| 1. |
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| 2. |
- Nielsen, Stine Piilgaard Porner, et al.
(författare)
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Introduction: Transformations of European Welfare States and Social Rights
- 2024
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Ingår i: Transformations of European Welfare States and Social Rights: Regulation, Professionals, and Citizens. - 9783031466373 - 9783031466366 ; , s. 1-15
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Bokkapitel (refereegranskat)abstract
- n this introductory chapter, we outline the literature in which the anthology is positioned and the anthology’s contribution hereto. We account for the questions addressed in the anthology and its structure based on three sections that each analyses transformations of European welfare states and social rights from macro, meso and micro level perspectives, respectively. As described in the chapter and illustrated throughout the anthology, the three levels are interlinked: Macro level welfare state transformations influence the meso level of public encounters between welfare professionals and citizens, and on micro level, these encounters have real effect for, for example, citizens’ access to social rights. Linking the levels, the anthology contributes with analytical insights into welfare state transformations and social rights.
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| 3. |
- Nielsen, Stine Piilgaard Porner, et al.
(författare)
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Youth Homelessness in the Danish Welfare State: How Do Young Persons in Homelessness Mobilise Rights?
- 2024
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Ingår i: Transformations of European Welfare States and Social Rights. - 9783031466373 - 9783031466366 ; , s. 187-205
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Bokkapitel (refereegranskat)abstract
- This chapter offers a bottom-up perspective on welfare rights in practice, analysing legal mobilisation by young persons in homelessness in the Danish welfare state. Youth homelessness is selected as case motivated by the fact that the number of persons aged 18 to 29 living in homelessness almost doubled from 2009 to 2019. Drawing on the young persons’ narratives, the chapter stresses that their rights consciousness, social network and sense of welfare bureaucracy are decisive for their ability to mobilise welfare rights. Without these factors, the young persons may find themselves lost in a complex welfare state system, leaving them in increasingly marginalised situations. Based on the chapter’s analyses, a distinction is made between active and passive agency to illustrate the dynamic character of legal mobilisation processes.
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| 4. |
- Lundberg, Martin, et al.
(författare)
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Multiplexed Homogeneous Proximity Ligation Assays for High-throughput Protein Biomarker Research in Serological Material
- 2011
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 10:4, s. M110.004978-
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Tidskriftsartikel (refereegranskat)abstract
- A high throughput protein biomarker discovery tool has been developed based on multiplexed proximity ligation assays in a homogeneous format in the sense of no washing steps. The platform consists of four 24-plex panels profiling 74 putative biomarkers with sub-pM sensitivity each consuming only 1 mu l of human plasma sample. The system uses either matched monoclonal antibody pairs or the more readily available single batches of affinity purified polyclonal antibodies to generate the target specific reagents by covalently linking with unique nucleic acid sequences. These paired sequences are united by DNA ligation upon simultaneous target binding forming a PCR amplicon. Multiplex proximity ligation assays thereby converts multiple target analytes into real-time PCR amplicons that are individually quantified using microfluidic high capacity qPCR in nano liter volumes. The assay shows excellent specificity, even in multiplex, by its dual recognition feature, its proximity requirement, and most importantly by using unique sequence specific reporter fragments on both antibody-based probes. To illustrate the potential of this protein detection technology, a pilot biomarker research project was performed using biobanked plasma samples for the detection of colorectal cancer using a multivariate signature.
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| 5. |
- Sievers, Susanne, et al.
