| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
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| 3. |
- Baudin, Katarina, 1971-
(författare)
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Assistive technology and welfare technology explorations : Aspects of perception, utilisation and decision-making
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: The overall aim of this thesis was to explore decision makers’ and professionals’ perceptions, utilisation, and decision-making about assistive technology (AT) and welfare technology (WT) within the interprofessional field of care for older adults. Methods: A literature review was conducted, including nine peer-reviewed scientific articles (I), analysed with a qualitative descriptive method. A web-based questionnaire, answered by 393 officials and health care providers in municipal eldercare (II and III), was analysed using content analysis of the open-ended answers (II) and descriptive and inferential statistics of the closed-ended answers (III). A semi-structured interview with 24 decision makers was also conducted and analysed with thematic reflexive analysis. Results: The studies revealed a lack of evidence-based decision models to support assistive and welfare technology decisions, partly due to the context being complex and multifaceted. The technology was perceived as progressive and cutting-edge, while organizational structure and culture were perceived as regressive and resistant to change. The results revealed personnel working with WT were generally very positive toward new technology, although there were age, gender, participation, and professional differences. Study IV results revealed that supportive aspects, technology aspects, patient aspects, and knowledge aspects influence AT-organizations' decision-making. Although AT/WT has been portrayed to have the potential to solve the challenges of an aging population, the decision-making regarding AT/WT is complex and evolving. Increased communication between government, regions, and municipalities to support the development of guidelines would enhance the goal of a person-centred care. Conclusion: This thesis contributes to knowledge of decision-making models, focusing on GATE´s model (Khasnabis et al., 2015) applicable in AT/WT. Further development and deepen knowledge in the area of AT/WT appears as needed due to results showing that there is a lack of structured knowledge about the decision-making processes and evaluations of effects of AT/WT.
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| 4. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 5. |
- Dellmuth, Lisa Maria, 1981-, et al.
(författare)
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Global adaptation governance : Explaining the governance responses of international organizations to new issue linkages
- 2020
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Ingår i: Environmental Science and Policy. - : Elsevier BV. - 1462-9011 .- 1873-6416. ; 114, s. 204-215
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Tidskriftsartikel (refereegranskat)abstract
- Climate change adaptation is increasingly perceived as a global and interconnected policy challenge among practitioners and academics, making localized solutions insufficient. In parallel to this trend, a growing number of international organizations that do not have climate as their core mandates link adaptation to various issue areas, such as energy, health, and conflict resolution. Yet we still know little about how and why international organizations respond to adaptation challenges. This article develops an innovative theoretical framework to understand the factors that influence the governance responses of international organizations to adaptation challenges in the context of their respective issue areas. Our analysis reveals that there are three main and interrelated factors influencing international governance responses: problem complexity, institutional frag- mentation, and fiscal pressures. We examine our framework by drawing on of two sources of data: first, a yearly large-n dataset at the level of fourteen international organizations from 2007 to 2017 created on the basis of official documents; and second, in-depth case studies of three UN agencies central in addressing three prominent issue linkages: climate-conflict, climate-health, and climate-migration. We conclude by sketching broader im- plications for the theory and practice of global adaptation governance.
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| 6. |
- Dellmuth, Lisa Maria, 1981-, et al.
(författare)
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Global adaptation governance : how intergovernmental organizations mainstream climate change adaptation
- 2021
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Ingår i: Climate Policy. - : Informa UK Limited. - 1469-3062 .- 1752-7457. ; 21:7, s. 868-883
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Tidskriftsartikel (refereegranskat)abstract
- Climate change adaptation is increasingly being mainstreamed into all types of organizations across the world. A large number of intergovernmental organizations (IGOs), such as the European Union, the World Bank, or Food and Agriculture Organization, have already started to mainstream adaptation. Yet, despite a surge in scholarly interest in climate policy integration over the past decade, adaptation is still predominantly studied as a local issue and mainstreaming in IGOs remains poorly understood. In this article, we develop and test an innovative framework for examining adaptation mainstreaming practices in IGOs. Using quantitative and qualitative data derived from extensive fieldwork conducted between 2017 and 2020, we examine mainstreaming practices in a large number of IGOs and arrive at two key findings. First, adaptation has been mainstreamed within the procedures and outputs of IGOs across ten (nonclimate) issue areas, while there is also evidence of important issue-specific variation. Second, there is variation across mainstreaming practices in the sense that discursive mainstreaming is most common, whereas more concrete collaboration, policy change affecting projects and programs, and budget allocations are less common. We conclude with a discussion of how our framework can inform the theory and practice of global adaptation governance.
