcribed. Per cent correct consonants (PCC) were calculated at word and sentence levels. For in-depth analyses, articulation errors were divided into cleft speech characteristics (CSCs), developmental speech characteristics (DSCs) and s-errors. Information on secondary palatal surgery and number of visits to an SLP was collected.

    Outcomes & Results: VPF differed significantly between the groups at both ages when assessed with VPC-Sum, but not with VPC-Rate. Regardless of the method for assessing VPF, a similar proportion in both groups had incompetent VPF but fewer IA than NA children had competent VPF at both ages. IA children had lower PCC at both ages at both word and sentence levels. More IA children had CSCs, DSCs and s-errors at age 5 years, and CSCs and s-errors at age 10. The development of PCC was significant in both groups between ages 5 and 10 years. The proportion of children receiving secondary palatal surgery did not differ significantly between the groups, nor did number of SLP visits.

    Conclusions & and Implications: CSCs were more persistent in IA children than in NA children at age 10 years. Interventions should target both cleft and DSCs, be comprehensive and continue past the pre-school years.

    Place, publisher, year, edition, pages
    Wiley, 2023
    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-511350 (URN)10.1111/1460-6984.12869 (DOI)000949286400001 ()
    Available from: 2023-09-12 Created: 2023-09-12 Last updated: 2024-01-23Bibliographically approved
    3. The impact of surgical technique and cleft width on the rate of secondary surgery and velopharyngeal function
    Open this publication in new window or tab >>The impact of surgical technique and cleft width on the rate of secondary surgery and velopharyngeal function
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-517722 (URN)
    Available from: 2023-12-12 Created: 2023-12-12 Last updated: 2024-01-14
    4. Associations between cleft type and width and the rate of secondary palatal surgery and articulation proficiency in 5-year-olds with cleft lip and/or palate
    Open this publication in new window or tab >>Associations between cleft type and width and the rate of secondary palatal surgery and articulation proficiency in 5-year-olds with cleft lip and/or palate
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-517194 (URN)
    Available from: 2023-12-05 Created: 2023-12-05 Last updated: 2024-01-14
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  • Public defence: 2024-03-01 10:15 Uppsala University Sal IX, Uppsala
    Bùi, Victoria
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Public Policy Exception and Arbitrability Defence under the New York Convention 1958: A study of public policy and arbitrability, including empirical evidence of national court decisions2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis investigates the public policy exception and arbitrability defence under the Convention on the Recognition and Enforcement of Foreign Arbitral Awards (“New York Convention 1958”) in international commercial arbitration. It examines the varied notions of public policy, including domestic/national, international, and transnational public policy, and scrutinises the nuances of the arbitrability concept, noting a distinct approach in the U.S. The study also investigates the relationship between public policy and arbitrability.  

    The New York Convention 1958 advocates a pro–enforcement policy, urging its Member States to interpret and apply the limited grounds for refusing recognition and enforcement of arbitral awards restrictively. Over time, this pro–enforcement approach has evolved into a consensus, yet there is a lack of empirical evidence substantiating this widely held view. The study seeks evidence-based law insights on the consensus.

    The research comprises three steps: first, examining the general notions of public policy and arbitrability. Second, analysis of specific provisions of the New York Convention 1958 related to public policy and arbitrability, along with the UNCITRAL Model Law’s role in attempting to shape Member States’ arbitration legislations. It highlights the very great diversity of interpretation and applications by different Member States due to their varied legal, cultural, and economic backgrounds. Last, investigation of the enforcement friendly stance, through a quantitative study of national court decisions. It analyses the frequency and success rates of the public policy and arbitrability defences. The findings suggest, contrary to the conclusion one would reach from a study limited to the diversity of interpretation and application noted above, that there is in fact a strong pro–enforcement approach, with only 11% of cases successfully invoking the public policy or inarbitrability defences in challenged proceedings.

    This study brings to the surface the unexpectedly strong influence of the New York Convention 1958 and the Model Law in achieving consensus despite the diversity highlighted. It contributes to the understanding of public policy and arbitrability as concepts as well as defences, underscoring their application in different legal contexts and providing empirical evidence on the pro–enforcement spirit. The study’s insights offer suggestions for future research and legislative development in this field.

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  • Public defence: 2024-03-01 13:00 Hambergsalen, Uppsala
    Joshi, Niranjan
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Bias-adjusted analysis of global natural disaster records and an assessment of seismic hazard in Sweden2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Natural disasters pose significant challenges today and demand efficient allocation of society’s limited resources for disaster risk reduction. This relies on analysis of natural disaster records, which are prone to (reporting) biases that can affect the inferences drawn from their analysis. Data incompleteness is common in earthquake seismology, and, with a starting point in the Gutenberg-Richter law, this thesis studies the power-law behaviour between fatalities and the frequency of global natural disasters recorded by EM-DAT from 1900 to 2020. 

    Analysing, first, the power-law behaviour of global earthquake frequency and magnitude reveals overlapping patterns, and apparent improved reporting completeness over the studied periods, implying any increase in recorded earthquakes is a reporting artefact. Similarly, “frequency-magnitude” analysis of earthquake disasters shows power-law behaviour and an almost-unchanged distribution of fatalities over time, which also implies improved reporting. Similar analysis of hydro-meteorological disasters in EM-DAT shows their substantially increased number with time to be a reporting artefact driven by improved reporting of low-fatality disasters. The increasing gradient of the power-law part of the frequency-magnitude graphs implies that the worst events have become less fatal on average.  

    Climate-related disaster risk reduction actions have thus been very successful, resulting in a continuous decline in aggregate associated fatalities, to the extent that earthquakes have been the most fatal natural disasters over the last few decades.  Notably, while the earthquake magnitude distribution is dominated by earthquakes in high-seismicity zones, fatalities predominantly occur in low-seismicity intraplate regions. This implies that seismic hazard in Sweden, an intraplate area, may be significant, especially as earthquakes as large as M8 have occurred in its recent deglaciation phase. Hazard analysis based on data from the recently expanded Swedish seismic network clearly unveils significant hazard posed by Post-Glacial faults in the North. 

    This research advances our understanding of natural disaster dynamics, emphasizing the necessity for non-conventional methodologies to analyze historical data. It offers important insights to help form effective disaster risk reduction strategies, particularly in the context of seismic hazard assessment for specific regions like Sweden.

    List of papers
    1. Earthquake disaster fatality data: Temporally stable power-law behavior and effects of underreporting
    Open this publication in new window or tab >>Earthquake disaster fatality data: Temporally stable power-law behavior and effects of underreporting
    (English)In: Seismological Research Letters, ISSN 0895-0695, E-ISSN 1938-2057Article in journal (Refereed) Submitted
    Abstract [en]

    We investigate changes in the global reported fatalities from earthquake disasters in theleading global disaster database EM-DAT. Drawing parallels with the Gutenberg-Richterfrequency-magnitude analysis, in terms of disaster frequency versus the number of casual-ties, we see a significant overlap of the curves and improving levels of completeness oversix 20-year periods. This implies a decrease in underreporting with time. We find that theapparent strong upwards trend in the number of (reported) earthquake disasters in EM-DATis caused by a gradually improved reporting primarily of events killing fewer than 10 peo-ple. An implication of our findings is that the true (reported and unreported) number ofearthquake disasters, according to the EM-DAT definition, has been surprisingly constantover, at least, the last 100 years. We also show that the average annual number of peoplekilled in earthquake disasters is relatively unaffected by spurious trends in reporting, and hasremained remarkably constant, at least since the 1960s, despite population increase.

    National Category
    Geophysics
    Identifiers
    urn:nbn:se:uu:diva-517254 (URN)
    Available from: 2023-12-06 Created: 2023-12-06 Last updated: 2023-12-13
    2. Incompleteness of natural disaster data and its implications on the interpretation of trends
    Open this publication in new window or tab >>Incompleteness of natural disaster data and its implications on the interpretation of trends
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We use data from a leading global database, primarily the reported numbers of disasters of different types and associated fatalities, to elucidate long-term trends in natural disaster impact. There are very strong upward trends in the number of reported disasters. However, we show that these trends are strongly biased by progressively improving reporting. Applying established methods based on analysing evolving differences in the patterns of large (many fatality) to small (fewer fatality) events can be used to compensate for this bias. For all disaster types investigated the long-term (multi-decade) true number of disasters appears to be unexpectedly stable over time, albeit with a significant temporary increase 1980-90. However, the corresponding numbers for the total number of fatalities from the weather-related disasters have declined strongly, due to very effective mitigation for  larger disasters. Data for the recent decades shows a systematic decrease in the number of larger (more fatality) disasters compared to smaller. In contrast, for the geophysical disasters, predominantly earthquakes, the relative numbers of larger versus smaller disasters is fairly constant, as are total fatalities.

