| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 13. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 14. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 15. |
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| 16. |
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| 17. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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| 18. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 19. |
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| 20. |
- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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| 21. |
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| 22. |
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| 23. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 24. |
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| 25. |
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| 26. |
- Aktas, Özge, 1987-, et al.
(författare)
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First observation of γ-ray transitions in 111Mo
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X.
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in the extremely neutron-rich nuclei 109Mo and 111Mo have been studied following nucleon knock-out reactions. Seven $\gamma$-ray transitions, some of them in prompt mutual coincidence, have been identified for the first time in 11Mo using the DALI2 and MINOS detector systems at the BigRIPS and ZeroDegree electromagnetic fragments separator at the RIBF, RIKEN, Japan. Total Routhian surface (TRS) and Particle- Plus Rotor calculations have been performed to investigate the predicted shape coexistence and its effect on the structure of nuclei in this region of the nuclear chart. Following the results of the calculations, theoretical level schemes are proposed for positive and negative parity states and compared with the experimental findings.
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| 27. |
- Aktas, Özge, et al.
(författare)
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Single-particle structures in 85,87Ge
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X.
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray transitions have been identified for the first time in the extremely neutron-rich (N =Z + 25) nucleus 87 Ge following nucleon knockout reactions studied at the RIBF, RIKEN, Japan.New γ-ray transitions from excited states in 85 Ge were also observed and placed in a tentative levelscheme. The exclusive parallel momentum distribution was measured for the 1/2 + state for theneutron knockout reaction leading to 85 Ge which is compared with calculated distorted wave impulseapproximation (DWIA) distributions. The 85,87 Ge results are compared with large-scale shell-modelcalculations and potential energy surface calculations based on the total Routhian surface formalism.
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| 28. |
- Springer, W, et al.
(författare)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 29. |
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| 30. |
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| 31. |
- Cinner, Joshua E., et al.
(författare)
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Comanagement of coral reef social ecological systems
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:14, s. 5219-5222
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Tidskriftsartikel (refereegranskat)abstract
- In an effort to deliver better outcomes for people and the ecosystems they depend on, many governments and civil society groups are engaging natural resource users in collaborative management arrangements (frequently called comanagement). However, there are few empirical studies demonstrating the social and institutional conditions conducive to successful comanagement outcomes, especially in small-scale fisheries. Here, we evaluate 42 comanagement arrangements across five countries and show that: (i) comanagement is largely successful at meeting social and ecological goals; (ii) comanagement tends to benefit wealthier resource users; (iii) resource overexploitation is most strongly influenced by market access and users' dependence on resources; and (iv) institutional characteristics strongly influence livelihood and compliance outcomes, yet have little effect on ecological conditions.
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| 32. |
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| 33. |
- Recchia, F., et al.
(författare)
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Isomer spectroscopy in odd–even Ti isotopes : Approaching n = 40
- 2019
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Ingår i: Acta Physica Polonica B. - : Jagellonian University. - 0587-4254 .- 1509-5770. ; 50:3, s. 669-674
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Tidskriftsartikel (refereegranskat)abstract
- Our understanding of the evolution of the shell structure in nuclei far from stability is based on the study of some key nuclei. Nuclei at or next to double shell closures play a special role in this. Presently, a lot of discussion is concentrated on the neutron-rich calcium isotopes, which provide a rich testing ground for various nuclear models with several traditional and new magic numbers. 60 Ca is now almost within reach with the most advanced radioactive beam facilities. In order to investigate the evolution of the shell gap at N = 40, the configuration of states in the odd–even titanium isotopes up to N = 37 ( 59 Ti) have been studied. In order to experimentally access the shell gap at N = 40, it is nowadays within the reach of the most advanced facility the investigation of neutron hole configuration states in odd–even titanium isotopes up to N = 37, in the 59 Ti nucleus. Such states correspond to relatively simple configurations that constitute a challenging testing ground for effective nuclear interactions. The new data obtained in our experiment allows to place the present predictions concerning the shell closure at N = 40 in the calcium region on a more solid ground.
