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  • Adler, Jeremy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sintorn, Ida-Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, S-40530 Gothenburg, Sweden.
    Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous2019In: COMMUNICATIONS BIOLOGY, ISSN 2399-3642, Vol. 2, article id 12Article in journal (Refereed)
    Abstract [en]

    Cells are neither flat nor smooth, which has serious implications for prevailing plasma membrane models and cellular processes like cell signalling, adhesion and molecular clustering. Using probability distributions from diffusion simulations, we demonstrate that 2D and 3D Euclidean distance measurements substantially underestimate diffusion on non-flat surfaces. Intuitively, the shortest within surface distance (SWSD), the geodesic distance, should reduce this problem. The SWSD is accurate for foldable surfaces but, although it outperforms 2D and 3D Euclidean measurements, it still underestimates movement on deformed surfaces. We demonstrate that the reason behind the underestimation is that topographical features themselves can produce both super- and subdiffusion, i.e. the appearance of anomalous diffusion. Differentiating between topography-induced and genuine anomalous diffusion requires characterising the surface by simulating Brownian motion on high-resolution cell surface images and a comparison with the experimental data.

  • Gerdle, Björn
    et al.
    Linkoping Univ, Pain & Rehabil Ctr, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden.
    Åkerblom, Sophia
    Skane Univ Hosp, Dept Pain Rehabil, Lund, Sweden;Lund Univ, Dept Psychol, Lund, Sweden.
    Jansen, Gunilla Brodda
    Danderyd Hosp, Div Rehabil Med, Dept Clin Sci, Stockholm, Sweden.
    Enthoven, Paul
    Linkoping Univ, Pain & Rehabil Ctr, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden.
    Ernberg, Malin
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden;SCON, Huddinge, Sweden.
    Dong, Huan-Ji
    Linkoping Univ, Pain & Rehabil Ctr, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden.
    Stålnacke, Britt-Marie
    Umea Univ, Dept Community Med & Rehabil, Rehabil Med, Umea, Sweden.
    Äng, Björn O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Huddinge, Sweden;Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Boersma, Katja
    Orebro Univ, Sch Law Psychol & Social Work, Orebro, Sweden.
    Who benefits from multimodal rehabilitation - an exploration of pain, psychological distress, and life impacts in over 35,000 chronic pain patients identified in the Swedish Quality Registry for Pain Rehabilitation2019In: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 12, p. 891-908Article in journal (Refereed)
    Abstract [en]

    Background: Chronic pain patients frequently suffer from psychological symptoms. There is no consensus concerning the prevalence of severe anxiety and depressive symptoms and the strength of the associations between pain intensity and psychological distress. Although an important aspect of the clinical picture is understanding how the pain condition impacts life, little is known about the relative importance of pain and psychological symptoms for individual's life impact. The aims of this study were to identify subgroups of pain patients; to analyze if pain, psychological distress, and life impact variables influence subgrouping; and to investigate how patients in the subgroups benefit from treatments. Methods: Background variables, pain aspects (intensity/severity and spreading), psychological distress (depressive and anxiety symptoms), and two life impact variables (pain interference and perceived life control) were obtained from the Swedish Quality Registry for Pain Rehabilitation for chronic pain patients and analyzed mainly using advanced multivariate methods. Results: Based on >35,000 patients, 35%-40% had severe anxiety or depressive symptoms. Severe psychological distress was associated with being born outside Europe (21%-24% vs 6%-8% in the category without psychological distress) and low education level (20.7%-20.8% vs 26%-27% in the category without psychological distress). Dose relationships existed between the two psychological distress variables and pain aspects, but the explained variances were generally low. Pain intensity/severity and the two psychological distress variables were significantly associated (R-2 =0.40-0.48; P>0.001) with the two life impact variables (pain interference and life control). Two subgroups of patients were identified at baseline (subgroup 1: n=15,901 16,119; subgroup 2: n=20,690-20,981) and the subgroup with the worst situation regarding all variables participated less in an MMRP (51% vs 58%, P<0.001) but showed the largest improvements in outcomes. Conclusion: The results emphasize the need to assess both pain and psychological distress and not take for granted that pain involves high psychological stress in the individual case. Not all patients benefit from MMRP. A better matching between common clinical pictures and the content of MMRPs may help improve results. We only partly found support for treatment resistance in patients with psychological distress burden.

  • Public defence: 2019-05-13 10:00 Axel Hamberg salen, Uppsala
    Conrady, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Wind Turbine Sound in Cold Climates2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The increase in the number of wind turbines (WTs) in populated areas in cold climates increases the number of people potentially being affected by WT sound. Outdoor sound propagation is strongly dependent on meteorological conditions, however, limitations in the knowledge exist regarding the implications of meteorological conditions in cold climates. Long-term acoustic and meteorological measurements were conducted in the vicinity of two wind farms in northern Sweden, to investigate the effect of snow and low-level wind maxima on WT sound, to analyse the occurrence of amplitude modulation and to evaluate selection methods for WT sound measurements. Different selection methodologies were applied to the acoustical data. The simplest method only includes a minimum rotational frequency of the WTs, while the most comprehensive method additionally includes criteria based on spectral resemblance, temporal variation of the sound level, amplitude modulation and wind speed. The effect of snow on WT sound depends on the snow quality. Snow on trees lowers the sound level by ca. 2 dBA. Low-level wind maxima below hub height reduce the sound level near the surface. Since this effect is increasing with increasing strength of the low-level wind maximum, the WT sound is assumed to be partly trapped above the low-level wind maximum. Amplitude modulation was shown to be dependent on atmospheric stability and was most common for very stable conditions. Moreover, a clear difference between the occurrences of amplitude modulation for the two crosswind sectors was observed. The choice of selection method needs to be taken into account when comparing different studies since it affects the results and conclusions. The studies emphasise to include the effects of individual meteorological conditions of a site in the formulation of guidelines on WT sound.

    List of papers
    1. Impact of snow on sound propagating from wind turbines
    Open this publication in new window or tab >>Impact of snow on sound propagating from wind turbines
    2018 (English)In: Wind Energy, ISSN 1095-4244, E-ISSN 1099-1824, Vol. 21, no 12Article in journal (Refereed) Published
    Abstract [en]

    The impact of snow on sound propagating from a wind farm in northern Sweden has been investigated. Simultaneous acoustic and meteorological measurements, combined with daily snow observations, have been analysed for the snow season in 2013 to 2014. Such measurements are crucial since significant knowledge gaps exist, especially for conditions in cold climates, in the implementation of atmospheric boundary layer complexity in sound propagation models. The effect of snow on sound propagation is shown to be dependent on the snow quality. Moreover, snow on trees (upplega) also has an influence on sound propagation. Compared with conditions without snow on trees, the average sound level is approximately 2 dBA lower. The effect is more distinct for higher frequencies compared with lower frequencies.

    Keywords
    atmospheric acoustics, refraction, snow, wind turbine sound
    National Category
    Meteorology and Atmospheric Sciences
    Identifiers
    urn:nbn:se:uu:diva-360285 (URN)10.1002/we.2254 (DOI)
    Funder
    Swedish Energy Agency, 40969-1
    Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2019-03-18Bibliographically approved
    2. Amplitude modulation of wind turbine sound in cold climates
    Open this publication in new window or tab >>Amplitude modulation of wind turbine sound in cold climates
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Natural Sciences Earth and Related Environmental Sciences Meteorology and Atmospheric Sciences
    Identifiers
    urn:nbn:se:uu:diva-379542 (URN)
    Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-18
    3. Selection criteria for filtering wind turbine sound measurements
    Open this publication in new window or tab >>Selection criteria for filtering wind turbine sound measurements
    (English)Manuscript (preprint) (Other academic)
    National Category
    Natural Sciences Earth and Related Environmental Sciences Meteorology and Atmospheric Sciences
    Identifiers
    urn:nbn:se:uu:diva-379543 (URN)
    Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-18
    4. Impact of low-level wind maxima on wind turbine sound propagation
    Open this publication in new window or tab >>Impact of low-level wind maxima on wind turbine sound propagation
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Natural Sciences Earth and Related Environmental Sciences Meteorology and Atmospheric Sciences
    Identifiers
    urn:nbn:se:uu:diva-379545 (URN)
    Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-18
  • Bjorkman, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Univ Gavle, Fac Hlth & Occupat Studies, Gavle, Sweden.
    Andersson, Kajsa
    Univ Gavle, Fac Hlth & Occupat Studies, Gavle, Sweden.
    Bergström, Jenny
    Univ Gavle, Fac Hlth & Occupat Studies, Gavle, Sweden.
    Salzmann-Erikson, Martin
    Univ Gavle, Fac Hlth & Occupat Studies, Gavle, Sweden.
    Increased Mental Illness and the Challenges This Brings for District Nurses in Primary Care Settings2018In: Issues in Mental Health Nursing, ISSN 0161-2840, E-ISSN 1096-4673, Vol. 39, no 12, p. 1023-1030Article in journal (Refereed)
    Abstract [en]

    Patients with mental illness generally make their initial healthcare contact via a registered nurse. Although studies show that encountering and providing care to care-seekers with mental illness might be a challenge, little research exists regarding Primary Care Nurses' (PCN) view of the challenges they face. The aim of this study was to qualitatively explore PCNs' reflections on encountering care-seekers with mental illness in primary healthcare settings. The results consist of three themes: constantly experiencing patients falling through the cracks, being restricted by lack of knowledge and resources, and establishing a trustful relationship to overcome taboo, shame, and guilt.

  • Williams, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Literature.
    Kvinnorna och den kluvna staden: Röster ur samtidens arbetarlitteratur2019In: Creating the City: Identity, Memory and Participation. Conference Proceedings / [ed] Pål Brunnström, Ragnhild Claesson, Malmö: Malmö University , 2019, 1, p. 45-54Conference paper (Other academic)
  • Frigoli, Enrico
    et al.
    Univ Bern, Clin Trials Unit, Bern, Switzerland.
    Smits, Pieter
    Maasstad Hosp, Dept Cardiol, Rotterdam, Netherlands.
    Vranckx, Pascal
    Jessa Ziekenhuis, Hartcentrum Hasselt, Dept Cardiol & Crit Care Med, Hasselt, Belgium;Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium.
    Ozaki, Yokio
    Fujita Hlth Univ, Sch Med, Dept Cardiol, Toyoake, Aichi, Japan.
    Tijssen, Jan
    Univ Amsterdam, Acad Med Ctr, AMC Heartctr, Amsterdam, Netherlands.
    Juni, Peter
    Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Appl Hlth Res Ctr, Toronto, ON, Canada.
    Morice, Marie-Claude
    CERC, Massy, France.
    Onuma, Yoshinobu
    Erasmus MC, Thorax Ctr, Rotterdam, Netherlands.
    Windecker, Stephan
    Bern Univ Hosp, Dept Cardiol, Bern, Switzerland.
    Frenk, Andre
    Bern Univ Hosp, Dept Cardiol, Bern, Switzerland.
    Spaulding, Christian
    Paris Descartes Univ, Hop Europeen Georges Pompidou, AP HP, INSERM,U 970,Sudden Death Expert Ctr,Cardiol Dept, Paris, France.
    Chevalier, Bernard
    Ramsay Gen Sante, Intervent Cardiol Dept, Inst Cardiovasc Paris Sud, Massy, France.
    Barbato, Emanuele
    Cardiovasc Res Ctr Aalst, Aalst, Belgium;Univ Federico II Naples, Dept Adv Biomed Sci, Div Cardiol, Naples, Italy.
    Tonino, Pim
    Catharina Hosp, Dept Cardiol, Eindhoven, Netherlands.
    Hildick-Smith, David
    Brighton & Sussex Univ Hosp NHSTrust, Brighton, E Sussex, England.
    Roffi, Marco
    Geneva Univ Hosp, Div Cardiol, Geneva, Switzerland.
    Kornowski, Ran
    Tel Aviv Univ, Sackler Sch Med, Rabin Med Ctr, Tel Aviv, Israel.
    Schultz, Carl
    Univ Western Australia, Royal Perth Hosp Campus, Dept Cardiol, Perth, WA, Australia.
    Lesiak, Maciej
    Univ Med Sci, Dept Cardiol 1, Poznan, Poland.
    Iniguez, Andres
    Hosp Alvaro Cunqueiro, Vigo, Spain.
    Colombo, Antonio
    IRCCS San Raffaele Sci Inst, Unit Cardiovasc Intervent, Milan, Italy.
    Alasnag, Mirvat
    King Fahad Armed Forces Hosp, Dept Cardiol, Jeddah, Saudi Arabia.
    Mullasari, Ajit
    Madras Med Mission, Chennai, Tamil Nadu, India.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Stankovic, Goran
    Univ Belgrade, Clin Ctr Serbia, Dept Cardiol, Belgrade, Serbia;Univ Belgrade, Fac Med, Belgrade, Serbia.
    Ong, Paul J. L.
    Tan Tock Seng Hosp, Singapore, Singapore.
    Rodriguez, Alfredo E.
    Otamendi Hosp, Buenos Aires Sch Med, Cardiac Unit, Cardiovasc Res Ctr CECI, Buenos Aires, DF, Argentina.
    Mahfoud, Felix
    Saarland Univ Hosp, Homburg, Germany.
    Bartunek, Jozef
    Bern Univ Hosp, Dept Cardiol, Bern, Switzerland.
    Moschovitis, Aris
    Bern Univ Hosp, Dept Cardiol, Bern, Switzerland.
    Laanmets, Peep
    North Estonia Med Ctr Fdn, Tallinn, Estonia.
    Leonardi, Sergio
    Fdn IRCCS Policlin San Matteo, Pavia, Italy.
    Heg, Dik
    Univ Bern, Clin Trials Unit, Bern, Switzerland.
    Sunnaker, Mikael
    Univ Bern, Clin Trials Unit, Bern, Switzerland.
    Valgimigli, Marco
    Bern Univ Hosp, Dept Cardiol, Bern, Switzerland.
    Design and rationale of the Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen (MASTER DAPT) Study2019In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 209, p. 97-105Article in journal (Refereed)
    Abstract [en]