    National Category
    Other Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-517255 (URN)
    Available from: 2023-12-06 Created: 2023-12-06 Last updated: 2023-12-13
    3. Probabilistic Seismic Hazard Assessment of Sweden
    Open this publication in new window or tab >>Probabilistic Seismic Hazard Assessment of Sweden
    (English)In: Natural hazards and earth system sciences, ISSN 1561-8633, E-ISSN 1684-9981Article in journal (Refereed) Submitted
    Abstract [en]

    Assessing seismic hazard in stable continental regions (SCR) such as Sweden poses unique challenges compared to active seismic regions. With diffuse seismicity, low seismicity rate, few large magnitude earthquakes and little strong motion data, estimating recurrence parameters and determining appropriate attenuation relationships is challenging. This study presents a probabilistic seismic hazard assessment of Sweden based on a recent earthquake catalogue which includes a large number of events with magnitudes ranging from 5.9 to -1.4, enabling recurrence parameters to be calculated for more source areas than in previous studies, and with less uncertainty. Recent ground motion models developed specifically for stable continental regions, including Fennoscandia, are used in logic trees accounting for their uncertainty and the hazard is calculated using the OpenQuake engine.The results are presented in the form of mean peak ground acceleration (PGA) maps at 475 and 2500 year return periods and hazard curves for four seismically active areas in Sweden. We find the highest hazard in the northernmost part of the country, in the post-glacial fault province. This is in contrast to previous studies, which have not considered the high seismic activity on the post-glacial faults. We also find relatively high hazard along the northeast coast and in southwestern Sweden, whereas the southeast and the mountain region to the northwest have low hazard.For a 475 year return period we estimate the highest PGAs to be 0.04-0.05g, in the far north, and for a 2500 year return period it is 0.1-0.15g in the same area. Significant uncertainties remain to be addressed in regards to the SCR seismicity in Sweden, including the homogenization of small local magnitudes with large moment magnitudes, the occurrence of large events in areas with little prior seismicity and the uncertainties surrounding the potential for large earthquakes on the post-glacial faults in northern Fennoscandia.

    National Category
    Geophysics
    Identifiers
    urn:nbn:se:uu:diva-517256 (URN)
    Available from: 2023-12-06 Created: 2023-12-06 Last updated: 2023-12-06
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  • Public defence: 2024-03-01 13:15 Bibliotekets föreläsningssal, Falun
    Ahlström, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The epidemiology of risk factors and short- and long-term outcome in the Swedish intensive care cohort2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The sepsis syndrome is present in ¼ to ⅓ of patients in intensive care units (ICUs) worldwide. The short-term prognosis is grim, with a 30-day mortality of 30–35%; however, the long- term outcomes are now being explored, as multi-professional follow-up after ICU care is increasingly being implemented. In 2020 the first and second waves of another severe infection, the Coronavirus disease 2019 (Covid-19) hit Sweden. The number of ICU beds were scaled up by several hundred percent while we simultaneously tried to understand the disease. Reports on risk factors for adverse outcomes in Covid-19 started to appear, but we needed to know more. Thus, we initiated this project aiming at assessing sepsis as an independent risk factor for later morbidity and mortality. Subsequently, with the onset of the pandemic, our focus shifted to identifying risk factors for adverse outcomes in Covid-19 and describing the functional recovery after severe Covid-19. We used the Swedish Intensive Care Registry and several governmental registries to this end.

    In Cox regression, we compared one-year ICU sepsis survivors without previous dementia with ICU patients without sepsis, finding no increased risk of dementia during follow- up. In a similar cohort, we assessed the impact of sepsis on long-term mortality and causes of death in a series of Cox and multinomial models. We found a surprisingly small overall association between sepsis and mortality and a persistently increased risk of infectious causes of death in sepsis patients. We compared the prevalence of several common comorbidities and medications as risk factors for ICU admission and mortality in ICU patients with Covid-19 with that of age- and sex-matched population controls and in patients discharged alive with those that were deceased at discharge. We found associations between several comorbidities and medications with these adverse outcomes. To better understand the meaning of these comorbidities as risk factors for short-term mortality, we compared them in logistic regression models on patients with Covid-19, sepsis and acute respiratory distress syndrome (ARDS). We found very similar impacts from the comorbidities; however, greater age was more associated with mortality in Covid-19 than in either sepsis or ARDS. Finally, we investigated the long-term functional recovery in ICU patients with Covid-19 compared to hospital-admitted patients with Covid-19 and population controls matched to the ICU group. The ICU patients had a markedly impeded recovery that was not explained by demographics or comorbidities in statistical models.

    List of papers
    1. A nationwide study of the long-term prevalence of dementia and its risk factors in the Swedish intensive care cohort
    Open this publication in new window or tab >>A nationwide study of the long-term prevalence of dementia and its risk factors in the Swedish intensive care cohort
    2020 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 24, no 1, article id 548Article in journal (Refereed) Published
    Abstract [en]

    BackgroundDeveloping dementia is feared by many for its detrimental effects on cognition and independence. Experimental and clinical evidence suggests that sepsis is a risk factor for the later development of dementia. We aimed to investigate whether intensive care-treated sepsis is an independent risk factor for a later diagnosis of dementia in a large cohort of intensive care unit (ICU) patients.MethodsWe identified adult patients admitted to an ICU in 2005 to 2015 and who survived without a dementia diagnosis 1year after intensive care admission using the Swedish Intensive Care Registry, collecting data from all Swedish general ICUs. Comorbidity, the diagnosis of dementia and mortality, was retrieved from the Swedish National Patient Registry, the Swedish Dementia Registry, and the Cause of Death Registry. Sepsis during intensive care served as a covariate in an extended Cox model together with age, sex, and variables describing comorbidities and acute disease severity.ResultsOne year after ICU admission 210,334 patients were alive and without a diagnosis of dementia; of these, 16,115 (7.7%) had a diagnosis of sepsis during intensive care. The median age of the cohort was 61years (interquartile range, IQR 43-72). The patients were followed for up to 11years (median 3.9years, IQR 1.7-6.6). During the follow-up, 6312 (3%) patients were diagnosed with dementia. Dementia was more common in individuals diagnosed with sepsis during their ICU stay (log-rank p<0.001), however diagnosis of sepsis during critical care was not an independent risk factor for a later dementia diagnosis in an extended Cox model: hazard ratio (HR) 1.01 (95% confidence interval 0.91-1.11, p=0.873). Renal replacement therapy and ventilator therapy during the ICU stay were protective. High age was a strong risk factor for later dementia, as was increasing severity of acute illness, although to a lesser extent. However, the severity of comorbidities and the length of ICU and hospital stay were not independent risk factors in the model.ConclusionAlthough dementia is more common among patients treated with sepsis in the ICU, sepsis was not an independent risk factor for later dementia in the Swedish national critical care cohort.Trial registrationThis study was registered a priori with the Australian and New Zeeland Clinical Trials Registry (registration no. ACTRN12618000533291).

    Place, publisher, year, edition, pages
    BMC, 2020
    Keywords
    Critical care, Sepsis, Dementia, Risk factors, Cohort studies
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-422802 (URN)10.1186/s13054-020-03203-y (DOI)000569782600004 ()32887659 (PubMedID)
    Available from: 2020-10-16 Created: 2020-10-16 Last updated: 2024-01-10Bibliographically approved
    2. Association of sepsis with long-term mortality and causes of death in the Swedish intensive care cohort
    Open this publication in new window or tab >>Association of sepsis with long-term mortality and causes of death in the Swedish intensive care cohort
    (English)Manuscript (preprint) (Other academic)
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-519454 (URN)
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-10
    3. The swedish covid-19 intensive care cohort: Risk factors of ICU admission and ICU mortality
    Open this publication in new window or tab >>The swedish covid-19 intensive care cohort: Risk factors of ICU admission and ICU mortality
    Show others...
    2021 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 65, no 4, p. 525-533Article in journal (Refereed) Published
    Abstract [en]

    Background: Several studies have recently addressed factors associated with severe Coronavirus disease 2019 (COVID-19); however, some medications and comorbidities have yet to be evaluated in a large matched cohort. We therefore explored the role of relevant comorbidities and medications in relation to the risk of intensive care unit (ICU) admission and mortality.

    Methods: All ICU COVID-19 patients in Sweden until 27 May 2020 were matched to population controls on age and gender to assess the risk of ICU admission. Cases were identified, comorbidities and medications were retrieved from high-quality registries. Three conditional logistic regression models were used for risk of ICU admission and three Cox proportional hazards models for risk of ICU mortality, one with comorbidities, one with medications and finally with both models combined, respectively.

    Results: We included 1981 patients and 7924 controls. Hypertension, type 2 diabetes mellitus, chronic renal failure, asthma, obesity, being a solid organ transplant recipient and immunosuppressant medications were independent risk factors of ICU admission and oral anticoagulants were protective. Stroke, asthma, chronic obstructive pulmonary disease and treatment with renin-angiotensin-aldosterone inhibitors (RAASi) were independent risk factors of ICU mortality in the pre-specified primary analyses; treatment with statins was protective. However, after adjusting for the use of continuous renal replacement therapy, RAASi were no longer an independent risk factor.

    Conclusion: In our cohort oral anticoagulants were protective of ICU admission and statins was protective of ICU death. Several comorbidities and ongoing RAASi treatment were independent risk factors of ICU admission and ICU mortality.

