| 1. |
- Dehasque, Marianne, et al.
(author)
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Temporal dynamics of woolly mammoth genome erosion prior to extinction
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Other publication (other academic/artistic)abstract
- A large number of species have recently recovered from near-extinction events. Understanding the genetic consequences of severe population declines followed by demographic recoveries is key to predict the long-term viability of species in order to mitigate future extinction risks. Although these species have avoided the immediate extinction threat, their long-term viability remains questionable due to the genetic consequences of population declines, which are not understood on a time scale beyond a few generations. The woolly mammoth (Mammuthus primigenius) population on Wrangel Island is an excellent model system to investigate long-term genetic consequences of a population bottleneck. Mammoths became isolated on the island in the early Holocene due to rising sea levels, and persisted for over 200 generations (~6,000 years) before becoming extinct ~4,000 years ago. To study the evolutionary processes leading up to the extinction of the woolly mammoth on the island, we analysed 21 Siberian woolly mammoth genomes, including that of one of the last known mammoths. Our results show that the Wrangel Island mammoths recovered quickly from an initially severe bottleneck, and subsequently remained demographically stable during the ensuing 6 millennia. Further, we find that highly deleterious mutations were gradually purged from the population, whereas there was an accumulation of mildly deleterious mutations. The gradual purging of highly deleterious mutations suggests an ongoing inbreeding depression that lasted for hundreds of generations. This time-lag between demographic and genetic recovery has wide-ranging implications for conservation management of recently bottlenecked present-day populations.
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| 2. |
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| 3. |
- Díez-del-Molino, David, 1984-, et al.
(author)
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Genomics of adaptive evolution in the woolly mammoth
- 2023
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In: Current Biology. - 0960-9822 .- 1879-0445. ; 33:9, s. 1753-1764
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Journal article (peer-reviewed)abstract
- Ancient genomes provide a tool to investigate the genetic basis of adaptations in extinct organisms. However, the identification of species-specific fixed genetic variants requires the analysis of genomes from multiple individuals. Moreover, the long-term scale of adaptive evolution coupled with the short-term nature of tradi-tional time series data has made it difficult to assess when different adaptations evolved. Here, we analyze 23 woolly mammoth genomes, including one of the oldest known specimens at 700,000 years old, to identify fixed derived non-synonymous mutations unique to the species and to obtain estimates of when these mutations evolved. We find that at the time of its origin, the woolly mammoth had already acquired a broad spectrum of positively selected genes, including ones associated with hair and skin development, fat storage and metabolism, and immune system function. Our results also suggest that these phenotypes continued to evolve during the last 700,000 years, but through positive selection on different sets of genes. Finally, we also identify additional genes that underwent comparatively recent positive selection, including multiple genes related to skeletal morphology and body size, as well as one gene that may have contributed to the small ear size in Late Quaternary woolly mammoths.
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| 4. |
- Ohman, E. Magnus, et al.
(author)
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Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1) : a double-blind, multicentre, randomised trial
- 2017
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10081, s. 1799-1808
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Journal article (peer-reviewed)abstract
- Background Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2.5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months.Methods In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1: 1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2.5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395.Findings Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1.09 [95% CI 0.80-1.50]; p=0.5840).Interpretation A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.
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| 5. |
- Povsic, Thomas J., et al.
(author)
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A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome : The design of the GEMINI-ACS-1 phase II study
- 2016
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 174, s. 120-128
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Journal article (peer-reviewed)abstract
- Dual antiplatelet therapy (DAPT), the combination of aspirin and a P2Y12 inhibitor, given for 12 months remains the standard of care after presentation with acute coronary syndrome (ACS) because it has been shown to be associated with a significant reduction in ischemic events compared with aspirin monotherapy. The factor Xa inhibitor rivaroxaban was shown to be associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, and stroke, and resulted in a nominal reduction in cardiovascular death, when added to background DAPT in the ATLAS ACS 2-TIMI 51 trial; however, there was excessive bleeding with this "triple-therapy" approach. The combination of rivaroxaban with P2Y12 inhibition in a "dual-pathway" approach may be an effective therapeutic regimen for the treatment of ACS, given the known importance of P2Y12 inhibition after stenting and intriguing data that the combination of an anticoagulant with clopidogrel after stenting in patients with atrial fibrillation appears an attractive option to this patient population. GEMINI-ACS-1 is a prospective, randomized, double-dummy, double-blind, active-controlled trial that will assess the safety of dual antithrombotic therapy (rivaroxaban [2.5 mg twice daily] + P2Y12 inhibitor) as compared with DAPT (aspirin [100 mg] + P2Y12 inhibitor) within 10 days of an ACS event in 3,000 patients. Patients will be randomized in a 1: 1 ratio stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily), with 1500 patients expected in each P2Y12 inhibitor strata. The primary end point is Thrombolysis in Myocardial Infarction clinically significant bleeding (major, minor, or requiring medical attention). The exploratory efficacy determination will be a composite of cardiovascular death, myocardial infarction, ischemic stroke, and stent thrombosis. GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with rivaroxaban and a P2Y12 inhibitor compared with conventional DAPT for the treatment for patients with recent ACS.
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| 6. |
- Povsic, Thomas J., et al.
(author)
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P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes
- 2019
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In: JAMA cardiology. - : AMER MEDICAL ASSOC. - 2380-6583 .- 2380-6591. ; 4:7, s. 680-684
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Journal article (peer-reviewed)abstract
- Importance Physician behavior in response to knowledge of a patient’s CYP2C19 clopidogrel metabolizer status is unknown.Objective To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.Design, Setting, and Participants The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.Interventions Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.Main Outcomes and Measures Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.Results Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.Conclusions and Relevance Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.
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