    Background The optimal duration of antiplatelet therapy in high-bleeding risk (HBR) patients with coronary artery disease treated with newer-generation drug-eluting bioresorbable polymer-coated stents remains unclear. Design MASTER DAPT (clinicaltrial.gov NCT03023020) is an investigator-initiated, open-label, multicenter, randomized controlled trial comparing an abbreviated versus a standard duration of antiplatelet therapy after bioresorbable polymer-coated Ultimaster (TANSEI) sirolimus-eluting stent implantation in approximately 4,300 HBR patients recruited from >= 100 interventional cardiology centers globally. After a mandatory 30-day dual-antiplatelet therapy (DAPT) run-in phase, patients are randomized to (a) a single antiplatelet regimen until study completion or up to 5 months in patients with clinically indicated oral anticoagulation (experimental 1-month DAPT group) or (b) continue DAPT for at least 5 months in patients without or 2 in patients with concomitant indication to oral anticoagulation, followed by a single antiplatelet regimen (standard antipkitelet regimen). With a final sample size of 4,300 patients, this study is powered to assess the noninferiority of the abbreviated antiplatelet regimen with respect to the net adverse clinical and major adverse cardiac and cerebral events composite end points and if satisfied for the superiority of abbreviated as compared to standard antiplatelet therapy duration in terms of major or clinically relevant nonmajor bleeding. Study end points will be adjudicated by a blinded Clinical Events Committee. Conclusions The MASTER DAPT study is the first randomized controlled trial aiming at ascertaining the optimal duration of antiplatelet therapy in HBR patients treated with sirolimus-eluting bioresorbable polymer-coated stent implantation.

  • Stenman, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Staehler, Michael
    Deparment of Urology, Ludwig-Maximilians University, Munich Germany.
    Szabados, Bernadett
    Deparment of Urology, Ludwig-Maximilians University, Munich Germany.
    Sandström, Per
    Department of Oncology-Pathology, Karolinska Institute, Sweden.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Harmenberg, Ulrika
    Department of Oncology-Pathology, Karolinska Institute, Sweden.
    Metastatic papillary renal cell carcinoma in the era of targeted therapy: a retrospective study from three European academic centres2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 306-312Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking.

    PATIENTS AND METHODS: mPRCC patients (n = 86) referred to three academic centres in Sweden and Germany in the years 2005-2015 were retrospectively identified from medical records. Statistical analyses included Kaplan-Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors.

    RESULTS: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age ≥60 years, worse PS and ≥3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors.

    CONCLUSION: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

  • Shi, Xun
    et al.
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    You, Wenjing
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    Zhang, Yingchao
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    Tao, Zhensheng
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    Oppeneer, Peter M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Wu, Xianxin
    Julius Maximilians Univ Wurzburg, Inst Theoret Phys & Astrophys, D-97074 Wurzburg, Germany.
    Thomale, Ronny
    Julius Maximilians Univ Wurzburg, Inst Theoret Phys & Astrophys, D-97074 Wurzburg, Germany.
    Rossnagel, Kai
    Univ Kiel, Inst Expt & Appl Phys, D-24098 Kiel, Germany;Deutsches Elektronen-Synchrotron DESY, D-22607 Hamburg, Germany;Ruprecht Haensel Laboratory, Kiel University and DESY, D-24098 Kiel and D-22607 Hamburg, Germany.
    Bauer, Michael
    Univ Kiel, Inst Expt & Appl Phys, D-24098 Kiel, Germany.
    Kapteyn, Henry
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    Murnane, Margaret
    Univ Colorado, Dept Phys, Boulder, CO 80309 USA;Univ Colorado, JILA, Boulder, CO 80309 USA;NIST, Boulder, CO 80309 USA.
    Ultrafast electron calorimetry uncovers a new long-lived metastable state in 1T-TaSe2 mediated by mode-selective electron-phonon coupling2019In: Science Advances, E-ISSN 2375-2548, Vol. 5, no 3, article id eaav4449Article in journal (Refereed)
    Abstract [en]

    Quantum materials represent one of the most promising frontiers in the quest for faster, lightweight, energy-efficient technologies. However, their inherent complexity and rich phase landscape make them challenging to understand or manipulate. Here, we present a new ultrafast electron calorimetry technique that can systematically uncover new phases of quantum matter. Using time- and angle-resolved photoemission spectroscopy, we measure the dynamic electron temperature, band structure, and heat capacity. This approach allows us to uncover a new long-lived metastable state in the charge density wave material 1T-TaSe2, which is distinct from all the known equilibrium phases: It is characterized by a substantially reduced effective total heat capacity that is only 30% of the normal value, because of selective electron-phonon coupling to a subset of phonon modes. As a result, less energy is required to melt the charge order and transform the state of the material than under thermal equilibrium conditions.

  • Brue, Thierry
    et al.
    Aix Marseille Univ, Inst Natl Sante & Rech Med INSERM, U1251, MMG, F-13005 Marseille, France;Hop Conception, AP HM, Ctr Reference Malad Rares Hypophyse HYPO, Dept Endocrinol, F-13005 Marseille, France.
    Lindberg, Anders
    Pfizer Hlth AB, Sollentuna, Sweden.
    van der Lely, Aart Jan
    Erasmus Univ MC, Dept Med, Rotterdam, Netherlands.
    Akerblad, Ann Charlotte
    Pfizer Hlth AB, Sollentuna, Sweden.
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Gomez, Roy
    Pfizer, European Med Affairs, B-1050 Brussels, Belgium.
    Droste, Michael
    Hey-Hadavi, Judith
    Pfizer Inc, Endocrine Care, New York, NY USA.
    Strasburger, Christian J.
    Campus Charite Mitte, Dept Med, Div Clin Endocrinol, Berlin, Germany.
    Camacho-Hubner, Cecilia
    Pfizer Inc, Endocrine Care, New York, NY USA.
    Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy2019In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 63, no 3, p. 563-572Article in journal (Refereed)
    Abstract [en]

    PurposeTo explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.MethodsPatients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5yrs of PEGV treatment.ResultsAmong 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.058.7mg/dl at baseline, 116.4 +/- 44.8mg/dl at year 1 and 120.0 +/- 44.3mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n=109), mean blood glucose decreased by 20.2mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.Conclusions p id=Par4 Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

  • Sopher, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Juhlin, Christopher
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Levendal, Tegan
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Erlstrom, Mikael
    Geol Survey Sweden SGU, Kiliansgatan 10, S-22350 Lund, Sweden;Lund Univ, Dept Geol, Solvegatan 12, S-22362 Lund, Sweden.
    Nilsson, Karl
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Da Silva Soares, José Pedro
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Evaluation of the subsurface compressed air energy storage (CAES) potential on Gotland, Sweden2019In: Environmental Earth Sciences, ISSN 1866-6280, E-ISSN 1866-6299, Vol. 78, no 6, article id 197Article in journal (Refereed)
    Abstract [en]

    Wind energy is an important field of development for the island of Gotland, Sweden, especially since the island has set targets to generate 100% of its energy from renewable sources by 2025. Due to the variability of wind conditions, energy storage will be an important technology to facilitate the continued development of wind energy on Gotland and ensure a stable and secure supply of electricity. In this study, the feasibility of utilizing the Middle Cambrian Faludden sandstone reservoir on Gotland for Compressed Air Energy Storage (CAES) is assessed. Firstly, a characterization of the sandstone beneath Gotland is presented, which includes detailed maps of reservoir thickness and top reservoir structure. Analysis of this information shows that the properties of the Faludden sandstone and associated cap rock appear favorable for the application of CAES. Seven structural closures are identified below the eastern and southern parts of Gotland, which could potentially be utilized for CAES. Scoping estimates of the energy storage capacity and flow rate for these closures within the Faludden sandstone show that industrial scale CAES could be possible on Gotland.

  • Widén, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Munkhammar, Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Solar Radiation Theory2019 (ed. 1)Book (Other academic)
    Abstract [en]

    One of the challenges in solar engineering is that the availability of the solar resource varies with time and location. An important engineering task is to design solar energy systems that are able to collect as much solar radiation as possible under these constraints. This book introduces the basic properties of solar radiation that are required to understand how the solar resource can be converted into useful heat and electricity, and what the limitations are. It also shows how solar radiation on planar surfaces can be modeled mathematically. This is useful when optimizing the orientation of collecting surfaces and predicting the performance of different system designs. The book builds upon lecture notes from solar engineering courses at Uppsala University, carefully edited to suit a wider scientific and engineering audience. The two authors have, together, more than two decades' experience of teaching, research and development in the field of solar irradiance modeling.

  • Simaeva, I.N.
    et al.
    Immanuel Kant Baltic Federal University, Kaliningrad.
    Budarina, Anna O.
    Immanuel Kant Baltic Federal University, Kaliningrad.
    Sundh, Stellan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Cостояние и привлекательность инклюзивного и специального образования в России и странах Балтии2019In: Baltic Region, ISSN 2079-8555, Vol. 11, no 1, p. 76-91Article in journal (Refereed)
    Abstract [en]

    In this study, we examine the current state and prospects of inclusive education for learners with special needs and disabilities in the countries of the Baltic region (Poland, Sweden, Germany, Denmark, Latvia, Lithuania, Estonia, Norway, and Russia). We present a SWOT analysis of the development of inclusive education in different countries and analyse its strengths and weaknesses, risks, threats, and challenges from a political, economic, and technological perspective. In our analysis, we dissociate the issue of inclusive education from the problem of teaching learners with disabilities and examine the political, economic, social, and technological aspects of the environment that affect the educational situation of learners with disabilities. We consider inclusive education in the context of the documents of the Euro­pean Agency for Special Needs and Inclusive Education — an active educational institution that facilitates the preparation and adaptation of all learners to life in complex multicultural and integrated societies through rights, freedom, tolerance, and non-discrimination of per­sons with disabilities. Our analysis of inclusive education trends relies on the assessment of the goals and objectives, accessibility, and socio-cultural and economic feasibility of inclu­sive educational systems. We stress political, socio-cultural, and technological differences in practices, dynamics, and prospects for inclusive education in the Baltic region countries and Russia.