(författare)
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The multicopy sRNA LhrC controls expression of the oligopeptide-binding protein OppA in Listeria monocytogenes
- 2015
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Ingår i: RNA Biology. - [Sievers, Susanne; Lund, Anja; Menendez-Gil, Pilar; Nielsen, Aaraby; Storm Mollerup, Maria; Lambert Nielsen, Stine; Buch Larsson, Pernille; Borch-Jensen, Jonas; Kallipolitis, Birgitte Haahr] Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark. [Sievers, Susanne] Ernst Moritz Arndt Univ Greifswald, Inst Microbiol, Greifswald, Germany. [Johansson, Joergen] Umea Univ, Dept Mol Biol, Umea, Sweden. : Informa UK Limited. - 1547-6286 .- 1555-8584. ; 12:9, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Listeria monocytogenes is the causative agent of the foodborne disease listeriosis. During infection, L. monocytogenes produces an array of non-coding RNAs, including the multicopy sRNA LhrC. These five, nearly identical sRNAs are highly induced in response to cell envelope stress and target the virulence adhesin lapB at the post-transcriptional level. Here, we demonstrate that LhrC controls expression of additional genes encoding cell envelope-associated proteins with virulence function. Using transcriptomics and proteomics, we identified a set of genes affected by LhrC in response to cell envelope stress. Three targets were significantly down-regulated by LhrC at both the RNA and protein level: lmo2349, tcsA and oppA. All three genes encode membrane-associated proteins: A putative substrate binding protein of an amino acid ABC transporter (Lmo2349); the CD4+ T cell-stimulating antigen TcsA, and the oligopeptide binding protein OppA, of which the latter 2 are required for full virulence of L. monocytogenes. For OppA, we show that LhrC acts by direct base paring to the ribosome binding site of the oppA mRNA, leading to an impediment of its translation and a decreased mRNA level. The sRNA-mRNA interaction depends on 2 of 3 CU-rich regions in LhrC allowing binding of 2 oppA mRNAs to a single LhrC molecule. Finally, we found that LhrC contributes to infection in macrophage-like cells. These findings demonstrate a central role for LhrC in controlling the level of OppA and other virulence-associated cell envelope proteins in response to cell envelope stress.
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| 6. |
- Arlien-Soborg, Mai C., et al.
(författare)
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Acromegaly management in the Nordic countries: A Delphi consensus survey
- 2024
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Ingår i: Clinical Endocrinology. - : WILEY. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 7. |
- Arlien-Soborg, Mai C., et al.
(författare)
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Acromegaly management in the Nordic countries: A Delphi consensus survey
- 2024
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Ingår i: CLINICAL ENDOCRINOLOGY. - : WILEY. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
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| 8. |
- Bollerup, Annemarie R, et al.
(författare)
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Access to highly active antiretroviral therapy (HAART) in the WHO European Region 2003-2005
- 2008
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 36:2, s. 183-189
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To assess changes in access to highly active antiretroviral therapy (HAART) between the end of 2002 and the end of 2005, and to review the capacity for further HAART scale-up in the then 52 Member States of the WHO European Region. Methods: Analysis of data from four surveys evaluating access to HAART, supplemented by regional estimates of the number of people receiving HAART. Changes in access to HAART are evaluated in terms of changes in the number of people receiving HAART over time and changes in country-level HAART coverage. Results: During 2003-2005, the total number of individuals receiving HAART increased by an estimated 101,000, from 242,000 to 343,000 (a 42% increase); 85,000 were in the west region (a 36% increase) and 16,000 in the centre and east regions (a 229% increase). The number of countries providing "high" coverage with HAART (>75% of those in need receiving it) increased from 29 to 38, and the number of countries providing no HAART declined from eight to four. Conclusions: Despite high and increasing coverage in many European countries, access to HAART remained inequitable in terms of geographical location. By the end of 2005, all countries in the west provided "high" HAART coverage as compared with half of countries in the centre and east. Six east countries still provided poor or no HAART coverage. Countries must address how to further equitably increase the number of people receiving HAART.
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| 9. |
- Donoghoe, Martin C., et al.
(författare)
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Access to highly active antiretroviral therapy (HAART) for injecting drug users in the WHO European Region 2002-2004
- 2007
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Ingår i: International Journal of Drug Policy. - : Elsevier BV. - 1873-4758 .- 0955-3959. ; 18:4, s. 271-280
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Tidskriftsartikel (refereegranskat)abstract
- Providing equitable access to highly active antiretroviral treatment (HAART) to injecting drug users (IDUs) is both feasible and desirable. Given the evidence that IDUs can adhere to HAART as well as non-IDUs and the imperative to provide universal and equitable access to HlV/AlDS treatment for all who need it, here we examine whether IDUs in the 52 countries in the WHO European Region have equitable access to HAART and whether that access has changed over time between 2002 and 2004. We consider regional and Country differences in IDU HAART access; examine preliminary data regarding the injecting status of those initiating HAART and the use of opioid substitution therapy among HAART patients, and discuss how HAART might be better delivered to injecting drug users. Our data adds to the evidence that IDUs in Europe have poor and inequitable access to HAART, with only a relatively small improvement in access between 2002 and 2004. Regional and country comparisons reveal that inequities in IDU access to HAART are worst in eastern European countries. (C) 2007 Elsevier B.V. All rights reserved.