    Place, publisher, year, edition, pages
    John Wiley & SonsWiley, 2021
    Keywords
    anticoagulants, cohort studies, coronavirus infections, critical care, renin angiotensin system, risk factors
    National Category
    Anesthesiology and Intensive Care
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-440109 (URN)10.1111/aas.13781 (DOI)000615874800001 ()33438198 (PubMedID)
    Available from: 2021-04-14 Created: 2021-04-14 Last updated: 2024-01-15Bibliographically approved
    4. A comparison of impact of comorbidities and demographics on 60-day mortality in ICU patients with COVID-19, sepsis and acute respiratory distress syndrome
    Open this publication in new window or tab >>A comparison of impact of comorbidities and demographics on 60-day mortality in ICU patients with COVID-19, sepsis and acute respiratory distress syndrome
    Show others...
    2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 15703Article in journal (Refereed) Published
    Abstract [en]

    Severe Coronavirus disease 2019 (COVID-19) is associated with several pre-existing comorbidities and demographic factors. Similar factors are linked to critical sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that age and comorbidities are more generically linked to critical illness mortality than a specific disease state. We used national databases to identify ICU patients and to retrieve comorbidities. The relative importance of risk factors for 60-day mortality was evaluated using the interaction with disease group (Sepsis, ARDS or COVID-19) in logistic regression models. We included 32,501 adult ICU patients. In the model on 60-day mortality in sepsis and COVID-19 there were significant interactions with disease group for age, sex and asthma. In the model on 60-day mortality in ARDS and COVID-19 significant interactions with cohort were found for acute disease severity, age and chronic renal failure. In conclusion, age and sex play particular roles in COVID-19 mortality during intensive care but the burden of comorbidity was similar between sepsis and COVID-19 and ARDS and COVID-19.

    Place, publisher, year, edition, pages
    Springer Nature, 2022
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-486398 (URN)10.1038/s41598-022-19539-0 (DOI)000857187000001 ()36127433 (PubMedID)
    Available from: 2022-10-10 Created: 2022-10-10 Last updated: 2024-01-10Bibliographically approved
    5. One-year functional recovery from severe Covid-19 is severely affected in the Swedish intensive care and hospital admitted working age cohort
    Open this publication in new window or tab >>One-year functional recovery from severe Covid-19 is severely affected in the Swedish intensive care and hospital admitted working age cohort
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Anesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-519456 (URN)
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-10
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  • Public defence: 2024-03-01 13:15 Ångströmlaboratoriet, 101121, Sonja Lyttkens, Uppsala
    Bengtsson Bernander, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Equivariant Neural Networks for Biomedical Image Analysis2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    While artificial intelligence and deep learning have revolutionized many fields in the last decade, one of the key drivers has been access to data. This is especially true in biomedical image analysis where expert annotated data is hard to come by. The combination of Convolutional Neural Networks (CNNs) with data augmentation has proven successful in increasing the amount of training data at the cost of overfitting. In this thesis, equivariant neural networks have been used to extend the equivariant properties of CNNs to more transformations than translations. The networks have been trained and evaluated on biomedical image datasets, including bright-field microscopy images of cytological samples indicating oral cancer, and transmission electron microscopy images of virus samples. By designing the networks to be equivariant to e.g. rotations, it is shown that the need for data augmentation is reduced, that less overfitting occurs, and that convergence during training is faster. Furthermore, equivariant neural networks are more data efficient than CNNs, as demonstrated by scaling laws. These benefits are not present in all problem settings and which benefits will occur is somewhat unpredictable. We have identified that the results to some extent depend on architectures, hyperparameters and datasets. Further research may broaden the performed studies to explain how the results occur with new theory.

    List of papers
    1. Replacing data augmentation with rotation-equivariant CNNs in image-based classification of oral cancer
    Open this publication in new window or tab >>Replacing data augmentation with rotation-equivariant CNNs in image-based classification of oral cancer
    2021 (English)Conference paper, Published paper (Refereed)
    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-460520 (URN)
    Conference
    25th Iberoamerican Congress on Pattern Recognition, Porto, Portugal, 10 - 13 May 2021
    Funder
    Wallenberg AI, Autonomous Systems and Software Program (WASP)
    Available from: 2021-12-07 Created: 2021-12-07 Last updated: 2024-01-09Bibliographically approved
    2. Rotation-Equivariant Semantic Instance Segmentation on Biomedical Images
    Open this publication in new window or tab >>Rotation-Equivariant Semantic Instance Segmentation on Biomedical Images
    2022 (English)In: MEDICAL IMAGE UNDERSTANDING AND ANALYSIS, MIUA 2022 / [ed] Yang, G Aviles-Rivero, A Roberts, M Schonlieb, CB, SPRINGER INTERNATIONAL PUBLISHING AG Springer Nature, 2022, Vol. 13413, p. 283-297Conference paper, Published paper (Refereed)
    Abstract [en]

    Advances in image segmentation techniques, brought by convolutional neural network (CNN) architectures like U-Net, show promise for tasks such as automated cancer screening. Recently, these methods have been extended to detect different instances of the same class, which could be used to, for example, characterize individual cells in whole-slide images. Still, the amount of data needed and the number of parameters in the network are substantial. To alleviate these problems, we modify a method of semantic instance segmentation to also enforce equivariance to the p4 symmetry group of 90-degree rotations and translations. We perform four experiments on a synthetic dataset of scattered sticks and a subset of the Kaggle 2018 Data Science Bowl, the BBBC038 dataset, consisting of segmented nuclei images. Results indicate that the rotation-equivariant architecture yields similar accuracy as a baseline architecture. Furthermore, we observe that the rotation-equivariant architecture converges faster than the baseline. This is a promising step towards reducing the training time during development of methods based on deep learning.

    Place, publisher, year, edition, pages
    Springer NatureSPRINGER INTERNATIONAL PUBLISHING AG, 2022
    Series
    Lecture Notes in Computer Science, ISSN 0302-9743, E-ISSN 1611-3349
    Keywords
    Deep learning, Training, Convergence
    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-489382 (URN)10.1007/978-3-031-12053-4_22 (DOI)000883331000022 ()978-3-031-12053-4 (ISBN)978-3-031-12052-7 (ISBN)
    Conference
    26th Annual Conference on Medical Image Understanding and Analysis (MIUA), JUL 27-29, 2022, Univ Cambridge, Cambridge, ENGLAND
    Funder
    Wallenberg AI, Autonomous Systems and Software Program (WASP)
    Available from: 2022-12-28 Created: 2022-12-28 Last updated: 2024-01-15Bibliographically approved
    3. Classification of Viruses in Transmission Electron Microscopy Images using Equivariant Neural Networks
    Open this publication in new window or tab >>Classification of Viruses in Transmission Electron Microscopy Images using Equivariant Neural Networks
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Image Processing
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-519609 (URN)
    Funder
    Wallenberg AI, Autonomous Systems and Software Program (WASP)
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-09
    4. Equivariant Neural Networks for Biomedical Images Improves Data Efficiency
    Open this publication in new window or tab >>Equivariant Neural Networks for Biomedical Images Improves Data Efficiency
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Image Processing
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-519610 (URN)
    Funder
    Wallenberg AI, Autonomous Systems and Software Program (WASP)
    Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-09
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  • Public defence: 2024-03-08 10:15 101195 (Heinz-Otto Kreiss), Ångströmlaboratoriet, Uppsala
    Clouard, Camille
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing.
    A computational and statistical framework for cost-effective genotyping combining pooling and imputation2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The information conveyed by genetic markers, such as single nucleotide polymorphisms (SNPs), has been widely used in biomedical research to study human diseases and is increasingly valued in agriculture for genomic selection purposes. Specific markers can be identified as a genetic signature that correlates with certain characteristics in a living organism, e.g. a susceptibility to disease or high-yield traits. Capturing these signatures with sufficient statistical power often requires large volumes of data, with thousands of samples to be analysed and potentially millions of genetic markers to be screened. Relevant effects are particularly delicate to detect when the genetic variations involved occur at low frequencies.

    The cost of producing such marker genotype data is therefore a critical part of the analysis. Despite recent technological advances, production costs can still be prohibitive on a large scale and genotype imputation strategies have been developed to address this issue. Genotype imputation methods have been extensively studied in human data and, to a lesser extent, in crop and animal species. A recognised weakness of imputation methods is their lower accuracy in predicting the genotypes for rare variants, whereas those can be highly informative in association studies and improve the accuracy of genomic selection. In this respect, pooling strategies can be well suited to complement imputation, as pooling is efficient at capturing the low-frequency items in a population. Pooling also reduces the number of genotyping tests required, making its use in combination with imputation a cost-effective compromise between accurate but expensive high-density genotyping of each sample individually and stand-alone imputation. However, due to the nature of genotype data and the limitations of genotype testing techniques, decoding pooled genotypes into unique data resolutions is challenging. 

    In this work, we study the characteristics of decoded genotype data from pooled observations with a specific pooling scheme using the examples of a human cohort and a population of inbred wheat lines. We propose different inference strategies to reconstruct the genotypes before devising them as input to imputation, and we reflect on how the reconstructed distributions affect the results of imputation methods such as tree-based haplotype clustering or coalescent models.

    List of papers
    1. A joint use of pooling and imputation for genotyping SNPs
    Open this publication in new window or tab >>A joint use of pooling and imputation for genotyping SNPs
    2022 (English)In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 23, article id 421Article in journal (Refereed) Published
    Abstract [en]

    Background

    Despite continuing technological advances, the cost for large-scale genotyping of a high number of samples can be prohibitive. The purpose of this study is to design a cost-saving strategy for SNP genotyping. We suggest making use of pooling, a group testing technique, to drop the amount of SNP arrays needed. We believe that this will be of the greatest importance for non-model organisms with more limited resources in terms of cost-efficient large-scale chips and high-quality reference genomes, such as application in wildlife monitoring, plant and animal breeding, but it is in essence species-agnostic. The proposed approach consists in grouping and mixing individual DNA samples into pools before testing these pools on bead-chips, such that the number of pools is less than the number of individual samples. We present a statistical estimation algorithm, based on the pooling outcomes, for inferring marker-wise the most likely genotype of every sample in each pool. Finally, we input these estimated genotypes into existing imputation algorithms. We compare the imputation performance from pooled data with the Beagle algorithm, and a local likelihood-aware phasing algorithm closely modeled on MaCH that we implemented.