  • Public defence: 2019-05-08 09:00 TLS, Carolina Rediviva Library, Uppsala
    Ayyalasomayajula, Kalyan Ram
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Learning based segmentation and generation methods for handwritten document images2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

    Place, publisher, year, edition, pages
    Springer, 2017
    Series
    Lecture Notes in Computer Science, ISSN 0302-9743 ; 10269
    National Category
    Computer Vision and Robotics (Autonomous Systems)
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-335335 (URN)10.1007/978-3-319-59126-1_32 (DOI)000454359300032 ()978-3-319-59125-4 (ISBN)
    Conference
    SCIA 2017, June 12–14, Tromsø, Norway
    Funder
    Swedish Research Council, 2012-5743Riksbankens Jubileumsfond, NHS14-2068:1
    Available from: 2017-05-19 Created: 2017-12-04 Last updated: 2019-03-19Bibliographically approved
    3. PDNet: Semantic segmentation integrated with a primal-dual network for document binarization
    Open this publication in new window or tab >>PDNet: Semantic segmentation integrated with a primal-dual network for document binarization
    2019 (English)In: Pattern Recognition Letters, ISSN 0167-8655, E-ISSN 1872-7344, Vol. 121, p. 52-60Article in journal (Refereed) Published
    National Category
    Computer Vision and Robotics (Autonomous Systems)
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-366933 (URN)10.1016/j.patrec.2018.05.011 (DOI)000459876700008 ()
    Funder
    Swedish Research Council, 2012-5743Riksbankens Jubileumsfond, NHS14-2068:1
    Available from: 2018-05-16 Created: 2018-11-27 Last updated: 2019-04-04Bibliographically approved
    4. Feature evaluation for handwritten character recognition with regressive and generative Hidden Markov Models
    Open this publication in new window or tab >>Feature evaluation for handwritten character recognition with regressive and generative Hidden Markov Models
    2016 (English)In: Advances in Visual Computing: Part I, Springer, 2016, p. 278-287Conference paper, Published paper (Refereed)
    Place, publisher, year, edition, pages
    Springer, 2016
    Series
    Lecture Notes in Computer Science ; 10072
    National Category
    Computer Vision and Robotics (Autonomous Systems)
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-308662 (URN)10.1007/978-3-319-50835-1_26 (DOI)978-3-319-50834-4 (ISBN)
    Conference
    ISVC 2016, December 12–14, Las Vegas, NV
    Projects
    q2b – From Quill to Bytes
    Available from: 2016-12-10 Created: 2016-11-29 Last updated: 2019-03-19Bibliographically approved
    5. CalligraphyNet: Augmenting handwriting generation with quill based stroke width
    Open this publication in new window or tab >>CalligraphyNet: Augmenting handwriting generation with quill based stroke width
    2019 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Realistic handwritten document generation garners a lot ofinterest from the document research community for its abilityto generate annotated data. In the current approach we haveused GAN-based stroke width enrichment and style transferbased refinement over generated data which result in realisticlooking handwritten document images. The GAN part of dataaugmentation transfers the stroke variation introduced by awriting instrument onto images rendered from trajectories cre-ated by tracking coordinates along the stylus movement. Thecoordinates from stylus movement are augmented with thelearned stroke width variations during the data augmentationblock. An RNN model is then trained to learn the variationalong the movement of the stylus along with the stroke varia-tions corresponding to an input sequence of characters. Thismodel is then used to generate images of words or sentencesgiven an input character string. A document image thus cre-ated is used as a mask to transfer the style variations of the inkand the parchment. The generated image can capture the colorcontent of the ink and parchment useful for creating annotated data.

    National Category
    Computer Systems
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-379633 (URN)
    Conference
    26th IEEE International Conference on Image Processing
    Note

    Currently under review

    Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-04-08
  • Enros, Marcus
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Sociology.
    Konflikter, mobbning och trakasserier på arbetsplatsen: Kan generationsskillnader och postmaterialistiska värderingar förklara något?2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Forskningen har visat att dysfunktionella beteende som mobbing och trakasserier på arbetsplatser ökar runt om i världen. Detta kan vara en konsekvens av att olika generationer har olika värderingar och attityder till arbete på grund av den tidsanda som var förhärskande när det växte upp. Eller så förändras värderingar från materialistiska till postmaterialistiska, där prioriteringar som gäller materiella ting minskar för att istället fokusera på mera mellanmänskliga värderingar. De äldre ska enligt teorin om värderingsförskjutning vara mer materialistiska och de yngre mer postmaterialistiska. I den här uppsatsen har vi som syfte att testa om generationstillhörighet och/eller den postmaterialistiska värderingsförskjutningen kan förklara en del av konflikterna, mobbningen och trakasserierna på arbetsplatsen. Med hjälp av regressionsanalys analyseras de olika variablerna för att utröna om de har någon påverkan på konflikter, mobbning och trakasserier på arbetsplatser.

  • Hansen, Julie
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Institute for Russian and Eurasian Studies. Department of Modern Languages.
    Living through Literature: Essays in Memory of Omry Ronen2019Collection (editor) (Refereed)
    Abstract [en]

    Omry Ronen (1937–2012) was a world-renowned scholar of Russian literature and an inspiring teacher. His most influential work focused on historical and descriptive poetics, metrics, structural analysis of verse and prose, Russian Modernist poetry, and particularly the work of Osip Mandelstam. He also studied Alexander Pushkin’s poetics, subtextual interpretive strategies, the poetry of the OBERIU, the work of Vladimir Nabokov and the problems of literary multilingualism, the picaresque in Russian literature, popular fiction and science fiction, children’s literature, intersemiotic transposition in the arts, literature and cinema, the history of Russian formalism and structuralism, twentieth-century Ukrainian poetry, and the history and theory of Russian Symbolism, Acmeism, and Futurism. 

    This volume honors Omry Ronen’s memory and scholarly legacy with ten essays by his former students Karen Evans-Romaine, Sara Feldman, Susanne Fusso, Julie Hansen, Kelly E. Miller, Nancy Pollak, Irena Ronen, Stephanie Sandler, Timothy D. Sergay, and Michael Wachtel. The volume also contains an introduction by Vyacheslav Vsevolodovich Ivanov. 

  • Larm, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Swedish Council Informat Alcohol & Other Drugs CA, Dept Anal & Method, Klara Norra Kyrkogata 34, SE-10725 Stockholm, Sweden;Karolinska Inst, Dept Clin Neurosci, Solna, Sweden.
    Raninen, Jonas
    Swedish Council Informat Alcohol & Other Drugs CA, Dept Anal & Method, Klara Norra Kyrkogata 34, SE-10725 Stockholm, Sweden;Karolinska Inst, Dept Clin Neurosci, Solna, Sweden.
    Åslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Svensson, Johan
    Swedish Council Informat Alcohol & Other Drugs CA, Dept Anal & Method, Klara Norra Kyrkogata 34, SE-10725 Stockholm, Sweden;Karolinska Inst, Dept Clin Neurosci, Solna, Sweden.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    The increased trend of non-drinking alcohol among adolescents: what role do internet activities have?2019In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 29, no 1, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Background: Recently, an increased trend toward non-drinking among adolescents has been observed in several countries. The aim of the present study is to evaluate a common suggestion in literature, that adolescents do not drink alcohol because they spend more time on the internet, monitored at home, by examining associations between internet activities (social media/chatting and computer gaming) and non-drinking.

    Methods: A health questionnaire was distributed to all 9th graders (1516 years) in a mid-sized Swedish county in 2008, 2010 and 2012. In total, 7089 students returned the questionnaire.

    Results: In contrast to the suggestion, no association was found between total time spent on computers and non-drinking. Social media/chatting was robustly associated with a decreased probability of non-drinking across the three survey years. On the other hand, computer gaming during weekends only (OR = 1.74, CI = 1.132.69) or both on weekdays and weekends increased the probability of non-drinking (OR = 1.82, CI = 1.312.54) in 2012 only. However, neither social media/chatting nor computer gaming was associated with the increased trend of non-drinking from 2008 to 2012.

    Conclusions: Internet activities were in general not associated with non-drinking among adolescents aged 1516 years in Sweden. Although, a weak positive association between computer gaming and non-drinking was found in 2012, this effect benefited the vast majority of the boys. The larger alcohol use among those with extensive social media use/chatting may indicate that these online platforms are arenas where adolescents are exposed for positive alcohol preferences and alcohol advertising without parental supervision.

  • de Waard, Anne-Karien M.
    et al.
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr, Dept Gen Practice, Utrecht, Netherlands.
    Hollander, Monika
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr, Dept Gen Practice, Utrecht, Netherlands.
    Korevaar, Joke C.
    Nivel Netherlands Inst Hlth Serv Res, Utrecht, Netherlands.
    Nielen, Mark M. J.
    Nivel Netherlands Inst Hlth Serv Res, Utrecht, Netherlands.
    Carlsson, Axel C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Family Med & Primary Care, Stockholm, Sweden.
    Lionis, Christos
    Univ Crete, Sch Med, Clin Social & Family Med, Iraklion, Greece.
    Seifert, Bohumil
    Charles Univ Prague, Fac Med 1, Inst Gen Practice, Prague, Czech Republic.
    Thilsing, Trine
    Univ Southern Denmark, Dept Publ Hlth, Res Unit Gen Practice, Odense C, Denmark.
    de Wit, Niek J.
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr, Dept Gen Practice, Utrecht, Netherlands.
    Schellevis, Francois G.
    Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Dept Gen Practice & Elderly Care Med, Amsterdam, Netherlands.
    Angelaki, Agapi
    Univ Crete, Sch Med, Clin Social & Family Med, Iraklion, Greece.
    Holzmann, Martin J.
    Karolinska Inst, Dept Med, Stockholm, Sweden.
    Kral, N.
    Charles Univ Prague, Fac Med 1, Inst Gen Practice, Prague, Czech Republic.
    Sondergaard, Jens
    Sonderlund, Anders L.
    Univ Southern Denmark, Dept Publ Hlth, Res Unit Gen Practice, Odense C, Denmark.
    Wandell, P.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Family Med & Primary Care, Stockholm, Sweden.
    Selective prevention of cardiometabolic diseases: activities and attitudes of general practitioners across Europe2019In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 29, no 1, p. 88-93Article in journal (Refereed)
    Abstract [en]

    Background: Cardiometabolic diseases (CMDs) are the number one cause of death. Selective prevention of CMDs by general practitioners (GPs) could help reduce the burden of CMDs. This measure would entail the identification of individuals at high risk of CMDsubut currently asymptomaticufollowed by interventions to reduce their risk. No data were available on the attitude and the extent to which European GPs have incorporated selective CMD prevention into daily practice.

    Methods: A survey among 575 GPs from the Czech Republic, Denmark, Greece, the Netherlands and Sweden was conducted between September 2016 and January 2017, within the framework of the SPIMEU-project.

    Results: On average, 71% of GPs invited their patients to attend for CMD risk assessment. Some used an active approach (47%) while others used an opportunistic approach (53%), but these values differed between countries. Most GPs considered selective CMD prevention as useful (82%) and saw it as part of their normal duties (84%). GPs who did find selective prevention useful were more likely to actively invite individuals compared with their counterparts who did not find prevention useful. Most GPs had a disease management programme for individuals with risk factor(s) for cardiovascular disease (71%) or diabetes (86%).

    Conclusions: Although most GPs considered selective CMD prevention as useful, it was not universally implemented. The biggest challenge was the process of inviting individuals for risk assessment. It is important to tailor the implementation of selective CMD prevention in primary care to the national context, involving stakeholders at different levels.

  • Burman, Lars
    Uppsala University, University Library.
    Glömd kärlek: Om Torsten Rudeens dikter2019In: Kungl. Humanistiska Vetenskaps-Samfundet i Uppsala. Årsbok, ISSN 0349-0416, Vol. 2017-2018, p. 37-41Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Forgotten Love. The Poetry of Torsten Rudeen

    Torsten Rudeen (1661–1729) was a productive and much-appreciatedwriter of occasional poetry, especially during the 1680s, but his most notablecontribution to Swedish literature are his love poems, not least those tohis wife Anna (1675–1695). These were not printed in his own time andhave never been scholarly collected and edited, a reason why Rudeen todayis less known. His poetry on love and matrimony will, however, be publishedby Lars Burman in a critical edition in early 2019 (Svenska Vitterhetssamfundet).This article introduces Rudeen who harkened from Värmlandand studied at Uppsala University. He was appointed poëseos professorat Turku (Åbo) University in 1692 and Superintendent (Bishop) inKarlstad in 1709. He crowned his career as Bishop in Linköping. The articlediscusses the fate of lesser-known but interesting authorships, andhighlights the poetic immediacy of Torsten Rudeen’s sentiments, unusualfor the Swedish 17th century.

