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| 3. |
- Bonham, LW, et al.
(författare)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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| 5. |
- Gao, YX, et al.
(författare)
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Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 12184-
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Tidskriftsartikel (refereegranskat)abstract
- We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
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| 8. |
- Ferrari, Raffaele, et al.
(författare)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 9. |
- Frisoni, G. B., et al.
(författare)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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| 11. |
- Bilde, M., et al.
(författare)
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Saturation Vapor Pressures and Transition Enthalpies of Low-Volatility Organic Molecules of Atmospheric Relevance: From Dicarboxylic Acids to Complex Mixtures
- 2015
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Ingår i: Chemical Reviews. - : American Chemical Society (ACS). - 0009-2665 .- 1520-6890. ; 115:10, s. 4115-4156
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Forskningsöversikt (refereegranskat)abstract
- There are a number of techniques that can be used that differ in terms of whether they fundamentally probe the equilibrium and the temperature range over which they can be applied. The series of homologous, straight-chain dicarboxylic acids have received much attention over the past decade given their atmospheric relevance, commercial availability, and low saturation vapor pressures, thus making them ideal test compounds. Uncertainties in the solid-state saturation vapor pressures obtained from individual methodologies are typically on the order of 50-100%, but the differences between saturation vapor pressures obtained with different methods are approximately 1-4 orders of magnitude, with the spread tending to increase as the saturation vapor pressure decreases. Some of the dicarboxylic acids can exist with multiple solid-state structures that have distinct saturation vapor pressures. Furthermore, the samples on which measurements are performed may actually exist as amorphous subcooled liquids rather than solid crystalline compounds, again with consequences for the measured saturation vapor pressures, since the subcooled liquid phase will have a higher saturation vapor pressure than the crystalline solid phase. Compounds with equilibrium vapor pressures in this range will exhibit the greatest sensitivities in terms of their gas to particle partitioning to uncertainties in their saturation vapor pressures, with consequent impacts on the ability of explicit and semiexplicit chemical models to simulate secondary organic aerosol formation.
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| 12. |
- Deodati, A, et al.
(författare)
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IGF2 methylation is associated with lipid profile in obese children
- 2013
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 79:6, s. 361-367
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Aim:</i></b> Our aim was to investigate the relationships between the degree of <i>IGF2 </i>methylation and the metabolic status in obese children and adolescents. <b><i>Subjects and Methods:</i></b> Eighty-five obese subjects aged 11.6 ± 2.1 years were studied. Anthropometry, metabolic parameters, blood pressure and body composition were assessed. DNA methylation analysis was performed by restriction enzyme digestion assay. The study population was subdivided into two groups according to the percentage of <i>IGF2</i> cytidine-guanosine (CpG) island methylation. <b><i>Results:</i></b> Twenty-two subjects showed intermediate methylation (a percentage of CpG site methylation comprised between 10 and 60%), 56 were hypomethylated (percentage of methylation lower than 10%), and only 1 showed a high rate of hypermethylation (percentage of methylation above 60%). Children with intermediate methylation showed significantly higher levels of triglycerides (107.6 ± 41.99 vs. 76.6 ± 30.18 mg/dl, p < 0.005) and a higher triglyceride/high-density lipoprotein-cholesterol ratio (2.23 ± 0.98 vs. 1.79 ± 0.98, p < 0.02) compared with hypomethylated children. <b><i>Conclusions:</i></b> These preliminary findings show for the first time a relationship between <i>IGF2</i> methylation pattern and lipid profile in obese children. Although the correlation does not imply causation, if our findings are confirmed in further studies, <i>IGF2</i> methylation might represent an epigenetic marker of metabolic risk.
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| 13. |
- Devries, K., et al.