    Results

    We conduct simulations based on human data from the 1000 Genomes Project, to aid comparison with other imputation studies. Based on the simulated data, we find that pooling impacts the genotype frequencies of the directly identifiable markers, without imputation. We also demonstrate how a combinatorial estimation of the genotype probabilities from the pooling design can improve the prediction performance of imputation models. Our algorithm achieves 93% concordance in predicting unassayed markers from pooled data, thus it outperforms the Beagle imputation model which reaches 80% concordance. We observe that the pooling design gives higher concordance for the rare variants than traditional low-density to high-density imputation commonly used for cost-effective genotyping of large cohorts.

    Conclusions

    We present promising results for combining a pooling scheme for SNP genotyping with computational genotype imputation on human data. These results could find potential applications in any context where the genotyping costs form a limiting factor on the study size, such as in marker-assisted selection in plant breeding.

    Place, publisher, year, edition, pages
    Springer Nature, 2022
    Keywords
    Pooling, Imputation, Genotyping
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Scientific Computing
    Identifiers
    urn:nbn:se:uu:diva-486864 (URN)10.1186/s12859-022-04974-7 (DOI)000867656900001 ()36229780 (PubMedID)
    Projects
    eSSENCE - An eScience Collaboration
    Funder
    Swedish Research Council Formas, 2017-00453Swedish National Infrastructure for Computing (SNIC), 2019/8-216Swedish National Infrastructure for Computing (SNIC), 2020/5-455Uppsala University
    Available from: 2022-10-18 Created: 2022-10-18 Last updated: 2024-01-17Bibliographically approved
    2. Consistency Study of a Reconstructed Genotype Probability Distribution via Clustered Bootstrapping in NORB Pooling Blocks
    Open this publication in new window or tab >>Consistency Study of a Reconstructed Genotype Probability Distribution via Clustered Bootstrapping in NORB Pooling Blocks
    2022 (English)Report (Other academic)
    Abstract [en]

    For applications with biallelic genetic markers, group testing techniques, synonymous to pooling techniques, are usually applied for decreasing the cost of large-scale testing as e.g. when detecting carriers of rare genetic variants. In some configurations, the results of the grouped tests cannot be decoded and the pooled items are missing. Inference of these missing items can be performed with specific statistical methods that are for example related to the Expectation-Maximization algorithm. Pooling has also been applied for determining the genotype of markers in large populations. The particularity of full genotype data for diploid organisms in the context of group testing are the ternary outcomes (two homozygous genotypes and one heterozygous), as well as the distribution of these three outcomes in a population, which is often ruled by the Hardy-Weinberg Equilibrium and depends on the allele frequency in such situation. When using a nonoverlapping repeated block pooling design, the missing items are only observed in particular arrangements. Overall, a data set of pooled genotypes can be described as an inference problem in Missing Not At Random data with nonmonotone missingness patterns. This study presents a preliminary investigation of the consistency of various iterative methods estimating the most likely genotype probabilities of the missing items in pooled data. We use the Kullback-Leibler divergence and the L2 distance between the genotype distribution computed from our estimates and a simulated empirical distribution as a measure of the distributional consistency.

    Place, publisher, year, edition, pages
    Uppsala: Uppsala University, 2022. p. 13
    Series
    Technical report / Department of Information Technology, Uppsala University, ISSN 1404-3203 ; 2022-005
    National Category
    Probability Theory and Statistics
    Identifiers
    urn:nbn:se:uu:diva-487718 (URN)
    Available from: 2022-10-31 Created: 2022-10-31 Last updated: 2024-01-10Bibliographically approved
    3. Genotyping of SNPs in bread wheat at reduced cost from pooled experiments and imputation
    Open this publication in new window or tab >>Genotyping of SNPs in bread wheat at reduced cost from pooled experiments and imputation
    2024 (English)In: Theoretical and Applied Genetics, ISSN 0040-5752, E-ISSN 1432-2242, Vol. 137, no 1, article id 26Article in journal (Refereed) Published
    Abstract [en]

    The plant breeding industry has shown growing interest in using the genotype data of relevant markers for performing selection of new competitive varieties. The selection usually benefits from large amounts of marker data and it is therefore crucial to dispose of data collection methods that are both cost-effective and reliable. Computational methods such as genotype imputation have been proposed earlier in several plant science studies for addressing the cost challenge. Genotype imputation methods have though been used more frequently and investigated more extensively in human genetics research. The various algorithms that exist have shown lower accuracy at inferring the genotype of genetic variants occurring at low frequency, while these rare variants can have great significance and impact in the genetic studies that underlie selection. In contrast, pooling is a technique that can efficiently identify low-frequency items in a population and it has been successfully used for detecting the samples that carry rare variants in a population. In this study, we propose to combine pooling and imputation, and demonstrate this by simulating a hypothetical microarray for genotyping a population of recombinant inbred lines in a cost-effective and accurate manner, even for rare variants. We show that with an adequate imputation model, it is feasible to accurately predictthe individual genotypes at lower cost than sample-wise genotyping and time-effectively. Moreover, we provide code resources for reproducing the results presented in this study in the form of a containerized workflow.

    Place, publisher, year, edition, pages
    Springer Nature, 2024
    Keywords
    genotyping, imputation, MAGIC population, pooling, wheat
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Scientific Computing
    Identifiers
    urn:nbn:se:uu:diva-518436 (URN)10.1007/s00122-023-04533-5 (DOI)001145311600001 ()38243086 (PubMedID)
    Projects
    eSSENCE - An eScience Collaboration
    Funder
    Swedish Research Council Formas, 2017-00453
    Available from: 2024-01-10 Created: 2024-01-10 Last updated: 2024-02-05Bibliographically approved
    4. Using feedback in pooled experiments augmented with imputation for high genotyping accuracy at reduced cost
    Open this publication in new window or tab >>Using feedback in pooled experiments augmented with imputation for high genotyping accuracy at reduced cost
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Conducting genomic selection in plant breeding programs can substantially speed up the development of new varieties. Genomic selection provides more reliable insights when it is based on dense marker data, in which the rare variants can be particularly informative while they are delicate to capture with sufficient statistical power. Despite the release of new performing technologies, the cost of large-scale genotyping remains a major limitation to the implementation of genomic selection. We suggest to combine pooled genotyping with population-based imputation as a cost-effective computational strategy for genotyping SNPs. Pooling saves genotyping tests and has proven to accurately capture the rare variants that are usually missed by imputation. In this study, we investigate an extension to our joint model of pooling and imputation via iterative coupling. In each iteration, the imputed genotype probabilities serve as feedback input for rectifying the decoded data, before running a new imputation in these adjusted data. Such flexible set up indirectly imposes consistency between the imputed genotypes and the pooled observations. We demonstrate that repeated cycles of feedback can take full advantage of the strengths in both pooling and imputation. The iterations improve greatly upon the initial genotype predictions, achieving very high genotype accuracy for both low and high frequency variants. We enhance the average concordance from 94.5% to 98.4% at a very limited computational cost and without requiring any additional genotype testing. We believe that these results could be of interest for plant breeders and crop scientists.

    Keywords
    SNP array, pooling, imputation, iterative refinement
    National Category
    Bioinformatics (Computational Biology)
    Research subject
    Scientific Computing
    Identifiers
    urn:nbn:se:uu:diva-518429 (URN)
    Funder
    Swedish Research Council Formas, 2017-00453
    Available from: 2023-12-19 Created: 2023-12-19 Last updated: 2024-01-10Bibliographically approved
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  • Public defence: 2024-03-08 13:15 Humanistiska teatern, Engelska parken, Uppsala
    Ginnerskov, Josef
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Sociology.
    Quest for Sociology: Revisiting Prevailing Understandings of a Discipline with Computational Text Analyses of Dissertations2024Doctoral thesis, monograph (Other academic)
    Abstract [en]

    What is sociology? For centuries sociologists have struggled to answer this question and repeatably proclaimed that their discipline is in crisis. The problem has generated a field of its own, the sociology of sociology, where sociologists of knowledge offer concepts for how the paradigmatic status of discipline and its crisis ought to be understood. Yet, the foundation of these understandings has often been limited to conceptual reasonings, historical exposes, and anecdotes from prominent scholars. Following the increasing availability of digitized texts and the development of computational techniques, new venues have been opened for investigating the empirical bearing of what sociology is. This dissertation offers a synthesis of, and a contribution to, this growing literature at the intersection of the sociology of knowledge and computational social science.

    The starting point is a review of literature in the sociology of sociology that has found that our discipline is believed to exist in a state of fragmentation, lacks a paradigm, and is conditioned by the context of its production. Akin to the supposed crisis, these conceptualizations are often taken for granted rather than being empirically put to test. This is why this dissertation aims to shed new light on the crisis of sociology by empirically scrutinizing prevailing disciplinary understandings with an interpretative and theory-driven methodological approach to computational text analysis (i.e., word correlation networks, topic modeling, stylometry, and shallow neural networks). 

    To account for textual representations of sociological knowledge that are firmly institutionalized and exist across different local contexts, hundreds of dissertations in this discipline published in Sweden between 1980 and 2019 by five main universities have been digitized to form two corpora – 380 full-texts and 850 abstracts. Using these corpora, the conceptualizations are operationalized to be able to scrutinize, and trace, reoccurring instances where dissertations allude to certain images of sociology, which, drawing on the work of Margaret Masterman, can be regarded as crude replicas of paradigms. The study design allows us to problematize prevailing understandings of what sociology is.