  • Janson, Svante
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Probability Theory.
    Linusson, Svante
    Matematiska institutionen, KTH, Stockholm, Sweden.
    Proportionella val inom kommunfullmäktige2019Report (Other academic)
    Abstract [sv]

    Vi diskuterar två olika problem som kan uppstå vid proportionella val i kommunfullmäktige och regionfullmäktige når ett parti försöker en kupp genom att utan samtycke gå i kartell med ett annat parti vid val till nämnd eller styrelse, vilket aktualiserades i åtminstone ett par fall hösten 2018. Det första problemet är vad sådana oönskade valkarteller kan få för effekter, och vilka möjligheter det finns för ett parti att skydda sig från att bli del i en oönskad valkartell. Det andra problemet är att i en sådan valkartell kan ett parti genom att splittra upp sina kandidater strategiskt  på flera olika valsedlar få fler platser i en nämnd är vad som är proportionellt. Detta andra problem bottnar i att lagen om proportionella val stipulerar att Thieles metod skall användas för fördelning inom kartellen. På detta problem finns en enkel matematisk lösning och vi argumenterar för att man skall byta till Phragméns metod som används för motsvarande val till utskott i riksdagen.

  • Sundell, Lars-Göran
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Modern Languages.
    I skuggan av Perrault: om Madame d'Aulnoy2018In: Kungl. Humanistiska Vetenskaps-Samfundet i Uppsala. Årsbok, ISSN 0349-0416, Vol. 2017-2018, p. 5-35Article in journal (Other academic)
    Abstract [en]

    In Perrault’s Shadow ‒ Madame d’Aulnoy

    Née Marie-Catherine Le Jumel de Barneville, Madame d’Aulnoy (1650/51‒1705), a once famous now mainly forgotten French writer of fairy tales, was born in Normandy to a noble family. At the age of sixteen she was married to Baron d’Aulnoy, but their marriage soon became a disaster. A failed coup to kill her husband resulted in exile for both herself and her mother. After a short incarceration Mme d’Aulnoy was set free, but her whereabouts between 1670‒1690 remain unclear. She obviously visited Spain and England, and her experiences from these countries would provide her with material for later writing. Mme d’Aulnoy rose to immediate literary fame in 1690 with the publication of her first novel Story of Hypolitus, Count of Douglas (Hypolite, comte de Duglas), in which was embedded her first fairy tale, later known as The Island of Happiness (L’Île de la Félicité). Her travel narratives include Memoirs of the Court in England in 1675 (Mémoires de la cour d’Angleterre), i.e. during the reign of the Stuart King Charles II, as well as Memoirs of the Court of Spain (Mémoires de la cour d’Espagne) around 1680, under Carlos II, the last of the Habsburg Kings on the Spanish throne. Her Travels in Spain (Relation du voyage d’Espagne), published in 1691, gives a vivid and evocative account of Spanish life and customs, as well as depicting the countryside as she crosses the Pyrenees on her way to her final destination, the capital Madrid. Mme d’Aulnoy’s claim to fame rests today on her two collections of fairy tales, Tales of the Fairies (Contes des Fées, 1697) and New Tales or Fairies in Fashion (Contes nouveaux ou les Fées à la mode, 1698). She isthe first to introduce fairies (les fées) into French tales. Her first collection was published, coincidentally, just a few months after Charles Perrault’s Tales of Mother Goose (Les Contes de ma Mère l’Oye) in 1697. Mme d’Aulnoy and her contemporary, mostly female, writers of fairytales have unquestionably been overshadowed in the literary canon by Charles Perrault. Nevertheless, Mme d’Aulnoy is well worth being read and studied on her own merits as she epitomizes the fairy tale genre of her time. In this article I look briefly into her turbulent life, examine her travel writings from Spain and England and eventually take into account her fairytales.

  • Barucca, G.
    et al.
    Martin, A.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Akram, Adeel
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Calén, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Andersson, Walter Ikegami
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Johansson, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Kupsc, Andrzej
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Marciniewski, Pawel
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Papenbrock, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Regina, Jenny
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Schönning, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Wolke, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Nuclear Physics.
    Zmeskal, J.
    Precision resonance energy scans with the PANDA experiment at FAIR: Sensitivity study for width and line shape measurements of the X(3872)2019In: European Physical Journal A, ISSN 1434-6001, E-ISSN 1434-601X, Vol. 55, no 3, article id 42Article in journal (Refereed)
    Abstract [en]

    This paper summarises a comprehensive Monte Carlo simulation study for precision resonance energy scan measurements. Apart from the proof of principle for natural width and line shape measurements of very narrow resonances with PANDA, the achievable sensitivities are quantified for the concrete example of the charmonium-like X(3872) state discussed to be exotic, and for a larger parameter space of various assumed signal cross-sections, input widths and luminosity combinations. PANDA is the only experiment that will be able to perform precision resonance energy scans of such narrow states with quantum numbers of spin and parities that differ from JPC=1--.

  • Rentoft, Matilda
    et al.
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden;Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden.
    Svensson, Daniel
    Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden.
    Sjödin, Andreas
    Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden;FOI Swedish Def Res Agcy, Div CBRN Secur & Def, Umea, Sweden.
    Olason, Pall I.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöström, Olle
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden;Unit Res Educ & Dev, Ostersund, Region Jamtland, Sweden.
    Nylander, Carin
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden.
    Osterman, Pia
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden.
    Sjögren, Rickard
    Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden.
    Netotea, Sergiu
    Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden;Chalmers Univ Technol, Dept Biol & Biol Engn, Sci Life Lab, Gothenburg, Sweden.
    Wibom, Carl
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden.
    Cederquist, Kristina
    Umea Univ, Dept Med Biosci Med & Clin Genet, Umea, Sweden.
    Chabes, Andrei
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden.
    Trygg, Johan
    Umea Univ, Dept Chem, Computat Life Sci Cluster, Umea, Sweden.
    Melin, Beatrice S.
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden.
    Johansson, Erik
    Umea Univ, Dept Med Biochem & Biophys, Umea, Sweden.
    A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213350Article in journal (Refereed)
    Abstract [en]

    Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e. g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

  • Bini, Monica
    et al.
    Univ Pisa, Dipartimento Sci Terra, Pisa, Italy.
    Zanchetta, Giovanni
    Univ Pisa, Dipartimento Sci Terra, Pisa, Italy.
    Persoiu, Aurel
    Romanian Acad, Emil Racovita Inst Speleol, Cluj Napoca, Romania.
    Cartier, Rosine
    Lund Univ, Dept Geol, Quaternary Sci, Lund, Sweden.
    Catala, Albert
    Univ Barcelona, Fac Geol, GRC Geociencies Marines, Dept Dinam Terra & Ocea, Barcelona, Spain.
    Cacho, Isabel
    Univ Barcelona, Fac Geol, GRC Geociencies Marines, Dept Dinam Terra & Ocea, Barcelona, Spain.
    Dean, Jonathan R.
    Univ Hull, Sch Environm Sci, Kingston Upon Hull, N Humberside, England.
    Di Rita, Federico
    Univ Roma La Sapienza, Dipartimento Biol Ambientale, Rome, Italy.
    Drysdale, Russell N.
    Univ Melbourne, Sch Geog, Melbourne, Vic, Australia.
    Finné, Martin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Archaeology and Ancient History, Classical archaeology and ancient history. Stockholm Univ, Dept Phys Geog, Stockholm, Sweden.
    Isola, Ilaria
    Ist Nazl Geofis & Vulcanol, Sez Pisa, Pisa, Italy.
    Jalali, Bassem
    Univ Paris 06, Sorbonne Univ, LOCEAN Lab, CNRS,IRD,MNHN,UPMC, Paris, France.
    Lirer, Fabrizio
    CNR Napoli, Ist Sci Marine ISMAR, Naples, Italy.
    Magri, Donatella
    Univ Roma La Sapienza, Dipartimento Biol Ambientale, Rome, Italy.
    Masi, Alessia
    Univ Roma La Sapienza, Dipartimento Biol Ambientale, Rome, Italy.
    Marks, Leszek
    Univ Warsaw, Fac Geol, Warsaw, Poland.
    Mercuri, Anna Maria
    Univ Reggio Emilia & Modena, Dipartimento Sci Vita, Modena, Italy.
    Peyron, Odile
    Univ Montpellier, Inst Sci Evolut ISEM, Montpellier, France.
    Sadori, Laura
    Univ Roma La Sapienza, Dipartimento Biol Ambientale, Rome, Italy.
    Sicre, Marie-Alexandrine
    Univ Paris 06, Sorbonne Univ, LOCEAN Lab, CNRS,IRD,MNHN,UPMC, Paris, France.
    Welc, Fabian
    Cardinal Stefan Wyszynski Univ, Inst Archaeol, Warsaw, Poland.
    Zielhofer, Christoph
    Univ Leipzig, Chair Phys Geog, Leipzig, Germany.
    Brisset, Elodie
    Inst Catala Paleoecol Humana & Evolucio Social, IPHES, Tarragona, Spain;Univ Rovira & Virgili, Area Prehist, Tarragona, Spain.
    The 4.2 ka BP Event in the Mediterranean region: an overview2019In: Climate of the Past, ISSN 1814-9324, E-ISSN 1814-9332, Vol. 15, no 2, p. 555-577Article, review/survey (Refereed)
    Abstract [en]

    The Mediterranean region and the Levant have returned some of the clearest evidence of a climatically dry period occurring around 4200 years ago. However, some regional evidence is controversial and contradictory, and issues remain regarding timing, progression, and regional articulation of this event. In this paper, we review the evidence from selected proxies (sea-surface temperature, precipitation, and temperature reconstructed from pollen, delta O-18 on speleothems, and delta O-18 on lacustrine carbonate) over the Mediterranean Basin to infer possible regional climate patterns during the interval between 4.3 and 3.8 ka. The values and limitations of these proxies are discussed, and their potential for furnishing information on seasonality is also explored. Despite the chronological uncertainties, which are the main limitations for disentangling details of the climatic conditions, the data suggest that winter over the Mediterranean involved drier conditions, in addition to already dry summers. However, some exceptions to this prevail - where wetter conditions seem to have persisted - suggesting regional heterogeneity in climate patterns. Temperature data, even if sparse, also suggest a cooling anomaly, even if this is not uniform. The most common paradigm to interpret the precipitation regime in the Mediterranean - a North Atlantic Oscillation-like pattern - is not completely satisfactory to interpret the selected data.

  • Public defence: 2019-05-10 01:15 Sal IX, Uppsala
    Drevin, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Measuring Pregnancy Planning and the Effect of Childhood Abuse on Reproductive Health2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The London Measure of Unplanned Pregnancy (LMUP) and the Swedish Pregnancy Planning Scale (SPPS) are two measurements of pregnancy planning. Adverse childhood experiences (ACEs) and childhood abuse are stressful events that have been suggested to have both short- and long-term effects.

    Study I investigated the psychometric properties of the LMUP and the SPPS and compared their assessments. Questionnaire data from 2,314 pregnant women showed medium-high construct validity and high test-retest reliability for both measurements. The convergent validity of LMUP was low. The assessments of the LMUP and the SPPS corresponded substantially.

    Study II explored how the SPPS was interpreted and what women considered when responding to it. Twenty-five pregnant women were interviewed. Women responding to the SPPS took into account their life situation, intentions, desires, timing, actions to prepare for, or avoid, pregnancy, having discussed becoming pregnant with their partner, and reactions after learning of the pregnancy.

    Study III analysed the association between ACEs and pregnancy-related pain. Pregnant women (n = 142) responded to questionnaires in early and late pregnancy, respectively, and reported their pain intensities and pain distributions. Greater exposure to ACEs was associated with higher pain distribution and women exposed to ACEs reported higher worst pain intensities compared to non-exposed.

    Study IV investigated effects of childhood emotional, physical and sexual abuse on pregnancy planning. The effect of a potential collider-stratification bias were also studied. Questionnaire data from 76,197 pregnant Norwegian women showed separate but no joint effects of the categories on having an unplanned pregnancy and a collider-stratification bias could not explain the effects.

    The LMUP and the SPPS measure somewhat different aspects of pregnancy planning and there is a substantial agreement between their assessments. Both the LMUP and the SPPS showed good validity and test-retest reliability. However, the LMUP would likely benefit from item reduction and the SPPS poorly captures any health-related changes made in and the preconception period.

    The results suggest that childhood abuse and ACEs have an effect on pregnancy planning and pregnancy-related pain. The findings suggest that preventing child abuse could have a positive effect on later reproductive health.

