| 1. |
- Schoenmakers, Daphne H., et al.
(författare)
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Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries
- 2024
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Ingår i: Orphanet Journal of Rare Diseases. - 1750-1172. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. Methods: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. Results: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1–3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1–5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. Conclusion: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians’ struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.
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| 2. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 3. |
- Hepworth, Jo, et al.
(författare)
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Natural variation in autumn expression is the major adaptive determinant distinguishing Arabidopsis FLC haplotypes
- 2020
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Ingår i: eLIFE. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- In Arabidopsis thaliana, winter is registered during vernalization through the temperature-dependent repression and epigenetic silencing of floral repressor FLOWERING LOCUS C (FLC). Natural Arabidopsis accessions show considerable variation in vernalization. However, which aspect of the FLC repression mechanism is most important for adaptation to different environments is unclear. By analysing FLC dynamics in natural variants and mutants throughout winter in three field sites, we find that autumnal FLC expression, rather than epigenetic silencing, is the major variable conferred by the distinct Arabidopsis FLChaplotypes. This variation influences flowering responses of Arabidopsis accessions resulting in an interplay between promotion and delay of flowering in different climates to balance survival and, through a post-vernalization effect, reproductive output. These data reveal how expression variation through non-coding cis variation at FLC has enabled Arabidopsis accessions to adapt to different climatic conditions and year-on-year fluctuations.
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| 4. |
- Hepworth, Jo, et al.
(författare)
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Natural variation in autumn expression is the major adaptive determinant distinguishing arabidopsis flc haplotypes
- 2020
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Ingår i: eLife. - 2050-084X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- In Arabidopsis thaliana, winter is registered during vernalization through the temperature-dependent repression and epigenetic silencing of floral repressor FLOWERING LOCUS C (FLC). Natural Arabidopsis accessions show considerable variation in vernalization. However, which aspect of the FLC repression mechanism is most important for adaptation to different environments is unclear. By analysing FLC dynamics in natural variants and mutants throughout winter in three field sites, we find that autumnal FLC expression, rather than epigenetic silencing, is the major variable conferred by the distinct Arabidopsis FLChaplotypes. This variation influences flowering responses of Arabidopsis accessions resulting in an interplay between promotion and delay of flowering in different climates to balance survival and, through a post-vernalization effect, reproductive output. These data reveal how expression variation through non-coding cis variation at FLC has enabled Arabidopsis accessions to adapt to different climatic conditions and year-on-year fluctuations.
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| 5. |
- Jensen, Benjamin A H, et al.
(författare)
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Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3+RORγt+IL-17+) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.
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| 6. |
- 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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| 7. |
- Kirkeleit, Jorunn, et al.
(författare)
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Early life exposures contributing to accelerated lung function decline in adulthood – a follow-up study of 11,000 adults from the general population
- 2023
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 66
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements. Methods: Participants (20–68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991–2013 and 1997–2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV1) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV1, FVC and height at baseline, accounting for personal smoking. Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV1 2.6 ml/year; 0.9, 4.4) (FEV1/FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found. Interpretation: Mothers’ smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV1 and FVC later in life comparable to smoking 10 pack-years. Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya.
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| 8. |
- Kirkeleit, Jorunn, et al.