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| 10. |
- Edvinsson, Lars, et al.
(författare)
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Plasticity of Cerebrovascular Smooth Muscle Cells After Subarachnoid Hemorrhage
- 2014
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Ingår i: Translational Stroke Research. - : Springer Science and Business Media LLC. - 1868-4483 .- 1868-601X. ; 5:3, s. 365-376
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Tidskriftsartikel (refereegranskat)abstract
- Subarachnoid hemorrhage (SAH) is most often followed by a delayed phase of cerebral ischemia which is associated with high morbidity and mortality rates. The causes underlying this delayed phase are still unsettled, but are believed to include cerebral vasospasm, cortical spreading depression, inflammatory reactions, and microthrombosis. Additionally, a large body of evidence indicates that vascular plasticity plays an important role in SAH pathophysiology, and this review aims to summarize our current knowledge on the phenotypic changes of vascular smooth muscle cells of the cerebral vasculature following SAH. In light of the emerging view that the whole cerebral vasculature and the cells of the brain parenchyma should be viewed as one integrated neurovascular network, phenotypical changes are discussed both for the cerebral arteries and the microvasculature. Furthermore, the intracellular signaling involved in the vascular plasticity is discussed with a focus on the Raf-MEK1/2-ERK1/2 pathway which seems to play a crucial role in SAH pathology.
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| 11. |
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| 12. |
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| 13. |
- Harju, Tekla, et al.
(författare)
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DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia : is there a causal relationship?
- 2023
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Ingår i: The Pharmacogenomics Journal. - : Springer Nature. - 1470-269X .- 1473-1150. ; 23, s. 105-111
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Tidskriftsartikel (refereegranskat)abstract
- Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.
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| 14. |
- Joormann, Martin, et al.
(författare)
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Asylum Case Adjudication in Sweden, Country of Origin Information and Epistemic Violence
- 2024
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Ingår i: Transformations of European Welfare States and Social Rights. - : Palgrave Macmillan. - 9783031466366 - 9783031466373 ; , s. 125-144
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Bokkapitel (refereegranskat)abstract
- This chapter on country of origin information (COI) draws on the semi-structured interviews I have been conducting between the years 2014 and 2022 with the responsible decision-makers of the Swedish welfare state: migration court judges. By applying Spivak’s concept of ‘epistemic violence’ in my qualitative content analysis of ten of these interviews, I problematise the COI that judges apply when they adjudicate. The epistemic violence embedded in asylum determination procedures in general is influenced by the institutionalised power imbalance that characterises the Swedish asylum system. The analysis of the corresponding power relations—between people seeking asylum from refugee-sending countries and decision-makers of a wealthy welfare state—leads the critical observer to detect parallels with the colonial bureaucratic violence of earlier historical periods.
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| 15. |
- Kehler, Jan, et al.
(författare)
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Discovery and Development of C-11-Lu AE92686 as a Radioligand for PET Imaging of Phosphodiesterase10A in the Brain
- 2014
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:9, s. 1513-1518
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Tidskriftsartikel (refereegranskat)abstract
- Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-C-11-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine (C-11-Lu AE92686) and its tritiated analog H-3-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and C-11-labeled compounds were synthesized. 3H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and C-11-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: C-11-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3H-Lu AE92686. The binding of C-11-Lu AE92686 and 3H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of C-11-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BP(ND)s were 6.5 +/- 0.3 (n = 3) and 7.5 +/- 1.0 (n = 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that C-11-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.
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| 16. |
- Klinger, Stine C., et al.
(författare)
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Polarized trafficking of the sorting receptor SorLA in neurons and MDCK cells
- 2016
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Ingår i: The FEBS Journal. - : Wiley-Blackwell. - 1742-464X .- 1742-4658. ; 283:13, s. 2476-2493
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Tidskriftsartikel (refereegranskat)abstract
- The sorting receptor SorLA is highly expressed in neurons and is also found in other polarized cells. The receptor has been reported to participate in the trafficking of several ligands, some of which are linked to human diseases, including the amyloid precursor protein, TrkB, and Lipoprotein Lipase (LpL). Despite this, only the trafficking in nonpolarized cells has been described so far. Due to the many differences between polarized and nonpolarized cells, we examined the localization and trafficking of SorLA in epithelial Madin-Darby canine kidney (MDCK) cells and rat hippocampal neurons. We show that SorLA is mainly found in sorting endosomes and on the basolateral surface of MDCK cells and in the somatodendritic domain of neurons. This polarized distribution of SorLA respectively depends on an acidic cluster and an extended version of this cluster and involves the cellular adaptor complex AP-1. Furthermore, we show that SorLA can mediate transcytosis across a tight cell layer.