    List of papers
    1. Measuring pregnancy planning: A psychometric evaluation and comparison of two scales
    Open this publication in new window or tab >>Measuring pregnancy planning: A psychometric evaluation and comparison of two scales
    2017 (English)In: Journal of Advanced Nursing, ISSN 0309-2402, E-ISSN 1365-2648, Vol. 73, no 11, p. 2765-2775Article in journal (Refereed) Published
    Abstract [en]

    Aims: To psychometrically test the London Measure of Unplanned Pregnancy and compare it with the Swedish Pregnancy Planning Scale. Background: The incidence of unplanned pregnancies is an important indicator of reproductive health. The London Measure of Unplanned Pregnancy measures pregnancy planning by taking contraceptive use, timing, intention to become pregnant, desire for pregnancy, partner agreement, and pre-conceptual preparations into account. It has, however, previously not been psychometrically evaluated using confirmatory factor analysis. The Likert-scored single-item Swedish Pregnancy Planning Scale has been developed to measure the woman's own view of pregnancy planning level. Design: Cross-sectional design. Methods: In 2012-2013, 5493 pregnant women living in Sweden were invited to participate in the Swedish Pregnancy Planning study, of whom 3327 (61%) agreed to participate and answered a questionnaire. A test-retest pilot study was conducted in 2011-2012. Thirty-two participants responded to the questionnaire on two occasions 14 days apart. Data were analysed using confirmatory factor analysis, Cohen's weighted kappa and Spearman's correlation. Results: All items of the London Measure of Unplanned Pregnancy contributed to measuring pregnancy planning, but four items had low item-reliability. The London Measure of Unplanned Pregnancy and Swedish Pregnancy Planning Scale corresponded reasonably well with each other and both showed good test-retest reliability. Conclusion: The London Measure of Unplanned Pregnancy may benefit from item reduction and its usefulness may be questioned. The Swedish Pregnancy Planning Scale is time-efficient and shows acceptable reliability and construct validity, which makes it more useful for measuring pregnancy planning.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2017
    Keywords
    antenatal care, confirmatory factor analysis, instrument development, midwives, nursing, pregnancy planning, psychometrics, reproducibility of results, reproductive health, unplanned pregnancy
    National Category
    Nursing
    Identifiers
    urn:nbn:se:uu:diva-339704 (URN)10.1111/jan.13364 (DOI)000418363000027 ()28620936 (PubMedID)
    Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2019-03-21Bibliographically approved
    2. 'How planned was your current pregnancy?' - What pregnant women take into account when responding to the Swedish Pregnancy Planning Scale
    Open this publication in new window or tab >>'How planned was your current pregnancy?' - What pregnant women take into account when responding to the Swedish Pregnancy Planning Scale
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Pregnancy planning, measurement, unplanned pregnancy, unintended pregnancy, reproductive health
    National Category
    Medical and Health Sciences
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-379621 (URN)
    Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-21
    3. Adverse childhood experiences influence development of pain during pregnancy.
    Open this publication in new window or tab >>Adverse childhood experiences influence development of pain during pregnancy.
    Show others...
    2015 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 8, p. 840-846Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate the association between adverse childhood experiences (ACE) and pain with onset during pregnancy.

    DESIGN: Cross-sectional study.

    SETTING: Eighteen antenatal clinics in southern Mid-Sweden.

    SAMPLE: Of 293 women invited to participate, 232 (79%) women agreed to participate in early pregnancy and were assessed in late pregnancy.

    METHODS: Questionnaires were distributed in early and late pregnancy. The questionnaires sought information on socio-demography, ACE, pain location by pain drawing and pain intensity by visual analogue scales. Distribution of pain was coded in 41 predetermined areas.

    MAIN OUTCOME MEASURES: Pain in third trimester with onset during present pregnancy: intensity, location and number of pain locations.

    RESULTS: In late pregnancy, 62% of the women reported any ACE and 72% reported any pain location with onset during the present pregnancy. Among women reporting any ACE the median pain intensity was higher compared with women without such an experience (p = 0.01). The accumulated ACE displayed a positive association with the number of reported pain locations in late pregnancy (rs  = 0.19, p = 0.02). This association remained significant after adjusting for background factors in multiple regression analysis (p = 0.01). When ACE was dichotomized the prevalence of pain did not differ between women with and without ACE. The subgroup of women reporting physical abuse as a child reported a higher prevalence of sacral and pelvic pain (p = 0.0003 and p = 0.02, respectively).

    CONCLUSIONS: Adverse childhood experiences were associated with higher pain intensities and larger pain distributions in late pregnancy, which are risk factors for transition to chronic pain postpartum.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-256150 (URN)10.1111/aogs.12674 (DOI)000357983900005 ()25965273 (PubMedID)
    Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2019-03-21Bibliographically approved
    4. Childhood abuse and unplanned pregnancies: A cross-sectional study of women in the Norwegian Mother and Child Cohort Study
    Open this publication in new window or tab >>Childhood abuse and unplanned pregnancies: A cross-sectional study of women in the Norwegian Mother and Child Cohort Study
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Childhood abuse, reproductive health, unplanned pregnancy, unintended pregnancy
    National Category
    Medical and Health Sciences
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-379622 (URN)
    Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-03-21
  • O'Hare, Paschal
    et al.
    Lund Univ, Dept Geol Quaternary Sci, S-22362 Lund, Sweden.
    Mekhaldi, Florian
    Lund Univ, Dept Geol Quaternary Sci, S-22362 Lund, Sweden.
    Adolphi, Florian
    Lund Univ, Dept Geol Quaternary Sci, S-22362 Lund, Sweden;Univ Bern, Phys Inst, Climate & Environm Phys & Oeschger Ctr Climate Ch, CH-3012 Bern, Switzerland.
    Raisbeck, Grant
    Univ Paris Saclay, CNRS, Ctr Sci Nucl & Sci Matiere, F-91405 Orsay, France.
    Aldahan, Ala
    United Arab Emirates Univ, Dept Geol, Al Ain, U Arab Emirates.
    Anderberg, Emma
    Lund Univ, Dept Geol Quaternary Sci, S-22362 Lund, Sweden.
    Beer, Jurg
    Swiss Fed Inst Aquat Sci & Technol, Dept Surface Waters, CH-8600 Dubendorf, Switzerland.
    Christl, Marcus
    Swiss Fed Inst Technol, Lab Ion Beam Phys, CH-8093 Zurich, Switzerland.
    Fahrni, Simon
    Swiss Fed Inst Technol, Lab Ion Beam Phys, CH-8093 Zurich, Switzerland.
    Synal, Hans-Arno
    Swiss Fed Inst Technol, Lab Ion Beam Phys, CH-8093 Zurich, Switzerland.
    Park, Junghun
    Korea Inst Geosci & Mineral Resources, Daejeon 34132, South Korea.
    Possnert, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, För teknisk-naturvetenskapliga fakulteten gemensamma enheter, Tandem Laboratory.
    Southon, John
    Univ Calif Irvine, Keck Accelerator Mass Spectrometry AMS Lab, Irvine, CA 92697 USA.
    Bard, Edouard
    Aix Marseille Univ, CNRS, Inst Natl Rech Agron, Coll France,CEREGE,IRD,UMR 34, F-13545 Aix En Provence, France.
    Muscheler, Raimund
    Lund Univ, Dept Geol Quaternary Sci, S-22362 Lund, Sweden.
    Multiradionuclide evidence for an extreme solar proton event around 2,610 BP (similar to 660 BC)2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 13, p. 5961-5966Article in journal (Refereed)
    Abstract [en]

    Recently, it has been confirmed that extreme solar proton events can lead to significantly increased atmospheric production rates of cosmogenic radionuclides. Evidence of such events is recorded in annually resolved natural archives, such as tree rings [carbon-14 (C-14)] and ice cores [beryllium-10 (Be-10), chlorine-36 (Cl-36)]. Here, we show evidence for an extreme solar event around 2,610 years B.P. (similar to 660 BC) based on high-resolution Be-10 data from two Greenland ice cores. Our conclusions are supported by modeled C-14 production rates for the same period. Using existing Cl-36 ice core data in conjunction with Be-10, we further show that this solar event was characterized by a very hard energy spectrum. These results indicate that the 2,610-years B.P. event was an order of magnitude stronger than any solar event recorded during the instrumental period and comparable with the solar proton event of AD 774/775, the largest solar event known to date. The results illustrate the importance of multiple ice core radionuclide measurements for the reliable identification of short-term production rate increases and the assessment of their origins.

  • Holmqvist, Elin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Linguistics and Philology.
    "Om man skriver dem istället för de så flyger jag i taket": på spaning efter språkpolisen2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    I den här studien har jag undersökt om särskilda grupper av människor reagerar starkare än andra på språkriktighetsfel. Jag har undersökt om det finns ett samband mellan ålder, kön, utbildning och språkattityder, och hur en person reagerar på språkriktighetsfel i skrivet språk. Jag har utfört ett experiment som gick ut på att informanter fick läsa en stimulustext, varefter de i en enkät fick svara på frågor om vilka känslor texten väckte hos dem, och hur de uppfattade texten. De fick även svara på frågor angående demografisk data och om språkattityder. Stimulustexten fanns i två versioner varav den ena hade manipulerats med språkriktighetsfel. Svaren från de informanter som läst texten med språkriktighetsfel jämfördes med svaren från informanterna som läst texten utan språkriktighetsfel, för att se om det fanns någon skillnad på hur de svarat. Sedermera jämfördes data från de informanter som svarat mest negativt på frågorna med data från den totala populationen, för att se om de avviker i något avseende när det gäller demografi och språkattityder. Resultaten av studien visade att det inte kunde fastställas något samband mellan personers reaktioner på språkriktighetsfel och ålder, kön eller utbildning. Däremot kunde man se att en text med språkriktighetsfel bedömdes som mindre välskriven, och något mer svårläst, än en text utan språkriktighetsfel. Dessutom kunde man se en antydan på att det kan finnas ett samband mellan hur arg eller irriterad en person blir av språkriktighetsfel, och hur viktigt de bedömer att korrekt grammatik och stavning är.

  • Juslenius, Adina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Klasskamrater som resurser i matematikundervisning2019Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • Janson, Svante
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Probability Theory.
    Shcherbakov, Vadim
    Royal Holloway Univ London, Egham, Surrey, England.
    Volkov, Stanislav
    Lund Univ, Lund, Sweden.
    Long Term Behaviour of a Reversible System of Interacting Random Walks2019In: Journal of statistical physics, ISSN 0022-4715, E-ISSN 1572-9613, Vol. 175, no 1, p. 71-96Article in journal (Refereed)
    Abstract [en]

    This paper studies the long-term behaviour of a system of interacting random walks labelled by vertices of a finite graph. We show that the system undergoes phase transitions, with different behaviour in various regions, depending on model parameters and properties of the underlying graph. We provide the complete classification of the long-term behaviour of the corresponding continuous time Markov chain, identifying whether it is null recurrent, positive recurrent, or transient. The proofs are partially based on the reversibility of the model, which allows us to use the method of electric networks. We also provide some alternative proofs (based on the Lyapunov function method and the renewal theory), which are of interest in their own right, since they do not require reversibility and can be applied to more general situations.

  • Sjösten, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Komplexa tal i gymnasiematematikens läromedel2019Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • Thufvesson Retzner, Anders
    Påverkan av bergstunnel på ovanförliggande jordlager: Modellering av geologi, grundvattenmagasin och Kista Science City VA-tunnel2019Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    To determine leakage into rock tunnels one can choose between a range of analytical models. Common to all analytical models is their inability to reflect complex hydrogeological settings and only taking into account hydraulic conductivity, dimensions of the tunnel and tunnel depth. In Stockholm, Sweden, a rock tunnel built in 2017 currently exceeds maximum allowed leakage which was derived from an analytical model.

    A model is developed to represent the site’s hydrogeological settings. The model is used to simulate groundwater levels with and without representation of the tunnel, the area of influence being the difference between the two. A Voronoi-cell unstructured grid is implemented in MODFLOW-USG to improve representation of complex geology and increase numerical stability. Geology is modeled using soil depth, bed rock surface and geotechnical investigations. Rock hydraulic conductivity is derived from a well archive. A second model is developed to represent geological fault zones and a connecting tunnel.

    The model verifies the positive relationship between magnitude of leakage and size of the zone of impact. Results also show an improved approximation of the zone of impact as compared to an earlier approximation derived from a simple water balance. The numerical models predicts a larger zone of impacts in some areas and a smaller zone of impact in other areas. Furthermore, the numerical model shows that a change in leakage of 0,01 l/min and m tunnel can alter the size of the zone of impact by about 19%.

