Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Acute Coronary Syndrome of Embolic Origin in a Patient on Direct Thrombin Inhibitor Three Years After Mechanical Mitral Valve Replacement

Dabigatran was shown to be inferior to warfarin for patients with mechanical heart valves. However it was postulated that its inferiority was limited to early post-operative period where the valves had not been adequately endothelialized. We present a case where thromboembolic acute coronary syndrome developed in a patient six months after switching from warfarin to dabigatran, despite three years after mechanical mitral valve replacement. We propose an alternative explanation for dabigatran failure

Clinical Outcomes of Left Atrial Appendage Occlusion Versus Switch of Direct Oral Antcoagulant in Atrial Fibrillation: A Territory‐Wide Retrospective Analysis

Background Left atrial appendage occlusion (LAAO) has emerged as an alternative to oral anticoagulation therapy for stroke prevention in atrial fibrillation, but data comparing LAAO with direct oral anticoagulant (DOAC) are sparse. Methods and Results This cohort study compared LAAO (with or without prior anticoagulation) with a switch of one DOAC to another DOAC by 1:2 propensity score matching. The primary outcome was a composite of all‐cause mortality, ischemic stroke, and major bleeding. A total of 2350 patients (874 in the LAAO group and 1476 in the DOAC switch group) were included. After a mean follow‐up of 1052±694 days, the primary outcome developed in 215 (24.6%) patients in the LAAO group and in 335 (22.7%) patients in the DOAC switch group (hazard ratio [HR], 0.94 [95% CI, 0.80–1.12]; P=0.516). The LAAO group had a lower all‐cause mortality (HR, 0.49 [95% CI, 0.39–0.60]; P<0.001) and cardiovascular mortality (HR, 0.49 [95% CI, 0.32–0.73]; P<0.001) but similar risk of ischemic stroke (HR, 0.83 [95% CI, 0.63–1.10]; P=0.194). The major bleeding risk was similar overall (HR, 1.18 [95% CI, 0.94–1.48], P=0.150) but was lower in the LAAO group after 6 months (HR, 0.71 [95% CI, 0.51–0.97]; P=0.032). Conclusions LAAO conferred a similar risk of composite outcome of all‐cause mortality, ischemic stroke, and major bleeding, as compared with DOAC switch. The risks of all‐cause mortality and cardiovascular mortality were lower with LAAO

Sensitivity of ventricular systolic function to afterload during veno‐arterial extracorporeal membrane oxygenation

Abstract Aims Veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) increases afterload to the injured heart and may hinder myocardial recovery. We aimed to compare the sensitivity of left ventricular (LV) systolic function to the afterload effects of peripheral V‐A ECMO during the acute and delayed stages of acute myocardial dysfunction. Methods and results A total of 46 adult patients who were supported by peripheral V‐A ECMO between April 2019 and June 2021 were analysed. Serial cardiac performance parameters were measured by transthoracic echocardiography (TTE) on mean day 1 ± 1 of V‐A ECMO initiation (n = 45, ‘acute phase’) and mean day 4 ± 2 of V‐A ECMO initiation (n = 36, ‘delayed phase’). Measurements were obtained at 100%, 120%, and 50% of ECMO target blood flow (TBF). LV global longitudinal strain (GLS) significantly improved from −6.1 (−8.9 to −4.0)% during 120% TBF to −8.8 (−11.5 to −6.0)% during 50% TBF (P < 0.001). The sensitivity of LV GLS to changes in ECMO flow was significantly greater in the acute phase of myocardial injury compared with the delayed phase [median (IQR) percentage change: 72.7 (26.8–100.0)% vs. 22.5 (14.9–43.8)%, P < 0.001]. Findings from other echocardiographic parameters including LV ejection fraction [43.0 (29.1–56.8)% vs. 22.8 (9.2–42.2)%, P = 0.012] and LV outflow tract velocity‐time integral [45.8 (18.6–58.7)% vs. 24.2 (12.6–34.0)%, P = 0.001] were similar. A total of 24 (52.2%) patients were weaned off ECMO successfully. Conclusions We demonstrated that LV systolic function was significantly more sensitive to the afterload effects of V‐A ECMO during the acute stage of myocardial dysfunction compared with the delayed phase. Understanding the evolution of the heart–ECMO interaction over the course of acute myocardial dysfunction informs the clinical utility of echocardiographic assessment in patients on V‐A ECMO