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| 17. |
- Klinger, Stine C, et al.
(författare)
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SorLA regulates the activity of lipoprotein lipase by intracellular trafficking
- 2011
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 124, s. 1095-1105
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Tidskriftsartikel (refereegranskat)abstract
- Many different tissues and cell types exhibit regulated secretion of lipoprotein lipase (LPL). However, the sorting of LPL in the trans Golgi network has not, hitherto, been understood in detail. Here, we characterize the role of SorLA (officially known as SorLA-1 or sortilin-related receptor) in the intracellular trafficking of LPL. We found that LPL bound to SorLA under neutral and acidic conditions, and in cells this binding mainly occurred in vesicular structures. SorLA expression changed the subcellular distribution of LPL so it became more concentrated in endosomes. From the endosomes, LPL was further routed to the lysosomes, which resulted in a degradation of newly synthesized LPL. Consequently, an 80% reduction of LPL activity was observed in cells that expressed SorLA. By analogy, SorLA regulated the vesicle-like localization of LPL in primary neuronal cells. Thus, LPL binds to SorLA in the biosynthetic pathway and is subsequently transported to endosomes. As a result of this SorLA mediated-transport, newly synthesized LPL can be routed into specialized vesicles and eventually sent to degradation, and its activity thereby regulated.
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| 18. |
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| 19. |
- Lazarus, Jeffrey, et al.
(författare)
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Factors affecting attitudes towards medical abortion in Lithuania
- 2006
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Ingår i: European Journal of Contraception & Reproductive Health Care. - : Informa UK Limited. - 1362-5187 .- 1473-0782. ; 11:3, s. 202-209
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Tidskriftsartikel (refereegranskat)abstract
- Objective Surgical abortion in Lithuania is governed by a 1994 ministerial decree that made it legal for any woman 16 or older. This article seeks to determine the key demographic factors in Lithuanian attitudes towards medical abortion, which is currently not legal. Methods A random sample of the adult population was asked if they supported medical abortion. The dependent variable of attitude towards medical abortion was tested against the eight independent variables reported for each respondent using Chi-square tests and odds ratios. The effects of the variables upon each other were tested with two logistic regression models. Results Among the respondents, 62.6% supported access to medical abortion. The independent variables of urban/rural residence, employment status and educational level significantly affected opinion. Overall, education level provided the strongest odds ratio for support of medical abortion. Conclusion The majority of the Lithuanian population supports the legalisation of medical abortion. There is somewhat less support for it in rural areas, among those who are least educated and in certain nonworking population groups. Lithuanian policy-makers should consider responding to popular sentiment and legalising medical abortion.
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| 20. |
- Lund Hansen, Stine, et al.
(författare)
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Distribution of zopiclone and main metabolites in hair following a single dose
- 2020
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Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 306
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Tidskriftsartikel (refereegranskat)abstract
- In forensic investigations, such as drug-facilitated crimes, reference values are useful for interpretation of hair results. The aim of this study was to establish levels of zopiclone and two main metabolites, N-desmethylzopiclone and zopiclone N-oxide, in hair after the administration of a single dose of zopiclone, as very limited data are published. A controlled study was performed, where 16 volunteers consumed either 5 or 10 mg zopiclone. Hair was sampled prior to consumption and 14, 30, 60, and 120 days after intake. The deposition of drug in hair segments of all sampling time points was followed in small hair segments of 5-mm, using a validated ultra-high performance liquid chromatography-tandem mass spectrometry method. In all participants, hair segments corresponding to the time of intake were positive for zopiclone, but also with lower concentrations in the neighbouring segments. The highest zopiclone concentrations were detected in samples collected 30 or 60 days after intake. For all sampling time points maximum values for the 5-mg dose ranged from 5.0-370 pg/mg for zopiclone and 5.4 to 300 pg/mg for N-desmethylzopiclone, where the maximum values for the 10-mg dose ranged from 17 to 590 pg/mg for zopiclone and 25-410 pg/mg for N-desmethylzopiclone for all sampling time points. No significant difference in concentrations was found between the two dosing groups for either zopiclone or N-desmethylzopiclone. Almost half of the participants showed lower levels 14 days after intake than in the later sampling time points. The metabolite to parent drug ratio of N-desmethylzopiclone to zopiclone varied from 0.6 to 3.4 (median = 1.2) for the maximum levels of all sampling time points. N-desmethylzopiclone are suggested to serve as an additional marker to confirm the intake of zopiclone. Traces of zopiclone N-oxide were detected in hair from only eight participants. This study showed, that it was possible to follow zopiclone and N-desmethylzopiclone in hair for 4 months even though the drugs was divided into several segments in the latest collected hair samples, and no obvious wash-out effect between the sampling time points by e.g. personal hygiene could be discerned because the cumulated amount at each sampling time point was similar. We conclude that the analysis of short segments e.g. segments of 5-mm can help determine the time of a single intake of zopiclone and that obtaining a sample 1-2 months after a drug exposure provide the best conditions to detect and interpret the results. (C) 2019 Elsevier B.V. All rights reserved.