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| 7. |
- Gustafsson, Maria, et al.
(författare)
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Pharmacological Pain Treatment in 2012 and 2017 Among Older People with Major Neurocognitive Disorder
- 2021
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Ingår i: Drugs & Aging. - : Adis. - 1170-229X .- 1179-1969. ; 38, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective: Pain is highly prevalent among older people, and treatment is complicated because of comorbidities and polypharmacy. Among people with major neurocognitive disorder additional difficulties might arise. The aim of this study was to describe analgesic drug use in 2012 and 2017 and associated factors among older people with major neurocognitive disorder.Methods: In this register-based study, the Swedish Dementia Registry and the Swedish Prescribed Drug Register were combined in order to obtain data regarding analgesic drug use among older people with major neurocognitive disorder. One or more filled prescriptions during the timeframe of 6 months (1 July–31 December 2012 and 1 July–31 December 2017) defined drug use during the respective period. A comparison between 2012 and 2017 was made, including a total of 56,101 people (20,889 and 35,212 respectively) with a mean age of 81.9 and 82.7 years, respectively.Results: The overall use of analgesic drugs increased significantly from 41.6% of individuals to 46.0% between the years 2012 and 2017. Users of opioid analgesics (15.2% vs 17.3%) and paracetamol (37.0% vs 42.3%) increased, while the users of non-steroidal anti-inflammatory drugs (4.9% vs 2.7%) declined between the two data collections. Multiple logistic regression analyses were performed for different drugs and drug classes, and it was found that the use of opioids and paracetamol was associated with older age and a longer time since diagnosis. In contrast, non-steroidal anti-inflammatory drugs were associated with younger age and a shorter time since diagnosis.Conclusions: The results indicate that on a population level, pharmacological drug treatment has changed in line with guidelines between 2012 and 2017, with an increase in paracetamol and strong opioids and a decrease in non-steroidal anti-inflammatory drugs and tramadol. The relatively high prevalence of opioids warrants concern given the significant risk of adverse effects among older people with major neurocognitive disorder.
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| 8. |
- Gustafsson, Maria, et al.
(författare)
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Prevalence of Drugs and Drug Combinations that Increase Risk of Prolonged QT Time Among People with Major Neurocognitive Disorder Living in Sweden : A Cross-Sectional Registry Study
- 2023
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Ingår i: Drugs - real world outcomes. - : Springer Nature. - 2199-1154 .- 2198-9788. ; 10, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- Background: People with major neurocognitive disorder might be susceptible to drug-induced QT interval prolongation due to the presence of a number of concomitant risk factors.Objective: The aim of this study was to investigate the prevalence of QT-prolonging drugs and QT-prolonging drug–drug interactions and associated factors among older people with major neurocognitive disorder.Methods: In this register-based study, we obtained information regarding QT-prolonging drug use in a large population of older people with major neurocognitive disorder, through record linkage between the Swedish registry for cognitive/dementia disorders, and the Swedish Prescribed Drug Register. QT-prolonging drugs were identified according to the CredibleMeds online database and interactions using the Janusmed interaction database. Drug use was defined as one or more filled prescriptions during a 6-month timeframe, July 01 to December 31, 2017. Associations between people with a QT-prolonging drug and the factors of age and gender were analysed through multiple logistic regression.Results: Of 35,212 people included in the study, 41.6% had one or more QT-prolonging drug prescribed. The most commonly prescribed drug was donepezil, with a prevalence of 25.0%, followed by citalopram and escitalopram, representing 14.5% and 3.9% of prescriptions in the study population, respectively. Significant associations were found between QT-prolonging drug use and the factors of younger age and female gender. The most prevalent interaction was between citalopram and donepezil (2.7%), followed by the combination of escitalopram and donepezil (0.7%).Conclusions: In this population of older people with major neurocognitive disorder, QT-prolonging drugs and interactions that increase the risk of torsade de pointes were prevalent. Due to the presence of many risk factors in this population, it is important to continuously evaluate current QT-prolonging drugs and concomitant drug treatment in each individual.