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| 34. |
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| 35. |
- Torrisi, Lorenzo, et al.
(författare)
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High intensity laser-generating plasmas in forward direction in thin films and Thomson parabola spectrometer monitorage
- 2010
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Asterix laser at PALS Laboratory of Prague, operating at 1315 nm fundamental wavelength, 300 ps pulse duration, 1016 W/cm2 intensity and single pulse mode, was employed to irradiate thin hydrogenated targets placed in high vacuum. Non-equilibrium plasmas were obtained in forward direction, i.e. along the normal to the target surface on the rear of the irradiated thin films. Plasmas were monitored with different ion detectors, placed around the direction normal to the target. The main detector was a Thomson parabola spectrometer aligned along the normal in forward direction. This spectrometer permits to provide many plasma parameters concerning the involved ions (energy, charge state, mass,...) obtained in a single laser shot. The spectrometer images, obtained by using a MCP coupled to a fast CCD camera, can be processed by a comparison with the simulation data obtained by a proper software. High ion energies and charge states have been obtained as a function of the laser parameters, target thickness and composition and irradiation conditions.
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| 36. |
- Torrisi, Lorenzo, et al.
(författare)
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Proton driven acceleration by intense laser pulses irradiating thin hydrogenated targets
- 2013
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Ingår i: Applied Surface Science. - : Elsevier. - 0169-4332 .- 1873-5584. ; 272, s. 2-5
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Tidskriftsartikel (refereegranskat)abstract
- The Asterix iodine laser of the PALS laboratory in Prague, operating at 1315 nm fundamental frequency, 300 ps pulse duration, 600 J maximum pulse energy and 1016 W/cm2 intensity, is employed to irradiatethin hydrogenated targets placed in high vacuum. Different metallic and polymeric targets allow togenerate multi-energetic and multi-specie ion beams showing peculiar properties. The plasma obtainedby the laser irradiation is monitored, in terms of properties of the emitted charge particles, by using time-of-flight techniques and Thomson parabola spectrometer (TPS). A particular attention is given tothe proton beam production in terms of the maximum energy, emission yield and angular distributionas a function of the laser energy, focal position (FP), target thickness and composition.
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| 37. |
- Tudisco, E., et al.
(författare)
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An extension of digital volume correlation for multimodality image registration
- 2017
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Ingår i: Measurement Science & Technology. - : IOP Publishing. - 0957-0233 .- 1361-6501. ; 28:9
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Tidskriftsartikel (refereegranskat)abstract
- The question of registering two images (or image volumes) acquired with different modalities, and thus exhibiting different contrast, at different positions is addressed based on an extension of global digital image (or volume) correlation. A specific comparison metric is introduced allowing the signature of the different phases to be related. A first solution consists of a Gaussian mixture to describe the joint distribution of gray levels, which not only provides a matching of both images, but also offers a natural segmentation indicator. A second 'self-adapting' solution does not include any postulated a priori model for the joint histogram and leads to a registration of the images based on their initial histograms. The algorithm is implemented with a pyramidal multiscale framework for the sake of robustness. The proposed multiscale technique is tested on two 3D images obtained from x-ray and neutron tomography respectively. The proposed approach brings the two images to coincidence with a sub-pixel accuracy and allows for a 'natural' segmentation of the different phases.
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| 38. |
- Wimmer, K., et al.