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| 21. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 22. |
- Mortensen, Camilla Bekker, et al.
(författare)
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Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium
- 2024
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Ingår i: Intensive Care Medicine. - 0342-4642. ; 50:1, s. 103-113
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. Methods: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. Results: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of − 6.4%-points (95% confidence interval [CI] − 12.8%-points to − 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI − 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI − 9.3 to 17.5; P = 0.142) for EQ VAS. Conclusions: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.
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| 23. |
- Nersting, Jacob, et al.
(författare)
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Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy.
- 2019
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Ingår i: Cancer chemotherapy and pharmacology. - : Springer Science and Business Media LLC. - 1432-0843 .- 0344-5704. ; 83:1, s. 53-60
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs=0.68 and rs=0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs≥0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p<0.00001), but collinearity precluded identification of the most informative subset.Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.
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| 24. |
- Nielsen, Stine Maria Louring, et al.
(författare)
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Beyond Vision: Moving and Feeling in Colour Illuminated Space
- 2021
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Ingår i: Nordic Journal of Architectural Research. - 1893-5281. ; 33:2, s. 81-112
-
Tidskriftsartikel (refereegranskat)abstract
- This article presents the results of an experiment exploring how four chosen light spectra illuminating a space in different colours affect observed body movements and reported sensory experiences. In addition, the experiment explores if these effects are apparent only when the light is perceived by the eye. In our light lab, 26 participants were immersed in white, blue, amber and red illumination and asked to move around while blindfolded and non-blindfolded. The movements of the participants were observed and video-recorded, and information on sensory experiences and spatial perceptions were retrieved by interviews. Thematic analysis shows patterns of how participants experienced feeling: sharp and clear in a dead space while moving in a hard manner (white), calm and introverted in a cold space while moving in a coherent manner (blue), happy and content in a supportive space while moving in a soft manner (amber) and grounded in a dense space while moving in a downwards manner (red) both while blindfolded and non-blindfolded. Statistical analyses show that the participants moved in significantly different manners and reported significantly different sensory experiences within the four lighting scenarios. Moreover, statistical analyses generally showed no significant differences between the two conditions of blindfolding and non-blindfolding.
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| 25. |
- Nielsen, Stine Nygaard, et al.
(författare)
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DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.
- 2017
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Ingår i: The Lancet. Oncology. - 1474-5488. ; 18:4, s. 515-524
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Tidskriftsartikel (refereegranskat)abstract
- Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival.In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m(2) once per day and methotrexate 20 mg/m(2) once per week, targeted to a leucocyte count of 1·5-3·0×10(9) cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2.Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001).Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts.Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.
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| 26. |
- Nielsen, Stine Piilgaard Porner, et al.
(författare)
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Digitalizing Welfare: The role of encounters in supporting marginalised citizens’ access to rights in the Danish welfare state
- 2022
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Ingår i: Recht der Werkelijkheid. - 1380-6424. ; 2022:2
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Tidskriftsartikel (refereegranskat)abstract
- Digitalisation of the public sector is advocated for as an efficient and responsive approach to the delivery of public services. In this article, we analyse the role of digitalisation from a bottom-up perspective as we zoom in on socially marginalised citizens’ access to welfare rights in the context of the digitalised Danish welfare state. In the Danish welfare state, the authority and responsibility to distribute welfare support rest mainly with the municipalities which thus play a significant role in the public sector infrastructure when it comes to ensuring efficient responses to citizens’ social problems. Yet, research suggests that citizens who lack legal and digital capabilities related to accessing welfare support in a digitalised welfare state may face challenges in this process. Drawing on observations of encounters between socially marginalised citizens and social workers who as intermediaries assist the citizens in the process of gaining access to welfare rights, and on semi-structured interviews with both parties, the article suggests that encounters between socially marginalised citizens and intermediaries can be decisive for citizens’ ability to access rights in the digitalised space of the welfare state.
