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- Ibanez, L., et al.
(författare)
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Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406
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Tidskriftsartikel (refereegranskat)abstract
- During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
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- Le Pavec, J. M., et al.
(författare)
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Lung transplantation for sarcoidosis: outcome and prognostic factors
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 58:2
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Tidskriftsartikel (refereegranskat)abstract
- Study question In patients with sarcoidosis, past and ongoing immunosuppressive regimens, recurrent disease in the transplant and extrapulmonary involvement may affect outcomes of lung transplantation. We asked whether sarcoidosis lung phenotypes can be differentiated and, if so, how they relate to outcomes in patients with pulmonary sarcoidosis treated by lung transplantation. Patients and methods We retrospectively reviewed data from 112 patients who met international diagnostic criteria for sarcoidosis and underwent lung or heart-lung transplantation between 2006 and 2019 at 16 European centres. Results Patient survival was the main outcome measure. At transplantation, median (interaquartile range (IQR)) age was 52 (46-59) years; 71 (64%) were male. Lung phenotypes were individualised as follows: 1) extended fibrosis only; 2) airflow obstruction; 3) severe pulmonary hypertension (sPH) and airflow obstruction; 4) sPH, airflow obstruction and fibrosis; 5) sPH and fibrosis; 6) airflow obstruction and fibrosis; 7) sPH; and 8) none of these criteria, in 17%, 16%, 17%, 14%, 11%, 9%, 5% and 11% of patients, respectively. Post-transplant survival rates after 1, 3, and 5 years were 86%, 76% and 69%, respectively. During follow-up (median (IQR) 46 (16-89) months), 31% of patients developed chronic lung allograft dysfunction. Age and extended lung fibrosis were associated with increased mortality. Pulmonary fibrosis predominating peripherally was associated with short-term complications. Answer to the study question Post-transplant survival in patients with pulmonary sarcoidosis was similar to that in patients with other indications for lung transplantation. The main factors associated with worse survival were older age and extensive pre-operative lung fibrosis.
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| 6. |
- Ntani, G., et al.
(författare)
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Patterns of change of multisite pain over 1 year of follow-up and related risk factors
- 2022
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Ingår i: European Journal of Pain. - : Wiley. - 1090-3801 .- 1532-2149. ; 26:7, s. 1499-1509
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Tidskriftsartikel (refereegranskat)abstract
- Background Multisite musculoskeletal pain is common and disabling. This study aimed to prospectively investigate the distribution of musculoskeletal pain anatomically, and explore risk factors for increases/reductions in the number of painful sites. Methods Using data from participants working in 45 occupational groups in 18 countries, we explored changes in reporting pain at 10 anatomical sites on two occasions 14 months apart. We used descriptive statistics to explore consistency over time in the number of painful sites, and their anatomical distribution. Baseline risk factors for increases/reductions by >= 3 painful sites were explored by random intercept logistic regression that adjusted for baseline number of painful sites. Results Among 8927 workers, only 20% reported no pain at either time point, and 16% reported >= 3 painful sites both times. After 14 months, the anatomical distribution of pain often changed but there was only an average increase of 0.17 painful sites. Some 14% workers reported a change in painful sites by >= 3. Risk factors for an increase of >= 3 painful sites included female sex, lower educational attainment, having a physically demanding job and adverse beliefs about the work-relatedness of musculoskeletal pain. Also predictives were as follows: older age, somatizing tendency and poorer mental health (each of which was also associated with lower odds of reductions of >= 3 painful sites). Conclusions Longitudinally, the number of reported painful sites was relatively stable but the anatomical distribution varied considerably. These findings suggest an important role for central pain sensitization mechanisms, rather than localized risk factors, among working adults. Significance Our findings indicate that within individuals, the number of painful sites is fairly constant over time, but the anatomical distribution varies, supporting the theory that among people at work, musculoskeletal pain is driven more by factors that predispose to experiencing or reporting pain rather than by localized stressors specific to only one or two anatomical sites.
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- Pavec, J. L., et al.