(författare)
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First spectroscopy of Ti-61 and the transition to the Island of Inversion at N=40
- 2019
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Ingår i: Physics Letters B. - : Elsevier. - 0370-2693 .- 1873-2445. ; 792, s. 16-20
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Tidskriftsartikel (refereegranskat)abstract
- Isomeric states in Ti-59,Ti-61 have been populated in the projectile fragmentation of a 345 AMeV( 238)U beam at the Radioactive Isotope Beam Factory. The decay lifetimes and delayed gamma-ray transitions were measured with the EURICA array. Besides the known isomeric state in Ti-59, two isomeric states in Ti-61 are observed for the first time. Based on the measured lifetimes, transition multipolarities as well as tentative spins and parities are assigned. Large-scale shell model calculations based on the modified LNPS interaction show that both Ti-59 and Ti-61 belong to the Island of Inversion at N = 40 with ground state configurations dominated by particle-hole excitations to the g(9/2 )and d(5/2) orbits.
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| 39. |
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| 40. |
- Bedding, Timothy R., et al.
(författare)
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A multi-site campaign to measure solar-like oscillations in Procyon. II. mode frequencies
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713:2, s. 935-949
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Tidskriftsartikel (refereegranskat)abstract
- We have analyzed data from a multi-site campaign to observe oscillations in the F5 star Procyon. The data consist of high-precision velocities that we obtained over more than three weeks with 11 telescopes. A new method for adjusting the data weights allows us to suppress the sidelobes in the power spectrum. Stacking the power spectrum in a so-called echelle diagram reveals two clear ridges, which we identify with even and odd values of the angular degree (l = 0 and 2, and l = 1 and 3, respectively). We interpret a strong, narrow peak at 446 mu Hz that lies close to the l = 1 ridge as a mode with mixed character. We show that the frequencies of the ridge centroids and their separations are useful diagnostics for asteroseismology. In particular, variations in the large separation appear to indicate a glitch in the sound-speed profile at an acoustic depth of similar to 1000 s. We list frequencies for 55 modes extracted from the data spanning 20 radial orders, a range comparable to the best solar data, which will provide valuable constraints for theoretical models. A preliminary comparison with published models shows that the offset between observed and calculated frequencies for the radial modes is very different for Procyon than for the Sun and other cool stars. We find the mean lifetime of the modes in Procyon to be 1.29(-0.49)(+0.55) days, which is significantly shorter than the 2-4 days seen in the Sun.
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| 41. |
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| 42. |
- Coelho, Teresa, et al.
(författare)
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Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen
- 2023
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Ingår i: Neurology and Therapy. - : Springer Nature. - 2193-8253 .- 2193-6536. ; 12, s. 267-287
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study.Methods: Patients eligible for NEURO-TTRansform were 18–82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II.Results: The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0.Conclusion: The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice.
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| 43. |
- Coelho, Teresa, et al.
(författare)
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Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy
- 2023
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 330:15, s. 1448-1458
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P <.001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P <.001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P <.001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
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| 44. |
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| 45. |
- Faulx, M. D., et al.
(författare)
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Obstructive sleep apnea and its management in patients with atrial fibrillation: An International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) global survey of practicing cardiologists
- 2022
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Ingår i: International journal of cardiology: Heart and Vasculature (IJCHA). - : Elsevier BV. - 2352-9067. ; 42
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Tidskriftsartikel (refereegranskat)abstract
- Background: Among international cardiologists it is unclear whether equipoise exists regarding the benefit of diagnosing and managing obstructive sleep apnea (OSA) to improve atrial fibrillation (AF) outcomes and whether clinical practice and equipoise are linked. Methods: Between January 2019 and June 2020 we distributed a web-based 12-question survey regarding OSA and AF management to practicing cardiologists in 16 countries. Results: The United States, Japan, Sweden, and Turkey accounted for two-thirds of responses. 863 cardiologists responded; half were general cardiologists, a quarter electrophysiologists. Responses regarding treating OSA with CPAP to improve AF endpoints were mixed. 33% of respondents referred AF patients for OSA screening. OSA was diagnosed in 48% of referred patients and continuous positive airway pressure (CPAP) was prescribed for 59% of them. Nearly 70% of respondents believed randomized controlled trials (RCTs) of OSA treatment in AF patients were necessary and indicated willingness to contribute to such trials. Conclusions: There was no clinical equipoise among surveyed cardiologists; a majority expressed certainty that combined OSA and AF treatment is superior to AF treatment alone for improving AF outcomes. However, a minority of surveyed cardiologists referred AF patients for OSA testing, and while half of screened AF patients had OSA, CPAP was prescribed in little more than half of them, reflecting the view that better clinical trial evidence is needed to support this practice. Our results underscore the need for larger, multi-national prospective studies of OSA treatment and AF outcomes to inform more uniform society guideline recommendations.