    In contrast to the notion of fragmentation, the corpora are constituted by a core conditioned by local institutions attuned to different paradigmatic images of sociology. A discrepancy is also found between the two corpora where the abstracts appear to follow a divide between qualitative and quantitative research, and the full-texts are characterized by five paradigms with distinct methodological, epistemological, and ontological positions. These results suggest that the coexistence of multiple paradigms has been conflated with fragmentation and that sociologists tend to present their knowledge along the lines of simplified dichotomies. In response to the crisis, a more fruitful approach might be to embrace paradigm pluralism.

    As a contribution to the sociology of knowledge, this dissertation is an example of how the methodological divide can be overcome by merging insights from the conceptual strand with a hermeneutical take on computational methods to empirically explore taken-for-granted assumptions behind the production of disciplinary knowledge.

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  • Public defence: 2024-03-08 13:15 room A1:107a, Uppsala
    Faraj, Alan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacometric models to inform dose selection and study design: Applied in hemophilia and tuberculosis2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner.   One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia.   A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical trials in adult and pediatric subjects were supported. One of the trials were performed and it was showed with a model-based analysis that the new drug which is given subcutanously has similar efficacy as current intravenously given standard of care alternatives. Using the developed models, different strategies for designing pharmacokinetic trials in children was also presented.   In conclusion, the work performed within this thesis has contributed to the development of new drugs against tuberculosis and hemophilia.

    List of papers
    1. Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development
    Open this publication in new window or tab >>Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development
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    2023 (English)In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 14, article id 1150243Article in journal (Refereed) Published
    Abstract [en]

    Background: A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms.

    Methods: Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated.

    Results: The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA(0-14) as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered.

    Conclusion: In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.

    Place, publisher, year, edition, pages
    Frontiers Media S.A., 2023
    Keywords
    tuberculosis, early bactericidal activity, sample size, pharmacometrics, model-based analysis
    National Category
    Pharmaceutical Sciences Microbiology in the medical area Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-502507 (URN)10.3389/fphar.2023.1150243 (DOI)000979799800001 ()37124198 (PubMedID)
    Funder
    EU, Horizon 2020
    Available from: 2023-05-29 Created: 2023-05-29 Last updated: 2024-01-18Bibliographically approved
    2. Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial
    Open this publication in new window or tab >>Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial
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    2022 (English)In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 205, no 10, p. 1228-1235Article in journal (Refereed) Published
    Abstract [en]

    Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.

    Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin.

    Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0-14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13.

    Measurements and Main Results: Sixty participants enrolled. Median EBA(CFU0-14) counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-037), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log(10) h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events.

    Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens.

    Place, publisher, year, edition, pages
    American Thoracic Society, 2022
    Keywords
    tuberculosis, carbapenem, early bactericidal activity, meropenem, phase 2A clinical trial
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-477728 (URN)10.1164/rccm.202108-1976OC (DOI)000798182100016 ()35258443 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC)Swedish Research Council, 2018-05973EU, Horizon 2020
    Available from: 2022-06-27 Created: 2022-06-27 Last updated: 2024-01-18Bibliographically approved
    3. Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling: A novel hemostatic drug
    Open this publication in new window or tab >>Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling: A novel hemostatic drug
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    2022 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 11, no 12, p. 1628-1637Article in journal (Refereed) Published
    Abstract [en]

    Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure-matching strategy with a wild-type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 μg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2022
    National Category
    Pharmacology and Toxicology Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-496818 (URN)10.1002/psp4.12872 (DOI)000869173200001 ()36191169 (PubMedID)
    Available from: 2023-02-21 Created: 2023-02-21 Last updated: 2024-01-18Bibliographically approved
    4. Model-informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy
    Open this publication in new window or tab >>Model-informed pediatric dose selection of marzeptacog alfa (activated): An exposure matching strategy
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    2023 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 12, no 7, p. 977-987Article in journal (Refereed) Published
    Abstract [en]

    Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human rFVII variant intended for subcutaneous (s.c.) administration to treat or prevent bleeding in individuals with hemophilia A (HA) or B (HB) with inhibitors, and other rare bleeding disorders. The s.c. administration provides benefits over i.v. injections. The objective of the study was to support the first-in-pediatric dose selection for s.c. MarzAA to treat episodic bleeding episodes in children up through 11 years in a registrational phase III trial. Assuming the same exposure-response relationship as in adults, an exposure matching strategy was used with a population pharmacokinetics model. A sensitivity analysis evaluating the impact of doubling in absorption rate and age-dependent allometric exponents on dose selection was performed. Subsequently, the probability of trial success, defined as the number of successful trials for a given pediatric dose divided by the number of simulated trials (n = 1000) was studied. A successful trial was defined as outcome where four, three, or two out of 24 pediatric subjects per trial were allowed to fall outside the adult exposures after s.c. administration of 60 mu g/kg. A dose of 60 mu g/ kg in children with HA/HB was supported by the clinical trial simulations to match exposures in adults. The sensitivity analyses further supported selection of the 60 mu g/kg dose level in all age groups. Moreover, the probability of trial success evaluations given a plausible design confirmed the potential of a 60 mu g/kg dose level. Taken together, this work demonstrates the utility of model-informed drug development and could be helpful for other pediatric development programs for rare diseases.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2023
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-510975 (URN)10.1002/psp4.12967 (DOI)000981341900001 ()37042339 (PubMedID)
    Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2024-01-18Bibliographically approved
    5. Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric Hemophilia B Patients
    Open this publication in new window or tab >>Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric Hemophilia B Patients
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    2023 (English)In: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 40, no 9, p. 3739-3750Article in journal (Refereed) Published
    Abstract [en]

    IntroductionDalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factor IX (FIX) variant is being developed for adult and paediatric patients with hemophilia B (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach.MethodsA population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection.ResultsAlmost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100 IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1 days. No every-other-day regimen met the target. A dose of 125 IU/kg resulted in adequate FIX levels down to 6 years, whereas a 150 IU/kg dose was needed below 6 down to 2 years of age. For subjects down to 6 years that did not reach target with 125 IU/kg, a dose escalation to 150 IU/kg was appropriate. The children below 6 to 2 years were shown to need a dose escalation to 200 IU/kg if 150 IU/kg given daily was insufficient.ConclusionThis study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds.

    Place, publisher, year, edition, pages
    Springer Nature, 2023
    Keywords
    Dalcinonacog alfa, Population pharmacokinetics, Hemophilia B, MID3, Dose selection
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-511032 (URN)10.1007/s12325-023-02570-6 (DOI)001019139000001 ()37341915 (PubMedID)
    Funder
    Uppsala University
    Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2024-01-18Bibliographically approved
    6. Subcutaneous Marzeptacog Alfa (Activated) for On‐Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors
    Open this publication in new window or tab >>Subcutaneous Marzeptacog Alfa (Activated) for On‐Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors
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    2024 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535Article in journal (Refereed) Published
    Abstract [en]

    Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-521050 (URN)10.1002/cpt.3172 (DOI)
    Available from: 2024-01-17 Created: 2024-01-17 Last updated: 2024-01-18
    7. Model-based approaches to prospectively power pediatric pharmacokinetic trials with limited sample size
    Open this publication in new window or tab >>Model-based approaches to prospectively power pediatric pharmacokinetic trials with limited sample size
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Rare disease studies in pediatric subjects are challenging due to small sample sizes. Pharmacokinetic (PK) information in pediatric subjects is important and often used for matching strategy towards adults informing pediatric development program. Prior to studying PK in children, it is important to optimize the sparse sampling schedule and show that the study is designed to estimate key PK parameters with sufficient certainty. In this work, the sampling schedule in children was optimized for marzeptacog alfa activated (MarzAA) and dalcinonacog alfa (DalcA), two drugs in development for treatment of hemophilia. Subsequently, evaluation of different model-based approaches to calculate the power to estimate clearance (CL) and volume of distribution (V) using a fixed sample size (n=24) was performed. Usage of Bayesian priors (up to 2x inflation of the adult priors) performed well (power   80 %), but with lower power with decreasing informativeness (5x and 10x inflation of the adult priors), in particular for DalcA. Reusing the full adult model or a simplified model for standalone analysis of the pediatric data did not perform well (<80% power). Fixing the adult PK parameters except for CL and V performed well when pooling adult and pediatric data (power 100 %). In general, the power to estimate V alone or CL together with V was lower than for CL, indicating that the sampling schedules were more informative for CL. Although Bayesian prior approaches were shown to perform well without need of pooling data, other approaches that require less technical expertise and no need for simplification of the adult model were found to be good alternatives when pooling of data is possible. 

    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-521051 (URN)
    Available from: 2024-01-17 Created: 2024-01-17 Last updated: 2024-01-18
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  • Public defence: 2024-03-13 10:00 E22, Visby
    Barney, Andrew
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Wind Energy.
    Energy planning for islands: Guiding island energy transition and decision-making2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The importance and benefits of transitioning away from fossil fuel based energy systems is becoming ever clearer. The transition is especially crucial for geographic islands that typically have limited, or no, access to mainland energy networks. This limited access means that they must rely on costly, economically and environmentally, imported fossil fuels for energy production. This isolation and reliance on imported fuels makes islands particularly energy insecure, which is only expected to worsen because of climate change. At the same time, much of the current guidance and policy developed to help plan for islands’ energy transition is based on the conditions and circumstances present on the mainland or on energy planning that focuses primarily on technical or economic parameters. To plan for a smoother, more successful transition away from fossil fuel based energy production on islands, more data is needed about islanders themselves and their local circumstances as well as planning guidance flexible enough to fit the variable needs of island planners that goes beyond a techno-economic focus.