    By comparing some of the most well-known analytical models to predict leakage it is found that the approximation can differ by a factor 3 using identical parameter values. To reflect the uncertainty in predicted leakage the author recommends simulating a numerical model with varying magnitudes of leakage. This will help in risk assessment and identify a site specific relationship between magnitude of leakage and area of influence.

  • Almqvist, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Orpwood, Graham
    Lundqvist, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Lidar, Malena
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Analysing validity: The case of Swedish national tests in year 6 science2019Report (Other academic)
    Abstract [en]

    The purpose of this article is to analyse and discuss standardized tests in biology, physics and chemistry with a special focus on their content validity. In the article we describe and discuss three different tensions between the Swedish curricula and standardized tests in science: (1) Curricular intentions and assessment choices, (2) The ‘knowledge requirements’ specified in the curriculum and the marking scheme used in the assessment and (3) The intention of the evaluation system and its actual result. These tensions have consequences for the validity of the tests. Hence, it is necessary to regard these tests as only one of many resources teachers can use in their teaching and assessment practices.

  • Erliksson, Agnes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Jonsér, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Fokus på personcentrerad vård: Sjuksköterskors uppfattningar och erfarenheter av handledningssituationer2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: Sjuksköterskans huvudsakliga område är omvårdnad. Omvårdnaden ska ske personcentrerat vilket innebär att sjuksköterskan ska ha en helhetssyn på varje ny individ som vårdas. Det ingår också i sjuksköterskeprofessionen att kunna handleda studenter och förmedla det personcentrerade förhållningssättet vidare till dem. Syfte: Syftet med studien var att undersöka sjuksköterskors uppfattningar och erfarenheter av att förmedla ett personcentrerat förhållningssätt i handledningssituationer till sjuksköterskestudenter. Metod: Kvalitativ, deskriptiv metod användes för studien. Semistrukturerade intervjuer genomfördes med sju legitimerade sjuksköterskor på ett av Sveriges universitetssjukhus. En kvalitativ innehållsanalys användes för att analysera data. Resultat: Innehållsanalysen resulterade i sex kategorier: Att lära studenterna att se alla patienter, att förmedla vikten av god kommunikation, att förmedla värdegrunder inom personcentrerad vård, att studenterna tar lärdom av sjuksköterskornas arbetssätt, att hinder försvårar förmedlingen av det personcentrerade förhållningssättet och att möjliggöra det personcentrerade förhållningssättet. Deltagarna framförde att det var viktigt att förmedla till studenterna att ha alla patienter i fokus där man ser människan och dennes resurser och inte endast dennes sjukdom samt att kommunikation var en värdefull färdighet att utveckla. Deltagarnas erfarenheter var att de diskuterade med studenterna om viktiga värdegrunder som lägger grunden för det personcentrerade förhållningssättet. Tid- och resursbrist visade sig vara ett hinder för att i handledningssituationer arbeta personcentrerat. Att introducera studenterna till ett nära teamarbete runt patienterna och att använda PCÖ, personcentrerad överlämning, var möjligheter till att främja det personcentrerade förhållningssättet. Slutsats: Hinder som tid- och resursbrist kan komplicera tillämpningen av det personcentrerade förhållningssättet i handledningssituationer. Trots det finns det goda möjligheter till att bibehålla det personcentrerade förhållningssättet i handledningssituationer då sjuksköterskestudenterna har en förmåga till att strukturera upp och prioritera omvårdnadsarbetet samt att beakta de viktigaste värdegrunderna. Detta resulterar i ökad tid till patienterna och högre kvalité på omvårdnaden.

  • Public defence: 2019-05-10 09:00 Akademiska sjukhuset (Arbets- och miljömedicin), Uppsala
    Alinaghizadeh, Hassan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Radioactive fall-out from the Chernobyl nuclear power plant accident in 1986 and cancer rates in Sweden, a 25-year follow up2019Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim: The current research aimed to study the association between exposure to low-dose radiation fallout after the Chernobyl accident in 1986 and the incidence of cancer in Sweden.

    Methods: A nationwide study population, selecting information from nine counties out of 21 in Sweden for the period from 1980 – 2010.

    In the first study, an ecological design was defined for two closed cohorts from 1980 and 1986. A possible exposure response pattern between the exposure to 137Cs on the ground and the cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (n=2.2 million). The activity of 137Cs at the county, municipality and parish level in 1986 was retrieved from the Swedish Radiation Safety Authority (SSI) and used as a proxy for received dose of ionizing radiation. Information about diagnoses of cancer (ICD-7 code 140-209) from 1958 – 2009 were received from the Swedish Cancer Registry, National Board of Health and Welfare (368,244 cases were reported for the period 1958 to 2009). The incidence rate ratios were calculated by using Poisson Regression for pre-Chernobyl (1980 – 1986) and post-Chernobyl (1986 – 2009) using average deposition of 137Cs at three geographical levels: county (n=9), municipality (n=95), and parish level (n=612). Also, a time trend analysis with age standardized cancer incidence in the study population and in the general Swedish population was drawn from 1980 – 2009.

    In the second study, a closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of 137Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the Swedish Cancer Registry, National Board of Health and Welfare. Individuals were assigned an annual 137Cs exposure based on their place of residence (1986 through 1990), from which 5-year cumulative 137Cs exposures were calculated, accounting for the physical decay of 137Cs and changing residencies. Hazard ratios for having cancer during the follow-up period, adjusted for age, sex, rural/non-rural residence, and pre-Chernobyl total cancer incidence, were calculated.

    Results: No obvious exposure-response pattern in the age-standardized total cancer incidence rate ratios could be seen in the first study. However, a spurious association between the fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of cesium-137. Increasing the geographical resolution of exposure from the average values of nine counties to the average values of 612 parishes resulted in two to three times higher degree of variance explanation by regression model. There was a secular trend, with an increase in age standardized incidence of cancer from 1980 – 2009. This trend was stronger in the general Swedish population compared to the nine counties of the present study.

    In the second study, 734,537 people identified were divided into three exposure categories: the first quartile was low exposure (0.0 to 45.4 kBq/m2), the second and third quartiles were intermediate exposure (45.41 to 118.8 kBq/m2), and the fourth quartile was highest exposure (118.81 to 564.71 kBq/m2). Between 1991 and 2010, 82,495 cancer cases were registered in the three counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure, and 1.05 (1.03 to 1.07) for the highest exposure, when comparing to the reference exposure.

    Conclusion: Using the ecological data, there was no exposure response trend; however, after refining the data to the individual level of exposure, there was an overall exposure response pattern. Nonetheless, due to the time dependency, these results were restricted to the age group of 25 – 49 among males. Using register-based data only, for determining the association between low-dose exposure to radiation and the risk of developing cancer, is difficult since we cannot control for other significant factors that are associated with cancer.

    List of papers
    1. Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    Open this publication in new window or tab >>Cancer incidence in northern Sweden before and after the Chernobyl nuclear power plant accident
    2014 (English)In: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 53, no 3, p. 495-504Article in journal (Refereed) Published
    Abstract [en]

    Sweden received about 5 % of the total release of Cs-137 from the Chernobyl nuclear power plant accident in 1986. The distribution of the fallout mainly affected northern Sweden, where some parts of the population could have received an estimated annual effective dose of 1-2 mSv per year. It is disputed whether an increased incidence of cancer can be detected in epidemiological studies after the Chernobyl nuclear power plant accident outside the former Union of Soviet Socialist Republics. In the present paper, a possible exposure-response pattern between deposition of Cs-137 and cancer incidence after the Chernobyl nuclear power plant accident was investigated in the nine northernmost counties of Sweden (2.2 million inhabitants in 1986). The activity of Cs-137 from the fallout maps at 1986 was used as a proxy for the received dose of ionizing radiation. Diagnoses of cancer (ICD-7 code 140-209) from 1980 to 2009 were received from the Swedish Cancer Registry (273,222 cases). Age-adjusted incidence rate ratios, stratified by gender, were calculated with Poisson regression in two closed cohorts of the population in the nine counties 1980 and 1986, respectively. The follow-up periods were 1980-1985 and 1986-2009, respectively. The average surface-weighted deposition of Cs-137 at three geographical levels; county (n = 9), municipality (n = 95) and parish level (n = 612) was applied for the two cohorts to study the pre- and the post-Chernobyl periods separately. To analyze time trends, the age-standardized total cancer incidence was calculated for the general Swedish population and the population in the nine counties. Joinpoint regression was used to compare the average annual percent change in the general population and the study population within each gender. No obvious exposure-response pattern was seen in the age-adjusted total cancer incidence rate ratios. A spurious association between fallout and cancer incidence was present, where areas with the lowest incidence of cancer before the accident coincidentally had the lowest fallout of Cs-137. Increasing the geographical resolution of exposure from nine county averages to 612 parish averages resulted in a two to three times higher value of variance in the regression model. There was a secular trend with an increase in age-standardized incidence of cancer in both genders from 1980 to 2009, but significant only in females. This trend was stronger and statistically significant for both genders in the general Swedish population compared to the nine counties. In conclusion, using both high quality cancer registry data and high resolution exposure maps of Cs-137 deposition, it was not possible to distinguish an effect of Cs-137 on cancer incidence after the Chernobyl nuclear power plant accident in Sweden.

    Keywords
    Cancer, Cesium-137, Chernobyl, Ecological study, Environment, Epidemiology, Ionizing radiation, Nuclear accident, Radiation, Sweden
    National Category
    Occupational Health and Environmental Health
    Identifiers
    urn:nbn:se:uu:diva-231289 (URN)10.1007/s00411-014-0545-6 (DOI)000339898300003 ()24811728 (PubMedID)
    Available from: 2014-09-08 Created: 2014-09-07 Last updated: 2019-03-28Bibliographically approved
    2. Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    Open this publication in new window or tab >>Total cancer incidence in relation to 137Cs fallout in the most contaminated counties in Sweden after the Chernobyl nuclear power plant accident: a register-based study
    2016 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 12, article id e011924Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: To determine the total cancer incidence in relation to a 5-year exposure to caesium-137 ((137)Cs) from the 1986 Chernobyl nuclear power plant accident.

    METHODS: A closed cohort was defined as all individuals living in the three most contaminated counties in mid-Sweden in 1986. Fallout of (137)Cs was retrieved as a digital map from the Geological Survey of Sweden, demographic data from Statistics Sweden, and cancer diagnosis from the National Board of Health and Welfare. Individuals were assigned an annual (137)Cs exposure based on their place of residence (1986-1990), from which 5-year cumulative (137)Cs exposures were calculated, accounting for the physical decay of (137)Cs and changing residencies. HRs were adjusted for age, sex, rural/non-rural residence and pre-Chernobyl total cancer incidence.

    RESULTS: The 734 537 people identified were categorised by exposure: the first quartile was low exposure (0.0-45.4 kBq/m(2)), the second and third quartiles were intermediate exposure (45.41-118.8 kBq/m(2)), and the fourth quartile was the highest exposure (118.81-564.71 kBq/m(2)). Between 1991 and 2010, 82 495 cancer cases were registered in the 3 counties. Adjusted HRs (95% CI) were 1.03 (1.01 to 1.05) for intermediate exposure and 1.05 (1.03 to 1.07) for the highest exposure compared to the reference exposure.

    CONCLUSIONS: We found a small overall exposure-response pattern of the total cancer incidence related to (137)Cs after adjustment for age, sex, rural residence and pre-Chernobyl cancer incidence.

