| 1. |
- Bjørnsbo, Kirsten Schroll, et al.
(författare)
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Protocol for the combined cardiometabolic deep phenotyping and registry-based 20-year follow-up study of the Inter99 cohort
- 2024
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Ingår i: BMJ Open. - 2044-6055. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50–80 years old Inter99 participants. Methods and analysis The Inter99 cohort comprises individuals aged 30–60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbidities. Ethics and dissemination The study was approved by the Medical Ethics Committee, Capital Region, Denmark (H-20076231) and by the Danish Data Protection Agency through the Capital Region of Denmark’s registration system (P-2020-1074). Informed consent will be obtained before examinations. Findings will be disseminated in peer-reviewed journals, at conferences and via presentations to stakeholders, including patients and public health policymakers.
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| 2. |
- Attauabi, Mohamed, et al.
(författare)
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Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study) : the protocol for a Copenhagen IBD Inception Cohort Study
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:6, s. e055779-e055779
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Inflammatory bowel diseases (IBD), encompassing Crohn's disease and ulcerative colitis, are chronic, inflammatory diseases of the gastrointestinal tract. We have initiated a Danish population-based inception cohort study aiming to investigate the underlying mechanisms for the heterogeneous course of IBD, including need for, and response to, treatment.Methods and analysis: IBD Prognosis Study is a prospective, population-based inception cohort study of unselected, newly diagnosed adult, adolescent and paediatric patients with IBD within the uptake area of Hvidovre University Hospital and Herlev University Hospital, Denmark, which covers approximately 1 050 000 inhabitants (~20% of the Danish population). The diagnosis of IBD will be according to the Porto diagnostic criteria in paediatric and adolescent patients or the Copenhagen diagnostic criteria in adult patients. All patients will be followed prospectively with regular clinical examinations including ileocolonoscopies, MRI of the small intestine, validated patient-reported measures and objective examinations with intestinal ultrasound. In addition, intestinal biopsies from ileocolonoscopies, stool, rectal swabs, saliva samples, swabs of the oral cavity and blood samples will be collected systematically for the analysis of biomarkers, microbiome and genetic profiles. Environmental factors and quality of life will be assessed using questionnaires and, when available, automatic registration of purchase data. The occurrence and course of extraintestinal manifestations will be evaluated by rheumatologists, dermatologists and dentists, and assessed by MR cholangiopancreatography, MR of the spine and sacroiliac joints, ultrasonography of peripheral joints and entheses, clinical oral examination, as well as panoramic radiograph of the jaws. Fibroscans and dual-energy X-ray absorptiometry scans will be performed to monitor occurrence and course of chronic liver diseases, osteopenia and osteoporosis.Ethics and dissemination: This study has been approved by Ethics Committee of the Capital Region of Denmark (approval number: H-20065831). Study results will be disseminated through publication in international scientific journals and presentation at (inter)national conferences.
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| 3. |
- Barnett, Ross, et al.
(författare)
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Genomic Adaptations and Evolutionary History of the Extinct Scimitar-Toothed Cat, Homotherium latidens
- 2020
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Ingår i: Current Biology. - 0960-9822 .- 1879-0445.
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Tidskriftsartikel (refereegranskat)abstract
- Summary Homotherium was a genus of large-bodied scimitar-toothed cats, morphologically distinct from any extant felid species, that went extinct at the end of the Pleistocene [1, 2, 3, 4]. They possessed large, saber-form serrated canine teeth, powerful forelimbs, a sloping back, and an enlarged optic bulb, all of which were key characteristics for predation on Pleistocene megafauna [5]. Previous mitochondrial DNA phylogenies suggested that it was a highly divergent sister lineage to all extant cat species [6, 7, 8]. However, mitochondrial phylogenies can be misled by hybridization [9], incomplete lineage sorting (ILS), or sex-biased dispersal patterns [10], which might be especially relevant for Homotherium since widespread mito-nuclear discrepancies have been uncovered in modern cats [10]. To examine the evolutionary history of Homotherium, we generated a ∼7x nuclear genome and a ∼38x exome from H. latidens using shotgun and target-capture sequencing approaches. Phylogenetic analyses reveal Homotherium as highly divergent (∼22.5 Ma) from living cat species, with no detectable signs of gene flow. Comparative genomic analyses found signatures of positive selection in several genes, including those involved in vision, cognitive function, and energy consumption, putatively consistent with diurnal activity, well-developed social behavior, and cursorial hunting [5]. Finally, we uncover relatively high levels of genetic diversity, suggesting that Homotherium may have been more abundant than the limited fossil record suggests [3, 4, 11, 12, 13, 14]. Our findings complement and extend previous inferences from both the fossil record and initial molecular studies, enhancing our understanding of the evolution and ecology of this remarkable lineage.