(författare)
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Early life origins of lung ageing : A study of lung function decline the ECRHS and NFBC1966 cohorts
- 2020
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Ingår i: European Respiratory Journal. - : ERS Publications. - 0903-1936 .- 1399-3003. ; 56
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To determine whether early life factors associated with poor lung growth and submaximal attained lung function contribute to accelerated lung function decline later in life.Methods: Participants in the European Community Respiratory Health Survey (ECRHS) and the Northern Finland Birth Cohort 1966 (NFBC1966) with lung function measured in a first (n=10,971), second (n=7,981) and third wave (n=4,849), aged 20 – 68 years, were included. Mean annual decline in maximum forced expired volume in 1 second (FEV1) and forced vital capacity (FVC) were main outcomes. Information on early life factors was provided by standardized interviews and questionnaires. We estimated the effect of early life factors including maternal age, parental smoking, season of birth, parental asthma and respiratory infections using mixed effects models, adjusted for age, FEV1 and FVC at baseline, height, and smoking habits.Results: Decline in FEV1 was accelerated in women born of a mother with asthma (β = 2.4 ml; 95% CI 0.6-4.3) or who smoked during pregnancy (1.9; 0.2-3.6), and in men having a father with asthma (3.5; 0.2-6.9) or born by Cesarean section (7.9; 1.6-14.2). Accelerated decline in FVC was associated with paternal asthma in men (4.3; 0.1-8.5) and early menarche (<12 years) in women (2.4; 0.4-4.4). No statistically significant effect on lung function decline was found for other investigated early life factors.Conclusion: Early life risk factors contribute to an accelerated lung function decline with ageing, following sex-specific patterns. Decline in FEV1 versus FVC showed slightly different patterns.
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| 9. |
- Leard, Lorriana E., et al.
(författare)
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Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation
- 2021
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Ingår i: Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498 .- 1557-3117. ; 40, s. 1349-1379
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Tidskriftsartikel (refereegranskat)abstract
- Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.
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| 10. |
- Lilliecreutz, Caroline, et al.
(författare)
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Participation in interventions and recommended follow-up for non-attendees in cervical cancer screening-taking the womens own preferred test method into account-A Swedish randomised controlled trial
- 2020
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- Background Cervical cancer is a highly preventable disease. To not attend an organized cervical cancer screening program increases the risk for cervical dysplasia and cervical cancer. The aim was to investigate the participation rate in three different intervention groups for non- attendees in the Swedish national program for cervical screening. The participation in the recommended follow up, and the histology found were also examined. Method Population-based randomized control trial. It included10,614 women that had not participated in the cervical cancer screening programme during the last six years (ages 30-49) and the last eight years (ages 50-64) were randomised 1:1:1(telephone call from a midwife (offering the choice between a visit for a pap smear or an HPV self-sampling test); an HPV self-sampling test only; or the routine procedure with a yearly invitation). Results In the intention to treat analysis the participation rates were 25.5% (N = 803/3146) vs 34.1% (N = 1047/3068) and 7.0% (N = 250/3538) (p<0.001) for telephone, HPV self-test and control groups respectively. In the by protocol analysis including women that answered the phone call the participation rates were 31.7% (N = 565/1784) vs 26.1% (N = 788/3002) and 7.0% (N = 250/3538) (p<0.001) for telephone, HPV self-test and control groups. The corresponding results in the by protocol analysis including women that did not answer the phone call was 19.7% (N = 565/2870) vs 26.1% (N = 788/3002) and 7.0% (N = 250/3538) (p< 0.001). The majority of the women 63,4% (1131/1784) who answered the telephone wanted to participate either by booking a visit for pap smear (38,5%) or to be sent a HPV self- sampling test (24,9%) (p<0.001). Women who chose an HPV self-test were older and gave anxiety/ fear as a reason to decline participation, and they were also less likely to participate in the follow-up if found to be HPV-positive compared to the women who chose a Pap smear. The attendance to the recommended follow-up after abnormality was in total 87%. The non-attendees had a three or eight times higher risk of having a cytology result of HSIL or suspected SCC respectively, in the index sample compared to women screened as recommended (OR 3.3 CI 95% 1.9-5.2, OR 8.6 CI 1.6-30). A total of ten SCC and one adenocarcinoma were found in the histopathology results from the non-attendee group with a study intervention, while there was only one SCC in the non-attendee group without any study intervention (p = 0.02, OR 8.1 CI 95% 1.2-350). Conclusions Our study suggests, according to intention to treat analysis, that the best intervention to get as many non-attendees as possible to participate is to send an HPV self-sampling test together with an invitation letter. Almost 90% of women in the study with an abnormal index sample attended follow-up. This is high enough to indicate that interventions to increase the participation among non-attendees are meaningful. Registry International Standard Randomised Controlled Trial Number (ISRCTN) Registration number.
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