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| 9. |
- Gustafsson, Maria-Therese, 1979-, et al.
(författare)
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Private adaptation to climate risks : Evidence from the world’s largest mining companies
- 2022
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Ingår i: Climate Risk Management. - : Elsevier BV. - 2212-0963. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Private companies have in recent years started to disclose information about their exposure and responses to climate risks. However, we still know little about how and why private actors engage in climate change adaptation, and to what extent they do so in ways that improve societal resilience. This article addresses these questions. It conceptualizes private adaptation as consisting of institutional, infrastructural and community-oriented responses to climate risks. It develops a political-economic framework about the drivers of private adaptation, where private adaptation is expected to be shaped by pressures exerted by governments, investors, and civil society actors. Empirically, the framework is explored by using an original dataset on the adaptation responses of the 37 largest mining companies worldwide. We select the mining sector as mineral extraction plays a critical role in the low-carbon transition, and can, at the same time, exacerbate climate vulnerability in extracting sites. The descriptive findings suggest that the majority of the investigated companies have set up procedures to assess climate impacts on business operations, integrated climate risks in water governance, and adapted their infrastructure. The explanatory results indicate that private adaptation is mainly driven by investor pressures, and not domestic regulations and civil society. By implication, companies rarely engage in community-oriented adaptation responses by cooperating with local communities in ways that would benefit these communities. Taken together, our findings help to better understand the limitations of private adaptation and barriers to achieve transformative change, and identify how private adaptation could help improve societal resilience.
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| 10. |
- Järlskog, Ida, 1991, et al.
(författare)
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Occurrence of tire and bitumen wear microplastics on urban streets and in sweepsand and washwater
- 2020
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 729
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Tidskriftsartikel (refereegranskat)abstract
- Tire and road wear particles have been identified as a potential major source of microplastics in the environment. However, more knowledge of the emissions and their further fate in the environment is needed, and the effectiveness and benefits of potential measures must be investigated to support future risk management efforts. Here the concentrations of tire and bitumen microplastic particles (TBMP) on roads and in nearby in stormwater, sweepsand and washwater were measured for the first time within the same area and time period. The analysis also included plastic, paint and fiber particles. Road dust was sampled on the road surface using a wet dust sampler, before and after street sweeping on two occasions. On each of these occasions, and several occasions during a four-month period with frequent street sweeping, sweepsand and washwater, as well as flow-weighted sampling of stormwater, were collected. TBMP concentrations were operationally defined, using density separation for some samples, followed by analysis by stereo microscopy. Sodium iodide (NaI) was found to be effective for density separation of TBMP. The largest proportion of anthropogenic microplastics detected consisted of tire tread wear and bitumen. The number of TBMP ≥100 μm in the WDS samples was up to 2561 particles/L. Sweepsand and washwater contained high amounts of TBMP ≥100 μm, up to 2170 particles/kg dw and 4500 particles/L, respectively. The results show that the sweeper collects considerable amounts of TBMP, and thus weekly sweeping might prevent further transport of TBMP to the receiving stormwater. In stormwater the number of particles ≥100 μm was up to 3 particles/L and ≥ 20 μm was up to 5900 particles/L showing the importance of analysing smaller microparticle sizes than 100 μm in all samples in future studies. This study also confirms that there is a substantial volume of TBMP generated from traffic that enters the environment.
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