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| 46. |
- Halasz, R, et al.
(författare)
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Relation between GB virus C/hepatitis G virus and fulminant hepatic failure may be secondary to treatment with contaminated blood and/or blood products
- 1999
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 44:2, s. 274-278
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Tidskriftsartikel (refereegranskat)abstract
- The role of the recently discovered GB virus C (GBV-C)/hepatitis G virus in fulminant hepatic failure (FHF) has been debated. Although GBV-C RNA has been detected in many cases of FHF, recent data suggest that the relation between GBV-C and FHF may be accidental.AimsTo retrospectively investigate the possible relation between the presence of GBV-C markers (RNA or antibodies to the GBV-C envelope 2 (E2) glycoprotein) and FHF.MethodsThe presence of GBV-C RNA was determined in serum samples from 58 patients diagnosed with FHF using a reverse transcriptase polymerase chain reaction. Amplified genetic fragments were directly sequenced by the dideoxy chain termination method. Antibodies to GBV-C in serum samples were detected by enzyme immunoassay based on a recombinant GBV-C E2 protein.ResultsNine (16%) patients with FHF had GBV-C RNA and 14 (24%) had GBV-C E2 antibodies, which are higher frequencies than in healthy subjects (p<0.01 and p<0.05 respectively). Seven of ten patients with GBV-C markers during FHF tested negative for these markers before therapy with blood and/or blood products. Sequence analysis of the GBV-C NS3 region fragments of six FHF patients showed no common sequence pattern or motif.ConclusionsThe frequencies of both GBV-C RNA and antibodies are higher in patients with FHF than in healthy subjects. However, these increased frequencies may in many cases be explained by the use of contaminated blood and/or blood products given as therapy.
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| 47. |
- Puschmann, Andreas, et al.
(författare)
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Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 140:1, s. 98-117
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Tidskriftsartikel (refereegranskat)abstract
- SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.
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| 48. |
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| 49. |
- Wimmer, K., et al.
(författare)
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Isomeric states in neutron-rich nuclei near N=40
- 2021
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Ingår i: Physical Review C. - : American Physical Society (APS). - 2469-9985 .- 2469-9993. ; 104:1
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Tidskriftsartikel (refereegranskat)abstract
- Neutron-rich nuclei in the vicinity of the N = 40 island of inversion are characterized by shell evolution and exhibit deformed ground states. In several nuclei isomeric states have been observed and attributed to excitations to the intruder neutron 1g(9/2) orbital. In the present paper we searched for isomeric states in nuclei around N = 40, Z = 22 produced by projectile fragmentation at the Radioactive Isotope Beam Factory. Delayed. rays were detected by the Euroball RIKEN Cluster Array germanium detector array gamma High statistics data allowed for an updated decay scheme of V-60. The lifetime of an isomeric state in V-64 was measured for the first time in the present experiment. A previously unobserved isomeric state was discovered in Sc-58. The measured lifetime suggests a parity changing transition, originating from an odd number of neutrons in the 1g(9/2) orbital. The nature of the isomeric state in Sc-58 is, thus, different from isomers in the less exotic V and Sc nuclei.
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| 50. |
- Adams, David, et al.
(författare)
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Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy
- 2021
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Ingår i: Journal of Neurology. - : Springer Berlin/Heidelberg. - 0340-5354 .- 1432-1459. ; 268:6, s. 2109-2122
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Forskningsöversikt (refereegranskat)abstract
- Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in theTTRgene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.
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