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- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 5. |
- Van den Brink, P. J., et al.
(författare)
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Toward sustainable environmental quality: Priority research questions for Europe
- 2018
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Ingår i: Environmental Toxicology and Chemistry. - : Wiley. - 0730-7268 .- 1552-8618. ; 37:9, s. 2281-2295
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Tidskriftsartikel (refereegranskat)abstract
- The United Nations' Sustainable Development Goals have been established to end poverty, protect the planet, and ensure prosperity for all. Delivery of the Sustainable Development Goals will require a healthy and productive environment. An understanding of the impacts of chemicals which can negatively impact environmental health is therefore essential to the delivery of the Sustainable Development Goals. However, current research on and regulation of chemicals in the environment tend to take a simplistic view and do not account for the complexity of the real world, which inhibits the way we manage chemicals. There is therefore an urgent need for a step change in the way we study and communicate the impacts and control of chemicals in the natural environment. To do this requires the major research questions to be identified so that resources are focused on questions that really matter. We present the findings of a horizon-scanning exercise to identify research priorities of the European environmental science community around chemicals in the environment. Using the key questions approach, we identified 22 questions of priority. These questions covered overarching questions about which chemicals we should be most concerned about and where, impacts of global megatrends, protection goals, and sustainability of chemicals; the development and parameterization of assessment and management frameworks; and mechanisms to maximize the impact of the research. The research questions identified provide a first-step in the path forward for the research, regulatory, and business communities to better assess and manage chemicals in the natural environment. Environ Toxicol Chem 2018;37:2281-2295. (c) 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
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| 7. |
- Ringleb, PA, et al.
(författare)
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Guidelines for management of ischaemic stroke and transient ischaemic attack 2008
- 2008
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Ingår i: Cerebrovascular diseases (Basel, Switzerland). - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 25:5, s. 457-507
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Tidskriftsartikel (refereegranskat)abstract
- This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.
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| 8. |
- Veltkamp, R., et al.
(författare)
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Characteristics of Recurrent Ischemic Stroke after Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:10, s. 1233-1240
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Tidskriftsartikel (refereegranskat)abstract
- Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS. Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke. Design, Setting, and Participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019. Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d. Main Outcomes and Measures: Association of recurrent ESUS with stroke characteristics. Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively). Conclusions and Relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.. © 2020 American Medical Association. All rights reserved.
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| 9. |
- Gnanapragasam, V. J., et al.
(författare)
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Using prognosis to guide inclusion criteria, define standardised endpoints and stratify follow-up in active surveillance for prostate cancer
- 2019
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Ingår i: Bju International. - : Wiley. - 1464-4096 .- 1464-410X. ; 124:5, s. 758-767
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To test whether using disease prognosis can inform a rational approach to active surveillance (AS) for early prostate cancer. Patients and methods: We previously developed the Cambridge Prognostics Groups (CPG) classification, a five-tiered model that uses prostate-specific antigen (PSA), Grade Group and Stage to predict cancer survival outcomes. We applied the CPG model to a UK and a Swedish prostate cancer cohort to test differences in prostate cancer mortality (PCM) in men managed conservatively or by upfront treatment in CPG2 and 3 (which subdivides the intermediate-risk classification) vs CPG1 (low-risk). We then applied the CPG model to a contemporary UK AS cohort, which was optimally characterised at baseline for disease burden, to identify predictors of true prognostic progression. Results were re-tested in an external AS cohort from Spain. Results: In a UK cohort (n = 3659) the 10-year PCM was 2.3% in CPG1, 1.5%/3.5% in treated/untreated CPG2, and 1.9%/8.6% in treated/untreated CPG3. In the Swedish cohort (n = 27 942) the10-year PCM was 1.0% in CPG1, 2.2%/2.7% in treated/untreated CPG2, and 6.1%/12.5% in treated/untreated CPG3. We then tested using progression to CPG3 as a hard endpoint in a modern AS cohort (n = 133). During follow-up (median 3.5 years) only 6% (eight of 133) progressed to CPG3. Predictors of progression were a PSA density ≥0.15 ng/mL/mL and CPG2 at diagnosis. Progression occurred in 1%, 8% and 21% of men with neither factor, only one, or both, respectively. In an independent Spanish AS cohort (n = 143) the corresponding rates were 3%, 10% and 14%, respectively. Conclusion: Using disease prognosis allows a rational approach to inclusion criteria, discontinuation triggers and risk-stratified management in AS. © 2019 The Authors. BJU International © 2019 BJU International Published by John Wiley & Sons Ltd
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| 10. |
- Hart, R. G., et al.
(författare)
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Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source
- 2018
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 378:23, s. 2191-2201
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding.
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