    In this PhD Thesis and in response to these transition issues, an energy planning platform, REACT-DECARB, has been developed to specifically address the needs of island energy planners. This platform seeks to be holistic in its approach to facilitate the island energy transition planning procedure by considering typical island characteristics and energy transition processes while also including key technical, social, environmental and economic dimensions and granting planners flexibility in how they incorporate them. Additionally, surveys and interviews with island residents are conducted to gain an understanding of islanders’ motivations, priorities and awareness in relation to energy and energy transition as well as to determine if these can be of guidance to island energy transition planners.

    The applications of the REACT-DECARB platform on geographic islands representing eight different countries from around the EU with varying populations, land areas and climates identified energy transition opportunities and obstacles specific to the islands where the platform was applied as well as to other islands seeking to transition their energy systems. Moreover, these applications of the planning platform demonstrated its ability to help island planners in the development of holistic energy transition paths. The platform takes island energy transition planning beyond a focus on techno-economics by including a wider range of planning dimensions allowing them to decide the methods best suited to their island’s needs. Further, the interactions with island residents demonstrated that their relationships to energy could be informative in the development of energy transition plans as well as likely being critical to their success. Islanders’ understandings, motivations, priorities and awareness were found to be not only directly useful in guiding planners during the designing of island energy transition plans but can also serve to inform planners in how best to educate local residents about and engage them in local energy transition projects. Ultimately, the work in this Thesis contributes to the efforts to make sure islands’, and islanders’, needs and perspectives are considered and included as a part of the wider energy transition.

    List of papers
    1. Towards Self-Sustainable Island Grids through Optimal Utilization of Renewable Energy Potential and Community Engagement
    Open this publication in new window or tab >>Towards Self-Sustainable Island Grids through Optimal Utilization of Renewable Energy Potential and Community Engagement
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    2020 (English)In: Energies, E-ISSN 1996-1073, Vol. 13, no 13, article id 3386Article in journal (Refereed) Published
    Abstract [en]

    Solving the issue of energy security for geographical islands presents a one-of-a-kind problem that has to be tackled from multiple sides and requires an interdisciplinary approach that transcends just technical and social aspects. With many islands suffering in terms of limited and costly energy supply due to their remote location, providing a self-sustainable energy system is of utmost importance for these communities. In order to improve upon the status quo, novel solutions and projects aimed at increasing sustainability not only have to consider optimal utilization of renewable energy potentials in accordance with local conditions, but also must include active community participation. This paper analyzes both of these aspects for island communities and brings them together in an optimization scenario that is utilized to determine the relationship between supposed demand flexibility levels and achievable savings in a setting with variable renewable generation. The results, specifically discussed for a use case with real-world data for the La Graciosa island in Spain, show that boosting community participation and thus unlocking crucial demand flexibility, can be used as a powerful tool to augment novel generation technologies with savings from flexibility at around 7.5% of what is achieved purely by renewable sources.

    Place, publisher, year, edition, pages
    MDPI AG, 2020
    Keywords
    renewable energy, sustainability, island communities, demand flexibility, energy management, optimization
    National Category
    Energy Systems
    Identifiers
    urn:nbn:se:uu:diva-419710 (URN)10.3390/en13133386 (DOI)000550367100001 ()
    Funder
    EU, Horizon 2020
    Available from: 2020-09-28 Created: 2020-09-28 Last updated: 2024-01-15Bibliographically approved
    2. Transition towards decarbonisation for islands: Development of an integrated energy planning platform and application
    Open this publication in new window or tab >>Transition towards decarbonisation for islands: Development of an integrated energy planning platform and application
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    2021 (English)In: Sustainable Energy Technologies and Assessments, ISSN 2213-1388, E-ISSN 2213-1396, Vol. 47, article id 101501Article in journal (Refereed) Published
    Abstract [en]

    This paper presents REACT-DECARB, an energy planning decarbonisation platform employing renewable energy sources coupled with storage for islands. The paper implements the energy scenario creation and economic evaluation steps of the platform on eight geographic islands in seven countries within the EU. Twenty-one technologically feasible energy scenarios, applicable to the specific conditions of each island, are specified and their economic assessment via a levelized cost of energy (LCOE) calculation is then performed. The main aim of this application is to verify the noted steps of the platform as well as to test its flexibility across geographically, socially and dimensionally disparate islands with various scenario generation methods. The results of the economic analysis show a wide variation of LCOE depending primarily on whether full island autonomy is assumed. In some cases the islands’ scenarios’ costs approach current market prices but are never below them; some scenarios are, however, below the current price of the island’s thermal generation. The sensitivity and uncertainty of the economic performance results’ and the variables used to calculate them are evaluated and discussed for two of the islands. The overall analysis and application has shown that the REACT-DECARB platform is suitable for different islands, regardless of location and size and can be useful for island energy planners.

    Keywords
    Decarbonisation, Energy planning Islands, Levelized cost of energy, Renewable energy, Energy storage
    National Category
    Energy Systems
    Identifiers
    urn:nbn:se:uu:diva-452333 (URN)10.1016/j.seta.2021.101501 (DOI)000712229100005 ()
    Funder
    EU, Horizon 2020, 824395
    Available from: 2021-09-06 Created: 2021-09-06 Last updated: 2024-01-15Bibliographically approved
    3. Decarbonisation of islands: A multi-criteria decision analysis platform and application
    Open this publication in new window or tab >>Decarbonisation of islands: A multi-criteria decision analysis platform and application
    2022 (English)In: Sustainable Energy Technologies and Assessments, ISSN 2213-1388, E-ISSN 2213-1396, Vol. 52, no Part B, article id 102115Article in journal (Refereed) Published
    Abstract [en]

    In this paper the REACT-DECARB energy planning platform, designed to assist with the assessment of decarbonisation scenarios for islands’ electricity grids, is fully presented and applied to eight (8) EU islands. The scenarios were developed in the context of a Horizon 2020 EU project employing a renewable energy production forecasting and an optimisation mixed-integer linear programming model. The platform employs energy and economic modules, life-cycle assessment and multi-criteria decision analysis to facilitate the integrated evaluation of scenarios and enables decision makers to fully grasp the technical, environmental, economic and social aspects of energy systems’ decarbonisation. Results indicate that island electrical autonomy should be considered with caution and can be a valid option only if cost criteria are not prioritised. Further, it was determined that seeking autonomy in countries with low carbon costs for electricity production may be not be environmentally beneficial. A number of inter-island comparisons have been made and have shown that the REACT-DECARB platform can assist planners and decision-makers to identify the best available scenarios, define the sensitivity issues with respect to the criteria weights and, together with local communities, come to a common ground in order to establish a roadmap for the transition towards a decarbonised energy future for islands.

    Place, publisher, year, edition, pages
    ElsevierElsevier BV, 2022
    Keywords
    Sustainable Islands; Lifecycle assessment; Energy autonomy; Multi-Criteria Decision Analysis; PROMETHEE II
    National Category
    Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-459493 (URN)10.1016/j.seta.2022.102115 (DOI)000782163600003 ()
    Projects
    Horizon 2020 - Renewable Energy for self-sustAinable island CommuniTies (REACT)
    Funder
    EU, Horizon 2020, 824395
    Available from: 2021-11-24 Created: 2021-11-24 Last updated: 2024-01-15Bibliographically approved
    4. Energy scenarios for the Faroe Islands: A MCDA methodology including local social perspectives
    Open this publication in new window or tab >>Energy scenarios for the Faroe Islands: A MCDA methodology including local social perspectives
    2022 (English)In: Sustainable Futures, E-ISSN 2666-1888, Vol. 4, article id 100092Article in journal (Refereed) Published
    Abstract [en]

    Planning for the decarbonisation of island energy systems is both crucial and fraught with complexities. The process to develop and evaluate these plans needs to encompass not only technical and economic specifics but each plan's impacts on the environment and local inhabitants must also be considered. This inclusive planning involves multiple criteria and requires a means of handling them. In this paper a series of potential future energy systems are generated with the EnergyPlan software for the Faroe Islands before these systems are assessed using a set of criteria covering their environmental, social, technical and economic aspects. These criteria are used by two multi-criteria approaches, along with actual weights obtained from local stakeholders, to rank the energy systems. It is found that there is a clear shift in rankings towards systems employing offshore technologies due to the inclusion of social criteria specifically fitted to the Islands’ resident's preferences. This shift, however, was not sufficient for these offshore scenarios to outperform other scenarios that performed well on the other criteria. These findings indicate there is likely value in terms of local acceptance for transition planning on the Islands in adjusting to include greater quantities of offshore technologies in future energy strategies.