    National Category
    Occupational Health and Environmental Health
    Identifiers
    urn:nbn:se:uu:diva-311895 (URN)10.1136/bmjopen-2016-011924 (DOI)000391303600003 ()27998898 (PubMedID)
    Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2019-03-28Bibliographically approved
  • Public defence: 2019-05-03 09:00 Enghoffsalen, Uppsala
    Sundbom, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Asthma and Sleep Disturbances: Associations to Comorbidities and Asthma Control2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Background

     

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

     

    Methods

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

     

    Results

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

     

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

     

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

     

    Conclusion

     

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

    National Category
    Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-379139 (URN)
    Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-13
  • Fenn, Sebastian
    et al.
    Schiller, Christian B.
    Griese, Julia J.
    Duerr, Harald
    Imhof-Jung, Sabine
    Gassner, Christian
    Moelleken, Joerg
    Regula, Joerg Thomas
    Schaefer, Wolfgang
    Thomas, Markus
    Klein, Christian
    Hopfner, Karl Peter
    Kettenberger, Hubert
    Crystal Structure of an Anti-Ang2 CrossFab Demonstrates Complete Structural and Functional Integrity of the Variable Domain2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4Article in journal (Refereed)
    Abstract [en]

    Bispecific antibodies are considered as a promising class of future biotherapeutic molecules. They comprise binding specificities for two different antigens, which may provide additive or synergistic modes of action. There is a wide variety of design alternatives for such bispecific antibodies, including the "CrossMab" format. CrossMabs contain a domain crossover in one of the antigen-binding (Fab) parts, together with the "knobs-and-holes" approach, to enforce the correct assembly of four different polypeptide chains into an IgG-like bispecific antibody. We determined the crystal structure of a hAng-2-binding Fab in its crossed and uncrossed form and show that CH1-CL-domain crossover does not induce significant perturbations of the structure and has no detectable influence on target binding.

  • Griese, Julia J.
    et al.
    Witte, Gregor
    Hopfner, Karl Peter
    Structure and DNA binding activity of the mouse condensin hinge domain highlight common and diverse features of SMC proteins2010In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 38, no 10, p. 3454-3465Article in journal (Refereed)
    Abstract [en]

    Structural Maintenance of Chromosomes (SMC) proteins are vital for a wide range of processes including chromosome structure and dynamics, gene regulation and DNA repair. Eukaryotes have three SMC complexes, consisting of heterodimeric pairs of six different SMC proteins along with several specific regulatory subunits. In addition to their other functions, all three SMC complexes play distinct roles in DNA repair. Cohesin (SMC1-SMC3) is involved in DNA double-strand break repair, condensin (SMC2-SMC4) participates in single-strand break (SSB) repair, and the SMC5-SMC6 complex functions in various DNA repair pathways. SMC proteins consist of N- and C-terminal domains that fold back onto each other to create an ATPase ’head’ domain, connected to a central ’hinge’ domain via long coiled-coils. The hinge domain mediates dimerization of SMC proteins and binds DNA, but it is not clear to what purpose this activity serves. We studied the structure and function of the condensin hinge domain from mouse. While the SMC hinge domain structure is largely conserved from prokaryotes to eukaryotes, its function seems to have diversified throughout the course of evolution. The condensin hinge domain preferentially binds single-stranded DNA. We propose that this activity plays a role in the SSB repair function of the condensin complex.

  • Gottwald, Janna
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bird, Laura
    Keenaghan, Samantha
    Diamond, Clare
    Zampieri, Eliana
    Tosodduk, Haleema
    Bremner, Andrew J.
    Cowie, Dorothy
    The developing bodily self: Posture constrains embodiment in children and adultsManuscript (preprint) (Other academic)
    Abstract [en]

    For adults, the feeling of inhabiting a body (a sense of embodiment) is constrained by bottom-up multisensory information such as spatiotemporal correlations between visual and tactile sensations, and by top-down knowledge of the body such as its possible postures. However, to date it is unknown what kinds of body models children have. Here we asked whether common factors constrain embodiment in children and adults. In two experiments, we compared 6- to 7-year-olds’ and adults’ embodiment of a fake hand in the rubber hand illusion, measuring illusion-induced proprioceptive drift and questionnaire responses. In Experiment 1 (N = 120), the fake hand was either congruent with the participant’s own hand, or incongruent by 90° and, as a result, in an impossible posture with respect to the current position of their body. In Experiment 2 (N = 60), the fake hand was incongruent with the participant’s own hand by 20°, but still in a possible posture. Across both experiments, and in both children and adults, visual-proprioceptive congruency of posture, and visual-tactile spatiotemporal congruency in stroking independently yielded greater proprioceptive drift towards the rubber hand. Subjective ratings of embodiment were also higher when visual-tactile information was congruent, but were not affected by posture. Top-down knowledge of body posture therefore partially constrains embodiment in middle childhood, as in adulthood. This shows that, although childhood is a period of significant change in both bodily dimensions and sensory capabilities, 6- to 7-year-olds have sensitive, robust mechanisms for maintaining a sense of bodily self.

  • Das, Sarbashis
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frisk, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Maria J.
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Walentinsson, Anna
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Dept Thorac Surg, S-17176 Stockholm, Sweden.
    Hage, Camilla
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Kumar, Chanchal
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden;Karolinska Inst, ICMC, Dept Med, S-14157 Huddinge, Sweden.
    Asp, Michaela
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Lundeberg, Joakim
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Maret, Eva
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Persson, Hans
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, S-18288 Stockholm, Sweden;Danderyd Hosp, Dept Cardiol, S-18288 Stockholm, Sweden.
    Linde, Cecilia
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, S-17177 Stockholm, Sweden.
    Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3179Article in journal (Refereed)
    Abstract [en]

    Heart failure affects 2-3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics would show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction >= 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group.

  • Carter, Megan
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Jemth, Ann-Sofie
    Hagenkort, Anna
    Page, Brent D. G.
    Gustafsson, Robert
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Griese, Julia J.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Gad, Helge
    Valerie, Nicholas C. K.
    Desroses, Matthieu
    Boström, Johan
    Berglund, Ulrika Warpman
    Helleday, Thomas
    Stenmark, Pål
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH22015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7871Article in journal (Refereed)
    Abstract [en]

    Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.

  • Griese, Julia J.
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Högbom, Martin
    Stockholms universitet, Institutionen för biokemi och biofysik.
    X-ray reduction correlates with soaking accessibility as judged from four non crystallographically related diiron sites2012In: Metallomics, ISSN 1756-5901, E-ISSN 1756-591X, Vol. 4, no 9, p. 894-898Article in journal (Refereed)
    Abstract [en]

    X-ray crystallography is extensively used to determine the atomic structure of proteins and their cofactors. Though a commonly overlooked problem, it has been shown that structural damage to a redox active metal site may precede loss of diffractivity by more than an order of magnitude in X-ray dose. Therefore the risk of misassigning redox states is great. Adequate treatment and consideration of this issue is of paramount importance in metalloprotein science, from experimental design to interpretation of the data and results. Some metal sites appear to be much more amenable to reduction than others, but the underlying processes are poorly understood. Here, we have analyzed the four non-crystallographically related diiron sites in a crystal of the ribonucleotide reductase R2F protein from Corynebacterium ammoniagenes. We conclude that the amount of X-ray reduction a metal site suffers correlates with its soaking accessibility. This direct observation supports the hypothesis that a diffusion component is involved in the X-ray reduction process.

  • Griese, Julia J.
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Srinivas, Vivek
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Högbom, Martin
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Assembly of nonheme Mn/Fe active sites in heterodinuclear metalloproteins2014In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 19, no 6, p. 759-774Article, review/survey (Refereed)
    Abstract [en]

    The ferritin superfamily contains several protein groups that share a common fold and metal coordinating ligands. The different groups utilize different dinuclear cofactors to perform a diverse set of reactions. Several groups use an oxygen-activating di-iron cluster, while others use di-manganese or heterodinuclear Mn/Fe cofactors. Given the similar primary ligand preferences of Mn and Fe as well as the similarities between the binding sites, the basis for metal specificity in these systems remains enigmatic. Recent data for the heterodinuclear cluster show that the protein scaffold per se is capable of discriminating between Mn and Fe and can assemble the Mn/Fe center in the absence of any potential assembly machineries or metal chaperones. Here we review the current understanding of the assembly of the heterodinuclear cofactor in the two different protein groups in which it has been identified, ribonucleotide reductase R2c proteins and R2-like ligand-binding oxidases. Interestingly, although the two groups form the same metal cluster they appear to employ partly different mechanisms to assemble it. In addition, it seems that both the thermodynamics of metal binding and the kinetics of oxygen activation play a role in achieving metal specificity.

  • Griese, Julia J.
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Roos, Katarina
    Stockholms universitet, Fysikum.
    Cox, Nicholas
    Shafaat, Hannah S.
    Branca, Rui M. M.
    Lehtio, Janne
    Gräslund, Astrid
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Lubitz, Wolfgang
    Siegbahn, Per E. M.
    Stockholms universitet, Fysikum.
    Högbom, Martin
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Direct observation of structurally encoded metal discrimination and ether bond formation in a heterodinuclear metalloprotein2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 43, p. 17189-17194Article in journal (Refereed)
    Abstract [en]

    Although metallocofactors are ubiquitous in enzyme catalysis, how metal binding specificity arises remains poorly understood, especially in the case of metals with similar primary ligand preferences such as manganese and iron. The biochemical selection of manganese over iron presents a particularly intricate problem because manganese is generally present in cells at a lower concentration than iron, while also having a lower predicted complex stability according to the Irving-Williams series (Mn-II < Fe-II < Ni-II < Co-II < Cu-II > Zn-II). Here we show that a heterodinuclear Mn/Fe cofactor with the same primary protein ligands in both metal sites self-assembles from MnII and FeII in vitro, thus diverging from the Irving-Williams series without requiring auxiliary factors such as metallochaperones. Crystallographic, spectroscopic, and computational data demonstrate that one of the two metal sites preferentially binds FeII over MnII as expected, whereas the other site is nonspecific, binding equal amounts of both metals in the absence of oxygen. Oxygen exposure results in further accumulation of the Mn/Fe cofactor, indicating that cofactor assembly is at least a two-step process governed by both the intrinsic metal specificity of the protein scaffold and additional effects exerted during oxygen binding or activation. We further show that the mixed-metal cofactor catalyzes a two-electron oxidation of the protein scaffold, yielding a tyrosine-valine ether cross-link. Theoretical modeling of the reaction by density functional theory suggests a multistep mechanism including a valyl radical intermediate.

  • Griese, Julia J.
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Kositzki, Ramona
    Schrapers, Peer
    Branca, Rui M. M.
    Nordström, Anders
    Lehtiö, Janne
    Haumann, Michael
    Högbom, Martin
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Structural Basis for Oxygen Activation at a Heterodinuclear Manganese/Iron Cofactor2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 42, p. 25254-25272Article in journal (Refereed)
    Abstract [en]

    Two recently discovered groups of prokaryotic di-metal carboxylate proteins harbor a heterodinuclear Mn/Fe cofactor. These are the class Ic ribonucleotide reductase R2 proteins and a group of oxidases that are found predominantly in pathogens and extremophiles, called R2-like ligand-binding oxidases (R2lox). We have recently shown that the Mn/Fe cofactor of R2lox self-assembles from Mn(II) and Fe(II) in vitro and catalyzes formation of a tyrosine-valine ether cross-link in the protein scaffold (Griese, J. J., Roos, K., Cox, N., Shafaat, H. S., Branca, R. M., Lehtiö, J., Gräslund, A., Lubitz, W., Siegbahn, P. E., and Högbom, M. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 17189-17194). Here, we present a detailed structural analysis of R2lox in the nonactivated, reduced, and oxidized resting Mn/Fe- and Fe/Fe-bound states, as well as the nonactivated Mn/Mn-bound state. X-ray crystallography and x-ray absorption spectroscopy demonstrate that the active site ligand configuration of R2lox is essentially the same regardless of cofactor composition. Both the Mn/Fe and the diiron cofactor activate oxygen and catalyze formation of the ether cross-link, whereas the dimanganese cluster does not. The structures delineate likely routes for gated oxygen and substrate access to the active site that are controlled by the redox state of the cofactor. These results suggest that oxygen activation proceeds via similar mechanisms at the Mn/Fe and Fe/Fe center and that R2lox proteins might utilize either cofactor in vivo based on metal availability.

