| 1. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 12. |
- 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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| 21. |
- Davies, G., et al.
(författare)
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Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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| 22. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 25. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 26. |
- Klimkowska, Agata, et al.
(författare)
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Are we restoring functional fens? : The outcomes of restoration projects in fens re-analysed with plant functional traits
- 2019
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- In peatland restoration we often lack an information whether re-established ecosystems are functionally similar to non-degraded ones. We re-analysed the long-term outcomes of restoration on vegetation and plant functional traits in 38 European fens restored by rewetting (18 sites) and topsoil removal (20 sites). We used traits related to nutrient acquisition strategies, competitiveness, seed traits, and used single- and multi-trait metrics. A separate set of vegetation records from near-natural fens with diverse plant communities was used to generate reference values to aid the comparisons. We found that both restoration methods enhanced the similarity of species composition to non-degraded systems but trait analysis revealed differences between the two approaches. Traits linked to nutrient acquisition strategies indicated that topsoil removal was more effective than rewetting. After topsoil removal competitive species in plant communities had decreased, while stress-tolerant species had increased. A substantial reduction in nutrient availability ruled out the effect of initial disturbance. An ability to survive and grow in anoxic conditions was enhanced after restoration, but the reference values were not achieved. Rewetting was more effective than topsoil removal in restricting variation in traits values permitted in re-developing vegetation. We found no indication of a shift towards reference in seed traits, which suggested that dispersal constraint and colonization deficit can be a widespread phenomena. Two functional diversity indices: functional richness and functional dispersion showed response to restoration and shifted values towards reference mires and away from the degraded systems. We concluded that targeting only one type of environmental stressor does not lead to a recovery of fens, as it provides insufficient level of stress to restore a functional ecosystem. In general, restoration efforts do not ensure the re-establishment and long-term persistence of fens. Restoration efforts result in recovery of fen ecosystems, confirmed with our functional trait analysis, although more rigid actions are needed for restoring fully functional mires, by achieving high and constant levels of anoxia and nutrient stresses.
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| 27. |
- Pearce, Neil E, et al.
(författare)
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IARC Monographs : 40 Years of Evaluating Carcinogenic Hazards to Humans
- 2015
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 507-514
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.OBJECTIVES: The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed.DISCUSSION: We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
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| 28. |
- Savage, J. E., et al.
(författare)
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Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:7, s. 912-919
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Tidskriftsartikel (refereegranskat)abstract
- Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
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| 29. |
- Tielbeek, J. J., et al.
(författare)
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Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior
- 2017
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Ingår i: Jama Psychiatry. - : American Medical Association (AMA). - 2168-622X .- 2168-6238. ; 74:12, s. 1242-1250
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. OBJECTIVES To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). MAIN OUTCOME AND MEASURES This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. RESULTS The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R-2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P =.005) was detected. CONCLUSIONS AND RELEVANCE The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
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| 30. |
- Winkler, M., et al.
(författare)
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The rich sides of mountain summits - a pan-European view on aspect preferences of alpine plants
- 2016
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Ingår i: Journal of Biogeography. - : Wiley. - 0305-0270. ; 43:11, s. 2261-2273
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Tidskriftsartikel (refereegranskat)abstract
- Aim In the alpine life zone, plant diversity is strongly determined by local topography and microclimate. We assessed the extent to which aspect and its relatedness to temperature affect plant species diversity, and the colonization and disappearance of species on alpine summits on a pan-European scale. Methods Vascular plant species and their percentage cover were recorded in permanent plots in each cardinal direction on 123 summits in 32 regions across Europe. For a subset from 17 regions, resurvey data and 6-year soil temperature series were available. Differences in temperature sum and Shannon index as well as species richness, colonization and disappearance of species among cardinal directions were analysed using linear mixed-effects and generalised mixed-effects models, respectively. Results Temperature sums were higher in east-and south-facing aspects than in the north-facing ones, while the west-facing ones were intermediate; differences were smallest in northern Europe. The patterns of temperature sums among aspects were consistent among years. In temperate regions, thermal differences were reflected by plant diversity, whereas this relationship was weaker or absent on Mediterranean and boreal mountains. Colonization of species was positively related to temperature on Mediterranean and temperate mountains, whereas disappearance of species was not related to temperature. Main conclusions Thermal differences caused by solar radiation determine plant species diversity on temperate mountains. Advantages for plants on eastern slopes may result from the combined effects of a longer diurnal period of radiation due to convection cloud effects in the afternoon and the sheltered position against the prevailing westerly winds. In northern Europe, long summer days and low sun angles can even out differences among aspects. On Mediterranean summits, summer drought may limit species numbers on the warmer slopes. Warmer aspects support a higher number of colonization events. Hence, aspect can be a principal determinant of the pace of climate-induced migration processes.
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| 31. |
- Baker, Jillian M., et al.