(författare)
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Who perpetrates violence against children? A systematic analysis of age-specific and sex-specific data
- 2018
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Ingår i: BMJ Paediatr Open. - : BMJ. - 2399-9772. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The epidemiology of violence against children is likely to differ substantially by sex and age of the victim and the perpetrator. Thus far, investment in effective prevention strategies has been hindered by lack of clarity in the burden of childhood violence across these dimensions. We produced the first age-specific and sex-specific prevalence estimates by perpetrator type for physical, sexual and emotional violence against children globally. Design: We used random effects meta-regression to estimate prevalence. Estimates were adjusted for relevant quality covariates, variation in definitions of violence and weighted by region-specific, age-specific and sex-specific population data to ensure estimates reflect country population structures. Data sources: Secondary data from 600 population or school-based representative datasets and 43 publications obtained via systematic literature review, representing 13 830 estimates from 171 countries. Eligibility criteria for selecting studies: Estimates for recent violence against children aged 0-19 were included. Results: The most common perpetrators of physical and emotional violence for both boys and girls across a range of ages are household members, with prevalence often surpassing 50%, followed by student peers. Children reported experiencing more emotional than physical violence from both household members and students. The most common perpetrators of sexual violence against girls aged 15-19 years are intimate partners; however, few data on other perpetrators of sexual violence against children are systematically collected internationally. Few age-specific and sex-specific data are available on violence perpetration by schoolteachers; however, existing data indicate high prevalence of physical violence from teachers towards students. Data from other authority figures, strangers, siblings and other adults are limited, as are data on neglect of children. Conclusions: Without further investment in data generation on violence exposure from multiple perpetrators for boys and girls of all ages, progress towards Sustainable Development Goals 4, 5 and 16 may be slow. Despite data gaps, evidence shows violence from household members, peers in school and for girls, from intimate partners, should be prioritised for prevention. Trial registration number: PROSPERO 2015: CRD42015024315.
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| 14. |
- Garcia-Munoz, M., et al.
(författare)
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Active control of Alfven eigenmodes in magnetically confined toroidal plasmas
- 2019
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Ingår i: Plasma Physics and Controlled Fusion. - : Institute of Physics Publishing (IOPP). - 0741-3335 .- 1361-6587. ; 61:5
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Tidskriftsartikel (refereegranskat)abstract
- Alfven waves are electromagnetic perturbations inherent to magnetized plasmas that can be driven unstable by a free energy associated with gradients in the energetic particles' distribution function. The energetic particles with velocities comparable to the Alfven velocity may excite Alfven instabilities via resonant wave-particle energy and momentum exchange. Burning plasmas with large population of fusion born super-Alfvenic alpha particles in magnetically confined fusion devices are prone to excite weakly-damped Alfven eigenmodes (AEs) that, if allowed to grow unabated, can cause a degradation of fusion performance and loss of energetic ions through a secular radial transport. In order to control the fast-ion distribution and associated Alfvenic activity, the fusion community is currently searching for external actuators that can control AEs and energetic ions in the harsh environment of a fusion reactor. Most promising control techniques are based on (i) variable fast-ion sources to modify gradients in the energetic particles' distribution, (ii) localized electron cyclotron resonance heating to affect the fast-ion slowing-down distribution, (iii) localized electron cyclotron current drive to modify the equilibrium magnetic helicity and thus the AE existence criteria and damping mechanisms, and (iv) externally applied 3D perturbative fields to manipulate the fast-ion distribution and thus the wave drive. Advanced simulations help to identify the key physics mechanisms underlying the observed AE mitigation and suppression and thus to develop robust control techniques towards future burning plasmas.
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| 21. |
- Dubois, B., et al.
(författare)
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Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group
- 2021
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Ingår i: Lancet Neurology. - : Elsevier BV. - 1474-4422. ; 20:6, s. 484-496
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Tidskriftsartikel (refereegranskat)abstract
- In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid beta and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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| 22. |
- Fabbri, C., et al.
(författare)
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Modelling the effect of the COVID-19 pandemic on violent discipline against children
- 2021
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Ingår i: Child Abuse and Neglect. - : Elsevier BV. - 0145-2134. ; 116:Pt 2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The COVID-19 pandemic could increase violence against children at home. However, collecting empirical data on violence is challenging due to ethical, safety, and data quality concerns. Objective: This study estimated the anticipated effect of COVID-19 on violent discipline at home using multivariable predictive regression models. Participants: Children aged 1–14 years and household members from the Multiple Indicator Cluster Surveys (MICS) conducted in Nigeria, Mongolia, and Suriname before the COVID-19 pandemic were included. Methods: A conceptual model of how the COVID-19 pandemic could affect risk factors for violent discipline was developed. Country specific multivariable linear models were used to estimate the association between selected variables from MICS and a violent discipline score which captured the average combination of violent disciplinary methods used in the home. A review of the literature informed the development of quantitative assumptions about how COVID-19 would impact the selected variables under a “high restrictions” pandemic scenario, approximating conditions expected during a period of intense response measures, and a “lower restrictions” scenario with easing of COVID-19 restrictions but with sustained economic impacts. These assumptions were used to estimate changes in violent discipline scores. Results: Under a “high restrictions” scenario there would be a 35%–46% increase in violent discipline scores in Nigeria, Mongolia and Suriname, and under a “lower restrictions” scenario there would be between a 4%–6% increase in violent discipline scores in these countries. Conclusion: Policy makers need to plan for increases in violent discipline during successive waves of lockdowns. © 2020 Elsevier Ltd
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