Background: Oral anticoagulants are prescribed for stroke prophylaxis in patients with atrial fibrillation, which is the most common heart arrhythmia worldwide. The vitamin K antagonist (VKA) warfarin is a long-established anticoagulant. However, newer direct oral anticoagulants (DOACs) have been recently introduced as an alternative. Given the prevalence of atrial fibrillation, anticoagulant choice has substantial clinical and financial implications for healthcare systems. In this study, we explore trends and geographic variation in anticoagulant prescribing in English primary care. Because national guidelines in England do not specify a first-line anticoagulant, we investigate the association between local policies and prescribing data. Methods: Primary care prescribing data of anticoagulants for all NHS practices from 2014 to 2019 in England was obtained from the ePACT2 database. Public formularies were accessed online to obtain local anticoagulation prescribing policies for 89.5% of clinical commissioning groups (CCGs). These were categorized according to their recommendations: no local policies, warfarin as first-line, or identification of a preferred DOAC (but not a preferred anticoagulant). Local policies were cross-tabulated with pooled prescribing data to measure the strength of association with Cramér's V. Results: Nationally, prescribing of DOACs increased from 9% of all anticoagulants in 2014 to 74% in 2019, while that of warfarin declined accordingly. Still, there was significant local variation. Across geographical regions, DOACs ranged from 53 to 99% of all anticoagulants. Most CCGs (73%) did not specify a first-line choice, and 16% recommended warfarin first line. Only 11% designated a preferred DOAC. Policies with a preferred DOAC indeed correlated with increased prescribing of that DOAC (Cramér's V = 0.25, 0.27, 0.38 for rivaroxaban, apixaban, edoxaban respectively). However, local policies showed a negligible relationship with the classes of anticoagulants prescribed-DOAC or VKA (Cramér's V = 0.01). Conclusions: Nationally, the use of DOACs to treat atrial fibrillation has increased rapidly. Despite this, significant geographical variation in uptake remains. This study provides insights on how local policies relate to this variation. Our findings suggest that, in the absence of a nationally recommended first-line anticoagulant, local prescribing policies may aid in deciding between individual DOACs, but not in adjudicating between DOACs and vitamin K antagonists (i.e. warfarin) as general classes.

Non-enzymatic RNA self-replication is integral to the emergence of the ‘RNA World’. Despite considerable progress in non-enzymatic template copying, demonstrating a full replication cycle remains challenging due to the difficulty of separating the strands of the product duplex. Here, we report a prebiotically plausible approach to strand displacement synthesis in which short ‘invader’ oligonucleotides unwind an RNA duplex through a toehold/branch migration mechanism, allowing non-enzymatic primer extension on a template that was previously occupied by its complementary strand. Kinetic studies of single-step reactions suggest that following invader binding, branch migration results in a 2:3 partition of the template between open and closed states. Finally, we demonstrate continued primer extension with strand displacement by employing activated 3′-aminonucleotides, a more reactive proxy for ribonucleotides. Our study suggests that complete cycles of non-enzymatic replication of the primordial genetic material may have been facilitated by short RNA oligonucleotides.

11Non-enzymatic RNA self-replication is integral to the 'RNA World' hypothesis. Despite 12 considerable progress in non-enzymatic template copying, true replication remains challenging 13 due to the difficulty of separating the strands of the product duplex. Here, we report a prebiotically 14 plausible solution to this problem in which short 'invader' oligonucleotides unwind an RNA 15 duplex through a toehold/branch migration mechanism, allowing non-enzymatic primer extension 16 on a template that was previously occupied by its complementary strand. Kinetic studies of single-17 step reactions suggest that following invader binding, branch migration results in a 2:3 partition of 18the template between open and closed states. Finally, we demonstrate continued primer extension 19 with strand displacement by employing activated 3′-aminonucleotides, a more reactive proxy for 20 ribonucleotides. Our study suggests that complete cycles of non-enzymatic replication of the 21 primordial genetic material may have been catalyzed by short RNA oligonucleotides. 22