    Place, publisher, year, edition, pages
    Elsevier, 2022
    Keywords
    Energy planning, Faroe Islands, Decarbonization, EnergyPLAN, MCDA, PROMETHEE II, TOPSIS, Social criteria
    National Category
    Energy Systems
    Identifiers
    urn:nbn:se:uu:diva-481000 (URN)10.1016/j.sftr.2022.100092 (DOI)000907773300006 ()
    Funder
    EU, Horizon 2020, 824395
    Available from: 2022-08-25 Created: 2022-08-25 Last updated: 2024-01-15Bibliographically approved
    5. Energy transition awareness: Can it guide local transition planning on islands?
    Open this publication in new window or tab >>Energy transition awareness: Can it guide local transition planning on islands?
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    2023 (English)In: Heliyon, E-ISSN 2405-8440, Vol. 9, no 9, article id e19960Article in journal (Refereed) Published
    Abstract [en]

    The consequences of climate change and reduced energy security are becoming increasingly apparent, especially on islands. At the same time, the energy transition is quickly spreading and its value to society becoming clearer. Two main obstacles to this transition, rigid policy and lack of local understanding, are particularly troubling on islands, where national policies often aren't flexible enough to consider local particularities and residents are exposed to different energy realities from those on the mainland. Using exploratory interviews and a survey on four islands, this article considers island residents' awareness of energy transition concepts and presents how it interacts with, and is potentially influenced by, relevant energy policies at the national level. The paper presents the comparative results for the geographically, demographically and climatologically diverse islands of Gotland (Sweden), Lesvos (Greece), La Réunion (France) and Mallorca (Spain) to focus on European island energy transitions. Differences were noted between the islands' residents with regards to awareness of and willingness to use specific energy transition tools or to join activities like energy communities. Additionally, differences were noted between the islands for what was the most important reason to consider when using demand response, though ‘Ease of use’ was important across all. The potential reasons for differences among the islands are discussed and suggestions to increase consumer engagement with energy transition activities on islands are given. Overall, the results show that while awareness of energy concepts isn't greater on these European islands, interest in prospective transition actions was high and provide an opportunity for planners to capitalize on. However, if there are potential policy obstacles, these higher levels of interest cannot ensure higher levels of willingness to engage. Taken together, these two findings indicate the potential for an acceleration of transition activity on these islands, and potentially beyond, should engagement with island residents be increased along with review, and amendment of policies impeding it.

    Place, publisher, year, edition, pages
    Elsevier, 2023
    Keywords
    Decarbonisation, Islands, Energy transition, Energy awareness, Consumer engagement
    National Category
    Social Sciences Interdisciplinary Other Earth and Related Environmental Sciences
    Identifiers
    urn:nbn:se:uu:diva-510327 (URN)10.1016/j.heliyon.2023.e19960 (DOI)
    Funder
    EU, Horizon 2020, 824395
    Available from: 2023-09-14 Created: 2023-09-14 Last updated: 2024-01-15Bibliographically approved
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  • Public defence: 2024-03-15 09:00 lecture room Heinz-Otto Kreiss, Uppsala
    Mattsson, Viktor
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Electrical Engineering, Solid-State Electronics.
    Data-Driven Methods for Microwave Sensor Devices in Musculoskeletal Diagnostics2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microwave sensors can be used within medicine as they use non-ionizing radiation, are often low cost, and can be designed for a specific purpose. The application of microwave sensors for diagnostics and monitoring can be improved using appropriate data analysis. The multi-layered structure of the human body makes the measurements on people complex. A tremendous effort is required to create an analytical model of the body. In this context a data-driven approach, building a model that learns from previous measurements, is more suitable to analyze the data. This thesis aims to address statistical and data-driven approaches based on microwave sensor data for biomedical applications.

    A significant part of this thesis deals with microwave sensors for assessing muscle quality. It details the progress from initial clinical campaign to the creation of a machine learning algorithm to assess the local body composition. Such a device would be suitable for screening age-related muscle disorders like sarcopenia and muscle atrophy. Statistical analysis following the initial clinical campaign revealed no significant differences in the microwave data. Therefore, new sensor designs were evaluated. The most promising sensor was used in a small clinical campaign where it was able to detect a change in muscle size for one patient with multiple measurements over time. Successive measurements followed on tissue emulating phantoms and volunteers. For data analysis a machine learning algorithm was designed to predict the skin, fat, and muscle properties. This changes the aim from assessing muscle quality to assessing local body composition. For phantom data the algorithm was accurate for skin and fat and for volunteer data for fat and muscle. Crucially, the algorithm also performed better with more data available, meaning that results should improve if more data is collected.

    Microwave sensors have also been employed to assess bone. The first of two applications was to monitor the bone healing progression post surgery treating craniosynostosis. No substantial conclusions could be drawn from the statistical analysis most likely due to measurement uncertainties. The second application used a purpose-built setup for controlled measurements in ex vivo bone samples submerged in liquid, to simulate an in vivo environment. The purpose was to estimate the dielectric properties of bone. The derived bone properties were lower than expected, probably due to air trapped inside the sample.

    List of papers
    1. MAS: Standalone Microwave Resonator to Assess Muscle Quality
    Open this publication in new window or tab >>MAS: Standalone Microwave Resonator to Assess Muscle Quality
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    2021 (English)In: Sensors, E-ISSN 1424-8220, Vol. 21, no 16, article id 5485Article in journal (Refereed) Published
    Abstract [en]

    Microwave-based sensing for tissue analysis is recently gaining interest due to advantages such as non-ionizing radiation and non-invasiveness. We have developed a set of transmission sensors for microwave-based real-time sensing to quantify muscle mass and quality. In connection, we verified the sensors by 3D simulations, tested them in a laboratory on a homogeneous three-layer tissue model, and collected pilot clinical data in 20 patients and 25 healthy volunteers. This report focuses on initial sensor designs for the Muscle Analyzer System (MAS), their simulation, laboratory trials and clinical trials followed by developing three new sensors and their performance comparison. In the clinical studies, correlation studies were done to compare MAS performance with other clinical standards, specifically the skeletal muscle index, for muscle mass quantification. The results showed limited signal penetration depth for the Split Ring Resonator (SRR) sensor. New sensors were designed incorporating Substrate Integrated Waveguides (SIW) and a bandstop filter to overcome this problem. The sensors were validated through 3D simulations in which they showed increased penetration depth through tissue when compared to the SRR. The second-generation sensors offer higher penetration depth which will improve clinical data collection and validation. The bandstop filter is fabricated and studied in a group of volunteers, showing more reliable data that warrants further continuation of this development.

    Place, publisher, year, edition, pages
    MDPIMDPI AG, 2021
    Keywords
    muscle quality, sarcopenia, microwave sensing, bandstop filter, substrate integrated waveguides
    National Category
    Medical Laboratory and Measurements Technologies
    Identifiers
    urn:nbn:se:uu:diva-455509 (URN)10.3390/s21165485 (DOI)000690024700001 ()34450927 (PubMedID)
    Available from: 2021-10-07 Created: 2021-10-07 Last updated: 2024-01-25Bibliographically approved
    2. Muscle Analyzer System: Exploring Correlation Between Novel Microwave Resonator and Ultrasound-based Tissue Information in the Thigh
    Open this publication in new window or tab >>Muscle Analyzer System: Exploring Correlation Between Novel Microwave Resonator and Ultrasound-based Tissue Information in the Thigh
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    2022 (English)In: 2022 16TH EUROPEAN CONFERENCE ON ANTENNAS AND PROPAGATION (EUCAP), IEEE Institute of Electrical and Electronics Engineers (IEEE), 2022Conference paper, Published paper (Refereed)
    Abstract [en]

    A microwave sensor to safely measure quality of muscle tissue for diagnosis and screening of diseases and medical conditions characterized by fat infiltration in muscle is presented. Fat infiltration in muscle may be seen by a lower dielectric constant of muscle at microwave frequencies corresponding to the large contrast between fat and muscle tissues. A planar resonator based on a bandstop filter and optimized to noninvasively interrogate muscle in the thigh on tissue quality is proposed. Currently, a study based on clinical trials is carried out, and, here, we present a preliminary correlation between skin and fat thicknesses and rectus femoris cross sectional area (CSA) measured with ultrasound and the proposed sensor's resonance frequency. CST simulations based on the ultrasound information guide the analysis. We see that although there are signs of a potential correlation between CSA and resonance, skin and fat variability is still an issue to overcome.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE)IEEE, 2022
    Series
    Proceedings of the European Conference on Antennas and Propagation, ISSN 2164-3342
    Keywords
    Sensors, Muscle Quality, Bandstop Filter, Clinical Measurements
    National Category
    Medical Laboratory and Measurements Technologies
    Identifiers
    urn:nbn:se:uu:diva-482471 (URN)000815113901017 ()978-88-31299-04-6 (ISBN)
    Conference
    16th European Conference on Antennas and Propagation (EuCAP), MAR 27-APR 01, 2022, Madrid, SPAIN
    Funder
    EU, Horizon 2020Swedish Foundation for Strategic Research, RIT17-0020Swedish Foundation for Strategic Research, CHI19-0003
    Available from: 2022-08-24 Created: 2022-08-24 Last updated: 2024-01-25Bibliographically approved
    3. Machine Learning Algorithm to Extract Properties of ATE Phantoms from Microwave Measurements
    Open this publication in new window or tab >>Machine Learning Algorithm to Extract Properties of ATE Phantoms from Microwave Measurements
    (English)In: Article in journal (Refereed) In press
    National Category
    Signal Processing Medical Equipment Engineering
    Identifiers
    urn:nbn:se:uu:diva-521534 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-01-25
    4. Machine Learning Powered Microwave Device for Local Body Composition Assessment
    Open this publication in new window or tab >>Machine Learning Powered Microwave Device for Local Body Composition Assessment
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    2023 (English)In: IEEE Sensors Journal, ISSN 1530-437X, E-ISSN 1558-1748, p. 1-1Article in journal (Refereed) Published
    Abstract [en]

    In this paper a standalone microwave device is evaluated for its ability to assess local body composition with the ultimate goal to assess muscle quality. Data have been collected from volunteers who were measured on their thigh using the microwave device and ultrasound. A machine learning algorithm with three stages is designed that utilizes the stacked nature of the tissues in the thigh to predict skin and fat thickness and the cross-sectional area of the rectus femoris muscle. The input to the algorithm is the signal response from the microwave sensor and also the prediction from the previous layers. The ultrasound measurements are used as the ground truth labels for each tissue to train the machine learning models. The measurements were performed with two sensors, where usage of the combined data from both sensors produced the best results for fat and muscle, 0.57 and 0.63 in R 2 score, respectively. In the drop analysis, a step where a select proportion of the data is temporarily removed, the identified models showed increased scores with a larger amount of data available indicating the learning of the models improves with more data. Although the results are encouraging more data is ultimately needed to further study the algorithm.