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| 27. |
- Nielsen, Stine Piilgaard Porner, et al.
(författare)
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Opfattelser og tings betydning for velfærdsprofessionelle på et dansk ungdomsherberg: En kombineret retlig bevidstheds- og ’Science and Technology Studies’-tilgang
- 2023
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Ingår i: Retfærd: Nordisk juridisk tidsskrift. - 0105-1121. ; 178:4, s. 57-70
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Tidskriftsartikel (refereegranskat)abstract
- I Danmark reguleres det sociale område i høj grad af rammelovgivning, som uddelegerer myndighed, regulerer gennem formålsbeskrivelser og gør det muligt for såkaldte velfærdsprofessionelle at udøve skøn. Denne artikel undersøger, hvordan samspillet mellem velfærdsprofessionelles opfattelser og de ting, der på forskellig vis regulerer deres praksis, får betydning for konstruktionen af legalitet i deres specifikke sociale kontekst. Artiklen inddrager ungdomshjemløshed som case, og teoretisk anvendes og kombineres begreber fra retlig bevidstheds- og Science and Technology Studies-litteraturen. Empirisk fokuserer artiklen på velfærdsprofessionelle, der arbejder på et ungdomsherberg, som tilbyder midlertidigt ophold til unge i hjemløshed. Artiklens empiriske resultater illustrerer, at skriftligt materiale såsom herbergets interne retningslinjer, samtykkeerklæringer samt skemaer, der skitserer procedurer, har afgørende betydning for hverdagens sociale orden på herberget, da materialet former opfattelser af socialt accepterede praksisser.
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| 28. |
- Nielsen, Stine Vang, et al.
(författare)
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Serine-Threonine Kinases Encoded by Split hipA Homologs Inhibit Tryptophanyl-tRNA Synthetase
- 2019
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 10:3
-
Tidskriftsartikel (refereegranskat)abstract
- Type II toxin-antitoxin (TA) modules encode a stable toxin that inhibits cell growth and an unstable protein antitoxin that neutralizes the toxin by direct protein-protein contact. hipBA of Escherichia coli strain K-12 codes for HipA, a serinethreonine kinase that phosphorylates and inhibits glutamyl-tRNA synthetase. Induction of hipA inhibits charging of glutamyl-tRNA that, in turn, inhibits translation and induces RelA-dependent (p) ppGpp synthesis and multidrug tolerance. Here, we describe the discovery of a three-component TA gene family that encodes toxin HipT, which exhibits sequence similarity with the C-terminal part of HipA. A genetic screening revealed that trpS in high copy numbers suppresses HipT-mediated growth inhibition. We show that HipT of E. coli O127 is a kinase that phosphorylates tryptophanyl-tRNA synthetase in vitro at a conserved serine residue. Consistently, induction of hipT inhibits cell growth and stimulates production of (p) ppGpp. The gene immediately upstream from hipT, called hipS, encodes a small protein that exhibits sequence similarity with the N terminus of HipA. HipT kinase was neutralized by cognate HipS in vivo, whereas the third component, HipB, encoded by the first gene of the operon, did not counteract HipT kinase activity. However, HipB augmented the ability of HipS to neutralize HipT. Analysis of two additional hipBSThomologous modules showed that, indeed, HipS functions as an antitoxin in these cases also. Thus, hipBST constitutes a novel family of tricomponent TA modules where hipA has been split into two genes, hipS and hipT, that function as a novel type of TA pair.IMPORTANCE: Bacterial toxin-antitoxin (TA) modules confer multidrug tolerance (persistence) that may contribute to the recalcitrance of chronic and recurrent infections. The first high-persister gene identified was hipA of Escherichia coli strain K-12, which encodes a kinase that inhibits glutamyl-tRNA synthetase. The hipA gene encodes the toxin of the hipBA TA module, while hipB encodes an antitoxin that counteracts HipA. Here, we describe a novel, widespread TA gene family, hipBST, that encodes HipT, which exhibits sequence similarity with the C terminus of HipA. HipT is a kinase that phosphorylates tryptophanyl-tRNA synthetase and thereby inhibits translation and induces the stringent response. Thus, this new TA gene family may contribute to the survival and spread of bacterial pathogens.