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| 4. |
- Christesen, Henrik Thybo, et al.
(författare)
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Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism
- 2020
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 63:1
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years’ age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
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| 5. |
- 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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| 6. |
- Kühnel, Line, et al.
(författare)
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Disease Progression in Multiple System Atrophy—Novel Modeling Framework and Predictive Factors
- 2022
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 37:8, s. 1719-1727
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course. Objectives: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease. Methods: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated. Results: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression. Conclusions: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions.
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| 7. |
- Kunnus, Kristjan, et al.
(författare)
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Vibrational wavepacket dynamics in Fe carbene photosensitizer determined with femtosecond X-ray emission and scattering
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The non-equilibrium dynamics of electrons and nuclei govern the function of photoactive materials. Disentangling these dynamics remains a critical goal for understanding photoactive materials. Here we investigate the photoinduced dynamics of the [Fe(bmip)2]2+ photosensitizer, where bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)-pyridine, with simultaneous femtosecond-resolution Fe Kα and Kβ X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS). This measurement shows temporal oscillations in the XES and XSS difference signals with the same 278 fs period oscillation. These oscillations originate from an Fe-ligand stretching vibrational wavepacket on a triplet metal-centered (3MC) excited state surface. This 3MC state is populated with a 110 fs time constant by 40% of the excited molecules while the rest relax to a 3MLCT excited state. The sensitivity of the Kα XES to molecular structure results from a 0.7% average Fe-ligand bond length shift between the 1 s and 2p core-ionized states surfaces.
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| 8. |
- Markmann, Verena, et al.
(författare)
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Real-time structural dynamics of the ultrafast solvation process around photo-excited aqueous halides
- 2024
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Ingår i: CHEMICAL SCIENCE. - 2041-6520 .- 2041-6539. ; 15:29, s. 11391-11401
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Tidskriftsartikel (refereegranskat)abstract
- This work investigates and describes the structural dynamics taking place following charge-transfer-to-solvent photo-abstraction of electrons from I- and Br- ions in aqueous solution following single- and 2-photon excitation at 202 nm and 400 nm, respectively. A Time-Resolved X-ray Solution Scattering (TR-XSS) approach with direct sensitivity to the structure of the surrounding solvent as the water molecules adopt a new equilibrium configuration following the electron-abstraction process is utilized to investigate the structural dynamics of solvent shell expansion and restructuring in real-time. The structural sensitivity of the scattering data enables a quantitative evaluation of competing models for the interaction between the nascent neutral species and surrounding water molecules. Taking the I0-O distance as the reaction coordinate, we find that the structural reorganization is delayed by 0.1 ps with respect to the photoexcitation and completes on a time scale of 0.5-1 ps. On longer time scales we determine from the evolution of the TR-XSS difference signal that I0: e- recombination takes place on two distinct time scales of similar to 20 ps and 100 s of picoseconds. These dynamics are well captured by a simple model of diffusive evolution of the initial photo-abstracted electron population where the charge-transfer-to-solvent process gives rise to a broad distribution of electron ejection distances, a significant fraction of which are in the close vicinity of the nascent halogen atoms and recombine on short time scales. Time-resolved X-ray solution scattering with a 1-photon and 2-photon pump qualitatively confirms the similar to 0.5 & Aring; increase in the nearest-neighbour halide-oxygen distances of iodide and bromide solvated in water.
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| 9. |
- Networked Learning Editorial Collective, (NLEC), et al.