    Keywords
    Muscles;Sensors;Fats;Phantoms;Ultrasonic variables measurement;Skin;Machine learning;Biomedical signal processing;Machine learning;Microwave sensor;Signal analysis
    National Category
    Signal Processing Medical Equipment Engineering
    Identifiers
    urn:nbn:se:uu:diva-521533 (URN)10.1109/JSEN.2023.3344581 (DOI)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-01-25
    5. Evaluation of Microwave Sensor for Bone Healing Monitoring after Craniosynostosis Surgery
    Open this publication in new window or tab >>Evaluation of Microwave Sensor for Bone Healing Monitoring after Craniosynostosis Surgery
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    (English)In: The Journal of Engineering, ISSN 1872-3284, E-ISSN 2051-3305Article in journal (Refereed) Submitted
    National Category
    Signal Processing Other Medical Engineering
    Identifiers
    urn:nbn:se:uu:diva-521535 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-01-25
    6. Setup to Perform Ex Vivo Coaxial Transmission Bone Measurements in a Simulated In Vivo Environment
    Open this publication in new window or tab >>Setup to Perform Ex Vivo Coaxial Transmission Bone Measurements in a Simulated In Vivo Environment
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Electrical Engineering, Electronic Engineering, Information Engineering Other Medical Engineering
    Identifiers
    urn:nbn:se:uu:diva-521536 (URN)
    Available from: 2024-01-25 Created: 2024-01-25 Last updated: 2024-01-25
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  • Public defence: 2024-03-15 09:00 Skoogsalen, Uppsala
    Edvardsson Rasmussen, Jesper
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Section of Otorhinolaryngology and Head and Neck Surgery, Department of Surgical Sciences, Uppsala University.
    Inner ear proteomics and barriers: Clinical and experimental findings2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hearing is important in many aspects of life, including communication, assessing one’s surroundings, entertainment and social interaction. Hearing loss is common and according to the Global Burden of Disease Study, 5% of the global population require hearing rehabilitation (1). Pharmacological treatment options are limited, so understanding cellular mechanisms in the damaged inner ear is crucial for developing novel therapies.

    In this thesis, the human inner ear proteome in patients with sporadic vestibular schwannoma (VS) and its association with hearing loss were investigated. Ototoxic effects induced by furosemide were also examined, focusing on inner ear barrier function, furosemide sensitive Na-K-Cl co-transporter 1 (NKCC1), Fetuin-A, linked to tumour-associated hearing loss, and Pigment epithelium-derived factor (PEDF), potentially important for blood-endolymph barrier integrity.

    Translabyrinthine surgery on 35 patients, 32 with VS and three with meningioma, provided samples from perilymph, endolymph, endolymphatic sac tissue, VS biopsies and cerebrospinal fluid (CSF) for proteome analysis. Effects of furosemide on the inner ear barriers were studied in mice using 9.4Tesla MRI, and in guinea pigs using immunohistochemistry and mRNA in situ hybridisation focusing on NKCC1, Fetuin-A, and PEDF.

    Proteomic analysis revealed consistent sets of proteins in perilymph (91/315) and endolymph (545/1211). The proteomes of perilymph and CSF exhibited specific differences, with proteins unique to each fluid, thereby emphasizing the distinct origin of perilymph separate from CSF. Fetuin-A was inversely related to tumour-associated hearing loss, while patients with severe to profound hearing loss exhibited upregulation of complement factor H-related protein 2 (CFHR2).

    Furosemide compromised the blood-endolymph barrier, allowing gadolinium contrast into scala media. It affected NKCC1 of type II fibrocytes coinciding with the onset of hearing loss following high-dose furosemide, suggesting early disruption in potassium ion recirculation. Fetuin-A and PEDF were identified in the cochlea at protein and mRNA level. Their staining intensity increased in various cochlear subsites 120 minutes after furosemide administration, indicating their involvement in the cochlear response to the effects of furosemide.

    In summary, this thesis uncovered significant inter-individual variability in both the perilymph and endolymph proteome, alongside a consistent subset of proteins. Further, associations between hearing loss and proteome changes suggest inflammation as a potential mechanism for hearing degradation caused by vestibular schwannomas. Experimentally, impact of furosemide on blood-inner ear barriers were visualised in vivo and type II fibrocytes were identified as potential initial targets for NKCC1 blockade. Fetuin-A and PEDF were confirmed in several cell types in the cochlea and may increase in response to very high furosemide doses.

    List of papers
    1. The proteome of perilymph in patients with vestibular schwannoma: A possibility to identify biomarkers for tumor associated hearing loss?
    Open this publication in new window or tab >>The proteome of perilymph in patients with vestibular schwannoma: A possibility to identify biomarkers for tumor associated hearing loss?
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    2018 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 6, article id e0198442Article in journal (Refereed) Published
    Abstract [en]

    Background Due to the surrounding bone, the human inner ear is relatively inaccessible and difficult to reach for cellular and molecular analyses. However, these types of investigations are needed to better understand the etiology, pathophysiology and progression of several inner ear disorders. Moreover, the fluid from the inner ear cannot be sampled for micro-chemical analyses from healthy individuals in vivo. Therefore, in the present paper, we studied patients with vestibular schwannoma (VS) undergoing trans-labyrinthine surgery (TLS). Our primary aim was to identify perilymph proteins in patients with VS on an individual level. Our second aim was to investigate the proteins identified at a functional level and our final aim was to search for biological markers for tumor-associated hearing loss and tumor diameter. Methods and findings Sixteen patients underwent TLS for sporadic VS. Perilymph was aspirated through the round window before opening the labyrinth. One sample was contaminated and excluded resulting in 15 usable samples. Perilymph samples were analyzed with an online tandem LTQ-Orbitrap mass spectrometer. Data were analyzed with MaxQuant software to identify the total number of proteins and to quantify proteins in individual samples. Protein function was analyzed using the PANTHER Overrepresentation tool. Associations between perilymph protein content, clinical parameters, tumor-associated hearing loss and tumor diameter were assessed using Random Forest and Boruta. In total, 314 proteins were identified; 60 in all 15 patients and 130 proteins only once in 15 patients. Ninety-one proteins were detected in at least 12 out of 15 patients. Random Forest followed by Boruta analysis confirmed that alpha-2-HS-glycoprotein (P02765) was an independent variable for tumor-associated hearing loss. In addition, functional analysis showed that numerous processes were significantly increased in the perilymph. The top three enriched biological processes were: 1) secondary metabolic processes; 2) complement activation and 3) cell recognition. Conclusions The proteome of perilymph in patients with vestibular schwannoma has an inter-individual stable section. However, even in a cohort with homogenous disease, the variation between individuals represented the majority of the detected proteins. Alpha-2-HS-glycoprotein, P02765, was shown to be an independent variable for tumor-associated hearing loss, a finding that needs to be verified in other studies. In pathway analysis perilymph had highly enriched functions, particularly in terms of increased immune and metabolic processes.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2018
    National Category
    Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-358705 (URN)10.1371/journal.pone.0198442 (DOI)000433900800126 ()29856847 (PubMedID)
    Funder
    Swedish Research Council, 2015-4870
    Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2024-01-26Bibliographically approved
    2. The proteome of the human endolymphatic sac endolymph
    Open this publication in new window or tab >>The proteome of the human endolymphatic sac endolymph
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    2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 11850Article in journal (Refereed) Published
    Abstract [en]

    The endolymphatic sac (ES) is the third part of the inner ear, along with the cochlea and vestibular apparatus. A refined sampling technique was developed to analyse the proteomics of ES endolymph. With a tailored solid phase micro-extraction probe, five ES endolymph samples were collected, and six sac tissue biopsies were obtained in patients undergoing trans-labyrinthine surgery for sporadic vestibular schwannoma. The samples were analysed using nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS) to identify the total number of proteins. Pathway identification regarding molecular function and protein class was presented. A total of 1656 non-redundant proteins were identified, with 1211 proteins detected in the ES endolymph. A total of 110 proteins were unique to the ES endolymph. The results from the study both validate a strategy for in vivo and in situ human sampling during surgery and may also form a platform for further investigations to better understand the function of this intriguing part of the inner ear.

    Place, publisher, year, edition, pages
    Springer Nature, 2021
    National Category
    Otorhinolaryngology
    Identifiers
    urn:nbn:se:uu:diva-451426 (URN)10.1038/s41598-021-89597-3 (DOI)000687328100009 ()34088924 (PubMedID)