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| 29. |
- Nielsen, Tobias, et al.
(författare)
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Pathways to sustainable plastics – A discussion brief
- 2018
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Rapport (populärvet., debatt m.m.)abstract
- The growing attention to the negative side-effects of our use of plastics has led to numerous calls for changing the current plastics system. However, there is lack of coherent and systematic assessments of how and in what direction the plastics system should change to become more sustainable. This discussion brief explores five potential pathways: Bio-based, Biodegradable, Recycled, Fewer types and Reduced use. Each pathway is assessed in terms of the promise it makes, what it entails and how it has been criticized. With a growing number of voices on the need for sustainable plastics, this discussion brief provides an overview of the opportunities and challenges of the pathways that can potentially take us there. The diversity and complexity of the system, as well as the lack of clear direction for what is a more sustainable plastics system, make it difficult to govern. Furthermore, there is no history of building an institutional capacity and expertise in, for example, government and research around policy and governance for plastics. Plastics is a critical material for sustainability in many areas (e.g. food, water and energy), but policies are needed to reduce the use of fossil feedstock, increase circularity and resource efficiency, and prevent leakage to the environment.
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| 30. |
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| 31. |
- Nilsson, Stefan K, 1979-, et al.
(författare)
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Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families.
- 2008
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 283:38, s. 25920-25927
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-V (apoA-V) is present in low amounts in plasma and has been found to modulate triacylglycerol levels in humans and in animal models. ApoA-V displays affinity for members of the low density lipoprotein receptor (LDL-R) gene family, known as the classical lipoprotein receptors, including LRP1 and SorLA/LR11. In addition to LDL-A binding repeats, the mosaic receptor SorLA/LR11 also possesses a Vps10p domain. Here we show that apoA-V also binds to sortilin, a receptor from the Vsp10p domain gene family that lacks LDL-A repeats. Binding of apoA-V to sortilin was competed by neurotensin, a ligand that binds specifically to the Vps10p domain. To investigate the biological fate of receptor-bound apoA-V, binding experiments were conducted with cultured human embryonic kidney cells transfected with either SorLA/LR11 or sortilin. Compared with nontransfected cells, apoA-V binding to SorLA/LR11- and sortilin-expressing cells was markedly enhanced. Internalization experiments, live imaging studies, and fluorescence resonance energy transfer analyses demonstrated that labeled apoA-V was rapidly internalized, co-localized with receptors in early endosomes, and followed the receptors through endosomes to the trans-Golgi network. The observed decrease of fluorescence signal intensity as a function of time during live imaging experiments suggested ligand uncoupling in endosomes with subsequent delivery to lysosomes for degradation. This interpretation was supported by experiments with (125)I-labeled apoA-V, demonstrating clear differences in degradation between transfected and nontransfected cells. We conclude that apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains and that apoA-V is internalized into cells via these receptors. This could be a mechanism by which apoA-V modulates lipoprotein metabolism in vivo.
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| 32. |
- Piilgaard Porner Nielsen, Stine, et al.
(författare)
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Retlig bevidsthed: Oplevelser og erfaringer af ret på tværs af tid og sted
- 2023
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Ingår i: Retfærd: Nordisk juridisk tidsskrift. - 0105-1121. ; 176:2, s. 69-81
-
Tidskriftsartikel (refereegranskat)abstract
- Studier i retlig bevidsthed analyserer personers oplevelser, forståelser og handlinger relateret til deres retlige kontekst og viser, hvor mangfoldig og foranderlig retlig bevidsthed kan være som følge af retlig bevidstheds subjektive karakter. Tidligere litteraturstudier understreger retlig bevidstheds iboende forskellighed og fokuserer særligt på metodologiske fællestræk eller fællestræk indenfor landegrænser. Denne artikel bidrager til forskningsfeltet ved at illustrere de fællestræk, der gør sig gældende i retlig bevidsthed på tværs af tid og sted. I artiklen gennemgås retssociologiske studier, der anvender retlig bevidsthed som analytisk begreb, og artiklens fokus er afgrænset til studier i retlig bevidsthed, der analyserer socialt marginaliserede personers opfattelser af rettens betydning i deres interaktion med velfærdsstaten. Eksisterende forskning viser, at denne gruppe af borgere typisk oplever retten som allestedsnærværende, hvilket understreger væsentligheden af at fokusere på netop deres retlig bevidsthed, og hvordan deres opfattelser og forståelser får betydning for deres handlinger i en velfærdsstatslig kontekst.
