| 1. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
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Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
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| 2. |
- Bergman, Peter, et al.
(författare)
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Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial
- 2021
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 74
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls.Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection.Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively.Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity.
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| 3. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 4. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 5. |
- Plan, Anders, et al.
(författare)
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Exceptional preservation of reidite in the Rochechouart impact structure, France: New insights into shock deformation and phase transition of zircon
- 2021
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Ingår i: Meteoritics and Planetary Science. - : Wiley. - 1086-9379 .- 1945-5100. ; 56:10, s. 1795-1828
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Tidskriftsartikel (refereegranskat)abstract
- Reidite, the high-pressure zircon (ZrSiO4) polymorph, is a diagnostic indicator of impact events. Natural records of reidite are, however, scarce, occurring mainly as micrometer-sized lamellae, granules, and dendrites. Here, we present a unique sequence of shocked zircon grains found within a clast from the Chassenon suevitic breccia (shock stageIII) from the ~200 Ma, 20–50 km wide Rochechouart impact structure in France. Our study comprises detailed characterization with scanning electron microscopy coupled with electron backscatter diffraction with the goal of investigating the stability and response of ZrSiO4 under extreme P–T conditions. The shocked zircon grains have preserved various amounts of reidite ranging from 4% up to complete conversion. The grains contain various variants of reidite, including the common habits: lamellae and granular reidite. In addition, three novel variants have been identified: blade, wedge, and massive domains. Several of these crosscut and offset each other, revealing that reidite can form at multiple stages during an impact event. Our data provide evidence that reidite can be preserved in impactites to a much greater extent than previously documented. We have further characterized reversion products of reidite in the form of fully recrystallized granular zircon grains and minute domains of granular zircon in reidite-bearing grains that occur in close relationship to reidite. Neoblasts in these grains have a distinct crystallography that is the result of systematic inheritance of reidite. We interpret that the fully granular grains have formed from prolonged exposure of temperatures in excess of 1200 °C. Reidite-bearing grains with granular domains might signify swift quenching from temperatures close to 1200 °C. Grains subjected to these specific conditions therefore underwent partial zircon-to-reidite reversion, instead of full grain recrystallization. Based on our ZrSiO4 microstructural constraints, we decipher the grains evolution at specific P–T conditions related to different impact stages, offering further understanding of the behavior of ZrSiO4 during shock.
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| 6. |
- Williamsson, Ia
(författare)
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Establishment Patterns of Model Diffusion Theory
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Information technology is now part of almost every product and service, and the ever-increasing rate of technology and software development demands an appropriate software development process model. The model, whichdescribes the software development process, plays a crucial role for success in software projects. Models are constantly produced and refined in academia and practice, but models from academia tend to remain unused in practice, or take a long time to reach practice. Currently there is a lack of knowledge on how models are transferred or diffused in and between academia and practice, which is the knowledge gap that this study aims to investigate.The research purpose has thus been to investigate and ground a theory about the diffusion of software process models in and between academia and practice. The study is based on data collected from 31 informants, from both academia and practice, and analyzed with a grounded theory method approach. The Diffusion of Innovation theory was consulted during theory development, and the perceived model characteristics, complexity, ando bservability are seen as distinguishing differences between the theories.The resulting grounded theory, “Establishment Patterns of Model Diffusion” describes four important areas, and how they affect each other ina model diffusion situation. The areas are: Motivation; Establishment; Usage; and Quality. How model diffusion takes place depends on the are as themselves, on the prevailing conditions, on the knowledge at hand and on how the areas are evaluated. This shows multi-faceted, time-dependent, and unpredictable patterns for model diffusion. The patterns include experience of model use, the past and future context of use, the characteristics of the model, requirements in the working process, individuals’ empowerment, availability of multiple models, composition of project groups, and the group members’ private and business networks.The findings have several implications. For academia, the benefits may be in the awareness of the multiple patterns for model diffusion and software process improvements, which cannot be separated from each other. Models are constantly adopted and simultaneously modified in practice. Practice may benefit from an awareness of the multiple patterns for model diffusionand sources of experience and knowledge, and how to make use of the existing knowledge capital strategically. Both academia and practice may also benefit from increased cooperation, each contributing their unique experience, and consequently increasing relevance for practice in the diffusion of models, and in developing and receiving research results in a useful format.
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| 7. |
- Aftab, Muhammad Usman, et al.
(författare)
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Towards A Distributed Ledger Based Verifiable Trusted Protocol for VANET
- 2021
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Ingår i: 2021 International Conference on Digital Futures and Transformative Technologies, ICoDT2 2021. - : Institute of Electrical and Electronics Engineers Inc.. - 9781665412858
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Konferensbidrag (refereegranskat)abstract
- To ensure traffic safety and proper operation of vehicular networks, safety messages or beacons are periodically broadcasted in Vehicular Adhoc Networks (VANETs) to neighboring nodes and road side units (RSU). Thus, authenticity and integrity of received messages along with the trust in source nodes is crucial and highly required in applications where a failure can result in life-threatening situations. Several digital signature based approaches have been described in literature to achieve the authenticity of these messages. In these schemes, scenarios having high level of vehicle density are handled by RSU where aggregated signature verification is done. However, most of these schemes are centralized and PKI based where our goal is to develop a decentralized dynamic system. Along with authenticity and integrity, trust management plays an important role in VANETs which enables ways for secure and verified communication. A number of trust management models have been proposed but it is still an ongoing matter of interest, similarly authentication which is a vital security service to have during communication is not mostly present in the literature work related to trust management systems. This paper proposes a secure and publicly verifiable communication scheme for VANET which achieves source authentication, message authentication, non repudiation, integrity and public verifiability. All of these are achieved through digital signatures, Hash Message Authentication Code (HMAC) technique and logging mechanism which is aided by blockchain technology.