(författare)
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Postnatal intervention for the treatment of FNAIT : a systematic review
- 2019
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Ingår i: Journal of Perinatology. - : Springer Science and Business Media LLC. - 0743-8346 .- 1476-5543. ; 39:10, s. 1329-1339
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Forskningsöversikt (refereegranskat)abstract
- Objective: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is associated with life-threatening bleeding. This systematic review of postnatal management of FNAIT examined transfusion of human platelet antigen (HPA) selected or unselected platelets, and/or IVIg on platelet increments, hemorrhage and mortality. Study design: MEDLINE, EMBASE and Cochrane searches were conducted until 11 May 2018. Result: Of 754 neonates, 382 received platelet transfusions (51%). HPA-selected platelets resulted in higher platelet increments and longer response times than HPA-unselected platelets. However, unselected platelets generally led to sufficient platelet increments to 30 × 10 9 /L, a level above which intracranial hemorrhage or other life-threatening bleeding rarely occurred. Platelet increments were not improved with the addition of IVIg to platelet transfusion. Conclusion: Overall, HPA-selected platelet transfusions were more effective than HPA-unselected platelets but unselected platelets were often effective enough to achieve clinical goals. Available studies do not clearly demonstrate a benefit for addition of IVIg to platelet transfusion.
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| 32. |
- Barker, D., et al.
(författare)
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Individually addressable double quantum dots formed with nanowire polytypes and identified by epitaxial markers
- 2019
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 114:18
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Tidskriftsartikel (refereegranskat)abstract
- Double quantum dots (DQDs) hold great promise as building blocks for quantum technology as they allow for two electronic states to coherently couple. Defining QDs with materials rather than using electrostatic gating allows for QDs with a hard-wall confinement potential and more robust charge and spin states. An unresolved problem is how to individually address these QDs, which is necessary for controlling quantum states. We here report the fabrication of DQD devices defined by the conduction band edge offset at the interface of the wurtzite and zinc blende crystal phases of InAs in nanowires. By using sacrificial epitaxial GaSb markers selectively forming on one crystal phase, we are able to precisely align gate electrodes allowing us to probe and control each QD independently. We hence observe textbooklike charge stability diagrams, a discrete energy spectrum, and electron numbers consistent with theoretical estimates and investigate the tunability of the devices, finding that changing the electron number can be used to tune the tunnel barrier as expected by simple band diagram arguments.
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| 33. |
- Bernal, Ximena E., et al.
(författare)
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Empowering Latina scientists
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 363:6429, s. 825-826
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 36. |
- Cirulli, Elizabeth T., et al.
(författare)
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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
- 2019
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Ingår i: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 156:6, s. 1707-1716
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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| 39. |
- Halim, Danny, et al.
(författare)
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ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:3, s. 571-583
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Tidskriftsartikel (refereegranskat)abstract
- Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.
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| 40. |
- Hentze, Julie L., et al.
(författare)
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The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs.
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| 41. |
- Jolles, S., et al.
(författare)
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Screening protocols to monitor respiratory status in primary immunodeficiency disease : findings from a European survey and subclinical infection working group
- 2017
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 190:2, s. 226-234
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Tidskriftsartikel (refereegranskat)abstract
- Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1–12 months for adult patients and every 3–6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.
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| 42. |
- Kjær, Mette, et al.
(författare)
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Maternal HPA-1a antibody level and its role in predicting the severity of Fetal/Neonatal Alloimmune Thrombocytopenia : a systematic review
- 2019
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Ingår i: Vox Sanguinis. - : Wiley. - 0042-9007. ; 114:1, s. 79-94
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most commonly due to maternal HPA-1a antibodies. HPA-1a typing followed by screening for anti-HPA-1a antibodies in HPA-1bb women may identify first pregnancies at risk. Our goal was to review results from previous published studies to examine whether the maternal antibody level to HPA-1a could be used to identify high-risk pregnancies. Materials and Methods: The studies included were categorized by recruitment strategies: screening of unselected pregnancies or samples analyzed from known or suspected FNAIT patients. Results: Three prospective studies reported results from screening programmes, and 10 retrospective studies focused on suspected cases of FNAIT. In 8 studies samples for antibody measurement, performed by the monoclonal antibody immobilization of platelet antigen (MAIPA) assay, and samples for determining fetal/neonatal platelet count were collected simultaneously. In these 8 studies, the maternal antibody level correlated with the risk of severe thrombocytopenia. The prospective studies reported high negative predictive values (88–95%), which would allow for the use of maternal anti-HPA-1a antibody level as a predictive tool in a screening setting, in order to identify cases at low risk for FNAIT. However, due to low positive predictive values reported in prospective as well as retrospective studies (54–97%), the maternal antibody level is less suited for the final diagnosis and for guiding antenatal treatment. Conclusion: HPA-1a antibody level has the potential to predict the severity of FNAIT.
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| 46. |
- Moreau, Philippe, et al.
(författare)
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Oral Ixazomib, lenalidomide, and dexamethasone for multiple myeloma
- 2016
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:17, s. 1621-1634
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P = 0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited.
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| 47. |
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| 48. |
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| 49. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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