(författare)
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Networked Learning in 2021: A Community Definition
- 2021
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Ingår i: Postdigital Science and Education. - : Springer. - 2524-4868 .- 2524-485X. ; 3, s. 326-369
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Tidskriftsartikel (refereegranskat)abstract
- Introduction (Networked Learning Editorial Collective): Since the turn of this century, much of the world has undergone a tectonic socio-technological change. Computers have left the isolated basements of research institutes and entered people's homes. Network connectivity has advanced from slow and unreliable modems to high-speed broadband. Devices have evolved: from stationary desktop computers to ever-present, always-connected smartphones. These developments have been accompanied by new digital practices, and changing expectations, not least in education, where enthusiasm for digital technologies has been kindled by quite contrasting sets of values. For example, some critical pedagogues working in the traditions of Freire and Illich have understood computers as novel tools for political and social emancipation, while opportunistic managers in cash-strapped universities have seen new opportunities for saving money and/or growing revenues. Irrespective of their ideological leanings, many of the early attempts at marrying technology and education had some features in common: instrumentalist understanding of human relationships with technologies, with a strong emphasis on practice and 'what works'.It is now clear that, in many countries, managerialist approaches have provided the framing, while local constraints and exigencies have shaped operational details, in fields such as e-learning, Technology Enhanced Learning, and others waving the 'Digital' banner. Too many emancipatory educational movements have ignored technology, burying their heads in the sand, or have wished it away, subscribing toa new form of Luddism, even as they sense themselves moving to the margins. But this situation is not set in stone. Our postdigital reality results from a complex interplay between centres and margins. Furthermore, the concepts of centres and margins 'have morphed into formations that we do not yet understand, and they have created (power) relationships which are still unsettled. The concepts … have not disappeared, but they have become somewhat marginal in their own right.' (Jandrić andHayes 2019) Social justice and emancipation are as important as ever, yet they require new theoretical reconfigurations and practices fit for our socio-technological moment.In the 1990s, networked learning (NL) emerged as a critical response to dominant discourses of the day. NL went against the grain in two main ways. First, it embarked on developing nuanced understandings of relationships between humans and technologies; understandings which reach beyond instrumentalism and various forms of determinism. Second, NL embraced the emancipatory agenda of the critical pedagogy movement and has, in various ways, politically committed to social justice (Beaty et al. 2002; Networked Learning Editorial Collective 2020). Gathered around the biennial Networked Learning Conference,1 the Research in NetworkedLearning book series,2 and a series of related projects and activities, the NL community has left a significant trace in educational transformations over the last few decades.Twenty years ago, founding members of the NL community offered a definition of NL which has strongly influenced the NL community’s theoretical perspectives and research approaches (Goodyear et al. 2004).3 Since then, however, the world has radically changed. With this in mind, the Networked Learning Editorial Collective (NLEC) recently published a paper entitled 'Networked Learning: InvitingRedefinition' (2020). In line with NL's critical agenda, a core goal for the paper was to open up a broad discussion about the current meaning and understandings of NL and directions for its further development.The current collectively authored paper presents the responses to the NLEC's open call. With 40 contributors coming from six continents and working across many fields of education, the paper reflects the breadth and depth of current understandings of NL. The responses have been collated, classified into main themes, and lightly edited for clarity. One of the responders, Sarah Hayes, was asked to write aconclusion. The final draft paper has undergone double open review. The reviewers, Laura Czerniewicz and Jeremy Knox, are acknowledged as authors.Our intention, in taking this approach, has been to further stimulate democratic discussion about NL and to prompt some much-needed community-building.
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| 10. |
- Nielsen, Rikke V., et al.
(författare)
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Personalized intervention based on early detection of atherosclerosis : JACC state-of-the-art review
- 2024
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 83:21, s. 2112-2127
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Forskningsöversikt (refereegranskat)abstract
- Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required—moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health.
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| 11. |
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| 12. |
- Tatsuno, Hideyuki, et al.
(författare)
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Hot Branching Dynamics in a Light-Harvesting Iron Carbene Complex Revealed by Ultrafast X-ray Emission Spectroscopy
- 2020
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Ingår i: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 59:1, s. 364-372
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Tidskriftsartikel (refereegranskat)abstract
- Iron N-heterocyclic carbene (NHC) complexes have received a great deal of attention recently because of their growing potential as light sensitizers or photocatalysts. We present a sub-ps X-ray spectroscopy study of an FeIINHC complex that identifies and quantifies the states involved in the deactivation cascade after light absorption. Excited molecules relax back to the ground state along two pathways: After population of a hot 3MLCT state, from the initially excited 1MLCT state, 30 % of the molecules undergo ultrafast (150 fs) relaxation to the 3MC state, in competition with vibrational relaxation and cooling to the relaxed 3MLCT state. The relaxed 3MLCT state then decays much more slowly (7.6 ps) to the 3MC state. The 3MC state is rapidly (2.2 ps) deactivated to the ground state. The 5MC state is not involved in the deactivation pathway. The ultrafast partial deactivation of the 3MLCT state constitutes a loss channel from the point of view of photochemical efficiency and highlights the necessity to screen transition-metal complexes for similar ultrafast decays to optimize photochemical performance.
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| 13. |
- Toussaint, Laura, et al.
(författare)
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Inter-observer variation in target delineation and dose trade-off for radiotherapy of paediatric ependymoma
- 2022
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 61:2, s. 235-238
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Tidskriftsartikel (refereegranskat)abstract
- Postoperative radiotherapy for intracranial paediatric ependymoma is challenging both for target definition and treatment planning [1]. Delineation of the tumour bed is difficult, as structures in prior contact with the tumour will shift back into their original positions after surgery. In infratentorial cases, the target is adjacent to the brainstem and upper spinal cord, therefore the relatively high prescription dose and sparing of surrounding organs at risk (OARs) need to be balanced. Through the radiotherapy working-group of the Nordic Organization of Pediatric Hematology and Oncology (NOPHO) and in collaboration with the Westdeutsches Protonentherapizentrum Essen (WPE), a study was performed to quantify inter-centre variations in target delineation and treatment plans for these tumours.
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| 14. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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