(författare)
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Characteristics, Survival, and Outcomes of Lung and Heart-Lung Transplantation for Pulmonary Sarcoidosis in a Multicenter European Study Characteristics, Survival, and Outcomes of Lung and Heart-Lung Transplantation for Pulmonary Sarcoidosis in a Multicenter European Study
- 2020
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Ingår i: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. - : Elsevier BV. - 1557-3117. ; 39:4
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In the context of sarcoidosis, lung transplantation is often performed in patients with irreversible advanced lung disease unresponsive to medical therapy. The clinical phenotypes and posttransplant survival remain unclear, due primarily to the recurring nature of the disease and extrapulmonary involvement. The objective of this study in a large multicenter European cohort was to describe the clinical characteristics and outcomes of patients with pulmonary sarcoidosis treated by lung transplantation. METHODS: We retrospectively reviewed the data of 147 patients with pulmonary sarcoidosis who underwent lung or heart-lung transplantation between 1990 and 2019 at 15 European centers. Inclusion criteria were sarcoidosis meeting international diagnostic criteria and availability of data from pretransplantation right heart catheterization, lung function testing, and chest computed tomography (CT) staged using a standardized system. RESULTS: At transplantation, mean age was 50±8 years, 62% were male, and 20% had extrapulmonary manifestations. Mean values before transplantation were as follows: FVC (%pred), 46±17%; FEV1 (%pred), 38±19; FVC/FEV1 (%), 55±32; DLCO (%pred), 31±13; mPAP (mmHg), 36±13; PCWP (mmHg), 10±5; cardiac index (L/min/m²), 3.0±0.8; and pulmonary vascular resistance (dyn·s·cm-5), 480±340; furthermore, 60% of patients had severe pulmonary hypertension. Posttransplant survival rates after 1, 3, and 5 years were 85%, 69%, and 63%, respectively. During the median [range] follow-up of 43 [17-79] months, 38% of patients developed chronic lung allograft dysfunction. Factors significantly associated with outcomes were high emergency transplantation, era of transplantation, preoperative extrapulmonary sarcoidosis, and extent of fibrosis by CT. CONCLUSION: Posttransplant survival rates and freedom from chronic lung allograft dysfunction in patients with pulmonary sarcoidosis were similar to those in patients with other reasons for lung transplantation. Factors associated with worse outcomes were high emergency transplantation, earlier transplantation era, preoperative extrapulmonary sarcoidosis, and greater burden of fibrosis by CT. Copyright © 2020. Published by Elsevier Inc.
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- Sarwar, Nadeem, et al.
(författare)
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Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
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Ingår i: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
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Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
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| 9. |
- Deming, Y., et al.
(författare)
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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
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Tidskriftsartikel (refereegranskat)abstract
- Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
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- Harari, A, et al.
(författare)
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An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses
- 2008
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:1, s. 63-77
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Tidskriftsartikel (refereegranskat)abstract
- The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon γ enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/106 mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of epitopes was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen.
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- Horsch, Antje, et al.
(författare)
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Reducing intrusive traumatic memories after emergency caesarean section : A proof-of-principle randomized controlled study
- 2017
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Ingår i: Behaviour Research and Therapy. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0005-7967 .- 1873-622X. ; 94, s. 36-47
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Tidskriftsartikel (refereegranskat)abstract
- Preventative psychological interventions to aid women after traumatic childbirth are needed. This proof of-principle randomized controlled study evaluated whether the number of intrusive traumatic memories mothers experience after emergency caesarean section (ECS) could be reduced by a brief cognitive intervention. 56 women after ECS were randomized to one of two parallel groups in a 1:1 ratio: intervention (usual care plus cognitive task procedure) or control (usual care). The intervention group engaged in a visuospatial task (computer-game 'Tetris' via a handheld gaming device) for 15 min within six hours following their ECS. The primary outcome was the number of intrusive traumatic memories related to the ECS recorded in a diary for the week post-ECS. As predicted, compared with controls, the intervention group reported fewer intrusive traumatic memories (M = 4.77, SD = 10.71 vs. M = 9.22, SD = 10.69, d = 0.647 [95% CI: 0.106,1.182]) over 1 week (intention-to-treat analyses, primary outcome). There was a trend towards reduced acute stress re-experiencing symptoms (d = 0.503 [95% CI: -0.032, 1.033]) after 1 week (intention-to-treat analyses). Times series analysis on daily intrusions data confirmed the predicted difference between groups. 72% of women rated the intervention "rather" to "extremely" acceptable. This represents a first step in the development of an early (and potentially universal) intervention to prevent postnatal posttraumatic stress symptoms that may benefit both mother and child. Clinical trial registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02502513. (C) 2017 The Authors. Published by Elsevier Ltd.
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