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| 8. |
- Baranowska, Julia, et al.
(författare)
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Associations between medical therapy after surgical aortic valve replacement for aortic stenosis and long-term mortality: a report from the SWEDEHEART registry.
- 2022
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Ingår i: European heart journal. Cardiovascular pharmacotherapy. - : Oxford University Press (OUP). - 2055-6837 .- 2055-6845. ; 8:8, s. 837-846
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Tidskriftsartikel (refereegranskat)abstract
- The association between use of statins, renin-angiotensin system (RAS) inhibitors and/or β-blockers and long-term mortality in patients with aortic stenosis who underwent surgical aortic valve replacement (SAVR) is unknown.All patients with aortic stenosis who underwent isolated first time SAVR in Sweden from 2006 to 2017 and survived six months after discharge were included. Individual patient data from four mandatory nationwide registries were merged. Cox proportional hazards models, with time-updated data on medication status and adjusted for age, sex, comorbidities, type of prosthesis, and year of surgery, were used to investigate associations between dispensed statins, RAS inhibitors, and β-blockers, and all-cause mortality. In total, 9553 patients were included, and median follow-up time was 4.9 years (range 0-11); 1738 patients (18.2%) died during follow-up. Statins were dispensed to 49.1% and 49.0% of the patients within six months of discharge from hospital and after ten years, respectively. Corresponding figures were 51.4% and 53.9% for RAS inhibitors, and 79.3% and 60.7% for β-blockers. Ongoing treatment was associated with lower mortality risk for statins [adjusted hazard ratio (aHR) 0.67 (95% confidence interval 0.60-0.74), p<0.001] and RAS inhibitors [aHR 0.84 (0.76-0.93), p<0.001] but not for β-blockers [aHR 1.17 (1.05-1.30), p=0.004]. The associations were robust in subgroups based on age, sex, and comorbidities (p for interactions>0.05).The results of this large population-based real-world study support the use of statins and RAS inhibitors for patients who underwent SAVR due to aortic stenosis.
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| 9. |
- Bergman, Lina, 1982, et al.
(författare)
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Study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT): a study protocol for a Swedish prospective multicentre cohort study
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055 .- 2044-6055. ; 10:9, s. e033851-e033851
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Tidskriftsartikel (refereegranskat)abstract
- Introduction First-trimester pregnancy risk evaluation facilitates individualised antenatal care, as well as application of preventive strategies for pre-eclampsia or birth of a small for gestational age infant. A range of early intervention strategies in pregnancies identified as high risk at the end of the first trimester has been shown to decrease the risk of preterm pre-eclampsia (<37 gestational weeks). The aim of this project is to create the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) database; a nationwide database with individual patient data, including predictors recorded at the end of the first trimester and later pregnancy outcomes, to identify women at high risk of pre-eclampsia. A second aim is to link the IMPACT database to a biobank with first-trimester blood samples. Methods and analysis This is a Swedish prospective multicentre cohort study. Women are included between the 11th and 14th weeks of pregnancy. At inclusion, pre-identified predictors are retrieved by interviews and medical examinations. Blood samples are collected and stored in a biobank. Additional predictors and pregnancy outcomes are retrieved from the Swedish Pregnancy Register. Inclusion in the study began in November 2018 with a targeted sample size of 45 000 pregnancies by end of 2021. Creation of a new risk prediction model will then be developed, validated and implemented. The database and biobank will enable future research on prediction of various pregnancy-related complications. Ethics and dissemination Confidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (Uppsala 2018-231) and national biobank approval at Uppsala Biobank (18237 2 2018 231). Results from the current as well as future studies using information from the IMPACT database will be published in peer-reviewed journals.
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| 10. |
- Björklund, Erik, et al.
(författare)
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Postdischarge major bleeding, myocardial infarction, and mortality risk after coronary artery bypass grafting
- 2023
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Ingår i: HEART. - 1355-6037 .- 1468-201X.
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the incidence and mortality risk associated with postdischarge major bleeding after coronary artery bypass grafting (CABG), and relate this to the incidence of, and mortality risk from, postdischarge myocardial infarction.Methods All patients undergoing first-time isolated CABG in Sweden in 2006-2017 and surviving 14 days after hospital discharge were included in a cohort study. Individual patient data from the SWEDEHEART Registry and five other mandatory nationwide registries were merged. Piecewise Cox proportional hazards models were used to investigate associations between major bleeding, defined as hospitalisation for bleeding, with subsequent mortality risk. Similar Cox proportional hazards models were used to investigate the association between postdischarge myocardial infarction and mortality risk.Results Among 36 633 patients, 2429 (6.6%) had a major bleeding event and 2231 (6.1%) had a myocardial infarction. Median follow-up was 6.0 (range 0-11) years. Major bleeding was associated with higher mortality risk <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30-365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. Myocardial infarction was associated with higher mortality risk <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30-365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event.Conclusions The increase in mortality risk associated with a postdischarge major bleeding after CABG is substantial and is similar to the mortality risk associated with a postdischarge myocardial infarction.
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