| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- 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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| 8. |
- Culvenor, Adam G., et al.
(författare)
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Loss of patellofemoral cartilage thickness over 5 years following ACL injury depends on the initial treatment strategy : Results from the KANON trial
- 2019
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Ingår i: British journal of sports medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 53:18, s. 1168-1173
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate changes in patellofemoral cartilage thickness over 5 years after anterior cruciate ligament (ACL) injury and to determine the impact of treatment strategy. Methods: 121 adults (ages 18-35 years, 26% women) had an ACL injury and participated in the KANON randomised controlled trial. Of those, 117 had available MRIs at baseline (<4 weeks post-ACL rupture) and at least one follow-up measurement (2, 5 years). Patellofemoral cartilage thickness was analysed by manual segmentation (blinded to acquisition order). Patellar, trochlear and total patellofemoral cartilage thickness changes were compared between as-randomised (rehabilitation+early ACL reconstruction (ACLR) (n=59) vs rehabilitation+optional delayed ACLR (n=58)) and as-treated groups (rehabilitation+early ACLR (n=59) vs rehabilitation +delayed ACLR (n=29) vs rehabilitation alone (n=29)). Results: Patellofemoral cartilage thickness decreased-58 μm (95% CI-104 to-11 μm) over 5 years post-ACL rupture, with the greatest loss observed in trochlea during the first 2 years. Participants randomised to rehabilitation+early ACLR had significantly greater loss of patellar cartilage thickness compared with participants randomised to rehabilitation+optional delayed ACLR over the first 2 years (-25 μm (-52, 1 μm) vs +14 μm (-6 to 34 μm), p=0.02) as well as over 5 years (-36 μm (-78 to 5 μm) vs +18 μm (-7, 42 μm), p=0.02). There were no statistically significant differences in patellofemoral cartilage thickness changes between as-treated groups. Conclusion: Patellofemoral (particularly trochlear) cartilage thickness loss was observed in young adults following acute ACL rupture. Early ACLR was associated with greater patellofemoral (particularly patellar) cartilage thickness loss over 5 years compared with optional delayed ACLR, indicating that early surgical intervention may be associated with greater short-term structural patellofemoral cartilage deterioration compared with optional delayed surgery. Trial registration number: ISRCTN84752559; Post-results.
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| 9. |
- Grady, Christine, et al.
(författare)
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Broad Consent for Research With Biological Samples : Workshop Conclusions
- 2015
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Ingår i: American Journal of Bioethics. - : Informa UK Limited. - 1526-5161 .- 1536-0075. ; 15:9, s. 34-42
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Tidskriftsartikel (refereegranskat)abstract
- Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Center's Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.
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| 10. |
- Hart, Robert G., et al.
(författare)
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Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source : Design of the NAVIGATE ESUS randomized trial
- 2016
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Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 1:3, s. 146-154
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Tidskriftsartikel (refereegranskat)abstract
- Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.
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