  • Public defence: 2019-05-03 09:15 B21, Uppsala
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Keywords
    Therapeutic drug monitoring, Pharmacokinetics, Modelling and simulation, Pharmacometrics, Population pharmacokinetics
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-379357 (URN)
    Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15
  • Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Cirenajwis, Helena
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Ericson-Lindquist, Kajsa
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22185 Lund, Sweden;Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22185 Lund, Sweden;Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Jonsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    Ortiz-Villalon, Cristian
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden.
    Hussein, Aziz
    Sahlgrens Univ Hosp, Dept Pathol & Cytol, Gothenburg, Sweden.
    Bergman, Bengt
    Sahlgrens Univ Hosp, Dept Resp Med, Gothenburg, Sweden.
    Vikström, Anders
    Univ Hosp Linkoping, Dept Pulm Med, Linkoping, Sweden.
    Monsef, Nastaran
    Linkoping Univ, Dept Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med Solna & CMM, Resp Med Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med Solna & CMM, Resp Med Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    de Petris, Luigi
    Karolinska Univ Hosp, Thorac Oncol Unit, Stockholm, Sweden;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Patthey, Annika
    Umea Univ Hosp, Dept Pathol, SE-90185 Umea, Sweden.
    Behndig, Annelie F.
    Umea Univ, Div Med, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden.
    Johansson, Mikael
    Umea Univ, Dept Radiat Sci, Oncol, SE-90185 Umea, Sweden.
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden;Skane Univ Hosp, Dept Resp Med & Allergol, SE-22185 Lund, Sweden.
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

  • Strassmann, Stephan
    et al.
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    Merten, Michaela
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    Schäfer, Simone
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    de Moll, Jonas
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    Brodie, Daniel
    Columbia Univ Coll Phys & Surg, Div Pulm Allergy & Crit Care, New York Presbyterian Hosp, 630 W 168th St, New York, NY 10032 USA.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Windisch, Wolfram
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    Karagiannidis, Christian
    Witten Herdecke Univ Hosp, Cologne Merheim Hosp, Dept Pneumol & Crit Care Med, ARDS & ECMO Ctr,Kliniken Stadt Koln gGmbH, Ostmerheimer Str 200, D-51109 Cologne, Germany.
    Impact of sweep gas flow on extracorporeal CO2 removal (ECCO2R)2019In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 7, article id 17Article in journal (Refereed)
    Abstract [en]

    Background: Veno-venous extracorporeal carbon dioxide (CO2) removal (vv-ECCO2R) is increasingly being used in the setting of acute respiratory failure. Blood flow rates range in clinical practice from 200mL/min to more than 1500mL/min, and sweep gas flow rates range from less than 1 to more than 10L/min. The present porcine model study was aimed at determining the impact of varying sweep gas flow rates on CO2 removal under different blood flow conditions and membrane lung surface areas.

    Methods: Two different membrane lungs, with surface areas of 0.4 and 0.8m(2), were used in nine pigs with experimentally-induced hypercapnia. During each experiment, the blood flow was increased stepwise from 300 to 900 mL/min, with further increases up to 1800 mL/min with the larger membrane lung in steps of 300 mL/min. Sweep gas was titrated under each condition from 2 to 8L/min in steps of 2 L/min. Extracorporeal CO2 elimination was normalized to a PaCO2 of 45 mmHg before the membrane lung.

    Results: Reversal of hypercapnia was only feasible when blood flow rates above 900mL/min were used with a membrane lung surface area of at least 0.8m(2). The membrane lung with a surface of 0.4m(2) allowed a maximum normalized CO2 elimination rate of 416mL/min with 8L/min sweep gas flow and 900mLbloodflow/min. The increase in sweep gas flow from 2 to 8L/min increased normalized CO2 elimination from 35 +/- 5 to 41 +/- 6 with 900mLbloodflow/min, whereas with lower blood flow rates, any increase was less effective, levelling out at 4Lsweepgasflow/min. The membrane lung with a surface area of 0.8 m(2) allowed a maximum normalized CO2 elimination rate of 101 +/- 12 mL/min with increasing influence of sweep gas flow. The delta of normalized CO2 elimination increased from 4 +/- 2 to 26 +/- 7 mL/min with blood flow rates being increased from 300 to 1800 mL/min, respectively.

    Conclusions: The influence of sweep gas flow on the CO2 removal capacity of ECCO2R systems depends predominantly on blood flow rate and membrane lung surface area. In this model, considerable CO2 removal occurred only with the larger membrane lung surface of 0.8m(2) and when blood flow rates of >= 900mL/min were used.

  • Berkström, Charlotte
    et al.
    Stockholm Univ, Dept Ecol Environm & Plant Sci, Stockholm, Sweden;Swedish Univ Agr Sci, Dept Aquat Resources, Inst Coastal Res, Oregrund, Sweden.
    Papadopoulos, Myron
    Stockholm Univ, Dept Ecol Environm & Plant Sci, Stockholm, Sweden.
    Jiddawi, Narriman Saleh
    State Univ Zanzibar, Trop Ctr Oceanog Environm Sci & Nat Resources, Zanzibar, Sweden.
    Nordlund, Lina M.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Natural Resources and Sustainable Development.
    Fishers' Local Ecological Knowledge (LEK) on Connectivity and Seascape Management2019In: Frontiers in Marine Science, E-ISSN 2296-7745, Vol. 6, article id 130Article in journal (Refereed)
    Abstract [en]

    In developing countries where data and resources are lacking, the practical relevance of local ecological knowledge (LEK) to expand our understanding of the environment, has been highlighted. The potential roles of the LEK varies from direct applications such as gathering environmental information to a more participative involvement of the community in the management of resources they depend on. Fishers' LEK could therefore be useful in order to obtain information on how to advance management of coastal fisheries. Many targeted fish species migrate between habitats to feed, spawn or recruit, connecting important habitats within the seascape. LEK could help provide answers to questions related to this connectivity and the identification of fish habitat use, and migrations for species and areas where such knowledge is scarce. Here we assess fishers' LEK on connectivity between multiple habitats within a tropical seascape, investigate the differences in LEK among fisher groups and the coherence between LEK and conventional scientific knowledge (CSK). The study was conducted in 2017 in Zanzibar, Tanzania, a tropical developing country. One hundred and thirty-five semi-structured interviews were conducted in six different locations focusing on fish migrations, and matching photos of fish and habitats. Differences between fisher groups were found, where fishers traveling further, exposed to multiple habitats, and who fish with multiple gears had a greater knowledge of connectivity patterns within the seascape than those that fish locally, in single habitats and with just one type of gear. A high degree of overlap in LEK and CSK was found, highlighting the potential benefits of a collaboration between scientists and fishers, and the use of LEK as complementary information in the management of small-scale fisheries.

  • Goncalves, Leticia C. P.
    et al.
    TU Wien, Inst Appl Synthet Chem, Getreidemarkt 9-163, A-1060 Vienna, Austria.
    Mansouri, Hanild R.
    TU Wien, Inst Appl Synthet Chem, Getreidemarkt 9-163, A-1060 Vienna, Austria.
    Bastos, Erick L.
    Univ Sao Paulo, Inst Chem, Dept Fundamental Chem, BR-03178200 Sao Paulo, Brazil.
    Abdellah, Mohamed
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. South Valley Univ, Qena Fac Sci, Dept Chem, Qena 83523, Egypt.
    Fadiga, Bruma S.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Univ Sao Paulo, Inst Chem, Dept Fundamental Chem, BR-03178200 Sao Paulo, Brazil.
    Sá, Jacinto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Polish Acad Sci, Inst Phys Chem, PL-01224 Warsaw, Poland.
    Rudroff, Florian
    TU Wien, Inst Appl Synthet Chem, Getreidemarkt 9-163, A-1060 Vienna, Austria.
    Mihovilovic, Marko D.
    TU Wien, Inst Appl Synthet Chem, Getreidemarkt 9-163, A-1060 Vienna, Austria.
    Morpholine-based buffers activate aerobic photobiocatalysis via spin correlated ion pair formation2019In: Catalysis Science & Technology, ISSN 2044-4753, E-ISSN 2044-4761, Vol. 9, no 6, p. 1365-1371Article in journal (Refereed)
    Abstract [en]

    The use of enzymes for synthetic applications is a powerful and environmentally-benign approach to increase molecular complexity. Oxidoreductases selectively introduce oxygen and hydrogen atoms into myriad substrates, catalyzing the synthesis of chemical and pharmaceutical building blocks for chemical production. However, broader application of this class of enzymes is limited by the requirements of expensive cofactors and low operational stability. Herein, we show that morpholine-based buffers, especially 3-(N-morpholino)propanesulfonic acid (MOPS), promote photoinduced flavoenzyme-catalyzed asymmetric redox transformations by regenerating the flavin cofactor via sacrificial electron donation and by increasing the operational stability of flavin-dependent oxidoreductases. The stabilization of the active forms of flavin by MOPS via formation of the spin correlated ion pair (3)[flavin(-)-MOPS+] ensemble reduces the formation of hydrogen peroxide, circumventing the oxygen dilemma under aerobic conditions detrimental to fragile enzymes.

  • Cronholm, Felix
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.
    Rosengren, Björn E.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.
    Nilsson, Jan-Åke
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr,Inst Med, Gothenburg, Sweden.
    Mellström, Dan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Geriatr Med,Inst Med, Gothenburg, Sweden.
    Ribom, Eva L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Karlsson, Magnus K.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.
    The fracture predictive ability of a musculoskeletal composite score in old men - data from the MrOs Sweden study2019In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 19, article id 90Article in journal (Refereed)
    Abstract [en]

    Background: Detection of high-risk individuals for fractures are needed. This study assessed whether level of physical activity (PA) and a musculoskeletal composite score could be used as fracture predictive tools, and if the score could predict fractures better than areal bone mineral density (aBMD).

    Methods: MrOs Sweden is a prospective population-based observational study that at baseline included 3014 men aged 69-81years. We assessed femoral neck bone mineral content (BMC), bone area, aBMD and total body lean mass by dual energy X-ray absorptiometry, calcaneal speed of sound by quantitative ultrasound and hand grip strength by a handheld dynamometer. PA was assessed by the Physical Activity Scale for the Elderly (PASE) questionnaire. We followed the participants until the date of first fracture, death or relocation (median 9.6years). A musculoskeletal composite score was calculated as mean Z-score of the five measured traits. A Cox proportional hazards model was used to analyze the association between the musculoskeletal traits, the composite score and incident fractures (yes/no) during the follow-up period. Data are presented as hazard ratios (HR) with 95% confidence intervals (95% CI) for fracture for a+1 standard deviation (SD) change (+1 Z-score) in the various musculoskeletal traits as well as the composite score. We used a linear regression model to estimate the association between level of PA, measured as PASE-score and the different musculoskeletal traits as well as the composite score.

    Results: A+1 SD higher composite score was associated with an incident fracture HR of 0.61 (0.54, 0.69), however not being superior to aBMD in fracture prediction. A+1 SD higher PASE-score was associated with both a higher composite score and lower fracture incidence (HR 0.83 (0.76, 0.90)).

    Conclusions: The composite score was similar to femoral neck aBMD in predicting fractures, and also low PA predicted fractures. This highlights the need of randomized controlled trials to evaluate if PA could be used as a fracture preventive strategy.

  • Fatsis-Kavalopoulos, Nikos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Gradientech AB, Uppsala, Sweden.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Xie, Beichen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hernández Vera, Rodrigo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Idevall Hagren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Formation of precisely composed cancer cell clusters using a cell assembly generator (CAGE) for studying paracrine signaling at single-cell resolution2019In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 19, no 6, p. 1071-1081Article in journal (Refereed)
    Abstract [en]

    The function and behaviour of any given cell in a healthy tissue, or in a tumor, is affected by interactions with its neighboring cells. It is therefore important to create methods that allow for reconstruction of tissue niches in vitro for studies of cell-cell signaling and associated cell behaviour. To this end we created the cell assembly generator (CAGE), a microfluidic device which enables the organization of different cell types into precise cell clusters in a flow chamber compatible with high-resolution microscopy. In proof-of-concept paracrine signalling experiments, 4-cell clusters consisting of one pancreatic -cell and three breast cancer cells were formed. It has previously been established that extracellular ATP induces calcium (Ca2+) release from the endoplasmic reticulum (ER) to the cytosol before it is cleared back into the ER via sarcoplasmic/ER Ca2+ ATPase (SERCA) pumps. Here, ATP release from the -cell was stimulated by depolarization, and dynamic changes in Ca2+ levels in the adjacent cancer cells measured using imaging of the calcium indicator Fluo-4. We established that changes in the concentration of cytosolic Ca2+ in the cancer cells were proportional to the distance from the ATP-releasing -cell. Additionally, we established that the relationship between distance and cytosolic calcium changes were dependent on Ca2+-release from the ER using 5-cell clusters composed of one -cell, two untreated cancer cells and two cancer cells pretreated with Thapsigargin (to deplete the ER of Ca2+). These experiments show that the CAGE can be used to create exact cell clusters, which affords precise control for reductionist studies of cell-cell signalling and permits the formation of heterogenous cell models of specific tissue niches.