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| 33. |
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| 34. |
- Schoultz, Isabel, et al.
(författare)
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Access to justice and social rights for victims of trafficking and labour exploitation in Sweden
- 2024
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Ingår i: Transformations of European Welfare States and Social Rights : Regulation, Professionals, and Citizens - Regulation, Professionals, and Citizens. - 9783031466373 - 9783031466366 ; , s. 147-167
-
Bokkapitel (refereegranskat)abstract
- This chapter delves into the challenges encountered by victims of human trafficking and other forms of labour exploitation in Sweden as they struggle to access social rights and justice. By drawing from theories of victimisation as an interactional process, the study examines the role of professionals such as government agents, social services, unions, and NGOs as facilitators in assisting victims in gaining access to social rights and justice. The chapter underscores how access to justice and social rights is intricately intertwined with the victim identification process, the migration regime, and the gendered nature of assistance programmes. The limited access to social rights for victims may be attributed to the principles of inclusion and exclusion associated with the welfare state and the logic of the migration regime.
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| 35. |
- Sørensen, Ole E, et al.
(författare)
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Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 124:10, s. 4539-4548
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Tidskriftsartikel (refereegranskat)abstract
- Papillon-Lefevre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18. into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection.
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| 36. |
- Takman, Maria, et al.
(författare)
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Biological degradation of organic micropollutants in GAC filters–temporal development and spatial variations
- 2024
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Ingår i: Journal of Hazardous Materials. - : Elsevier. - 0304-3894. ; 472
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Tidskriftsartikel (refereegranskat)abstract
- The capacity for organic micropollutant removal in granular activated carbon (GAC) filters for wastewater treatment changes over time. These changes are in general attributed to changes in adsorption, but may in some cases also be affected by biological degradation. Knowledge on the degradation of organic micropollutants, however, is scarce. In this work, the degradation of micropollutants in several full-scale GAC and sand filters was investigated through incubation experiments over a period of three years, using 14C-labeled organic micropollutants with different susceptibilities to biological degradation (ibuprofen, diclofenac, and carbamazepine), with parallel 16S rRNA gene sequencing. The results showed that the degradation of diclofenac and ibuprofen in GAC filters increased with increasing numbers of bed volumes when free oxygen was available in the filter, while variations over filter depth were limited. Despite relatively large differences in bacterial composition between filters, a degradation of diclofenac was consistently observed for the GAC filters that had been operated with high influent oxygen concentration (DO >8 mg/L). The results of this comprehensive experimental work provide an increased understanding of the interactions between microbial composition, filter material, and oxygen availability in the biological degradation of organic micropollutants in GAC filters.
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| 37. |
- Toksvang, Linea Natalie, et al.
(författare)
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Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia : a NOPHO ALL2008 sub-study
- 2021
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer. - 0344-5704 .- 1432-0843. ; 88:5, s. 911-917
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. Methods We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. Results After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged >= 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. Conclusion Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.
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| 38. |
-
Transformations of European Welfare States and Social Rights: Regulation, Professionals, and Citizens
- 2024
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Samlingsverk (redaktörskap) (refereegranskat)abstract
- This open access edited book investigates European social rights in practice from socio-legal perspectives. It brings together fourteen socio-legal scholars, representing Nordic and Western European countries, who analyse different aspects pertaining to European social rights, namely the regulation of social rights, encounters between welfare professionals and citizens, and citizens’ mobilisation of social rights. These three different aspects from the structure for the sections in the anthology, each analysing transformations related to regulation, encounters and rights mobilisation. The book contributes to the existing literature as it focuses on interdependent transformations on macro, meso and micro levels which are key for understanding processes and contexts related to European social rights in practice. It speaks particularly to academics in sociology of law and/or regulation.
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| 39. |
- Yui, Shiro, et al.
(författare)
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YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration
- 2018
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 22:1, s. 7-49
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Tidskriftsartikel (refereegranskat)abstract
- Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element.
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