| 1. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 2. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 3. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 4. |
- Bath, Jonathan, et al.
(författare)
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Contemporary outcomes after treatment of aberrant subclavian artery and Kommerell's diverticulum
- 2023
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Ingår i: Journal of Vascular Surgery. - : Elsevier BV. - 0741-5214 .- 1097-6809. ; 77:5, s. 1339-1348.e6
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset.Methods: Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak.Results: Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P < .0001), female (64% vs 36%; P < .0001), and symptomatic (85% vs 59%; P < .0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P = .13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P = .02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio [OR], 19.8; 95% confidence interval [CI], 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms.Conclusions: Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate.
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| 5. |
- Moffatt, Clare, et al.
(författare)
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International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell's Diverticulum
- 2023
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Ingår i: Annals of Vascular Surgery. - : Elsevier. - 0890-5096 .- 1615-5947. ; 95, s. 23-31
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch.METHODS: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions.RESULTS: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change.CONCLUSIONS: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality.
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| 6. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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