Maximum likelihood estimates of pairwise rearrangement distances

Accurate estimation of evolutionary distances between taxa is important for many phylogenetic reconstruction methods. In the case of bacteria, distances can be estimated using a range of different evolutionary models, from single nucleotide polymorphisms to large-scale genome rearrangements. In the case of sequence evolution models (such as the Jukes-Cantor model and associated metric) have been used to correct pairwise distances. Similar correction methods for genome rearrangement processes are required to improve inference. Current attempts at correction fall into 3 categories: Empirical computational studies, Bayesian/MCMC approaches, and combinatorial approaches. Here we introduce a maximum likelihood estimator for the inversion distance between a pair of genomes, using the group-theoretic approach to modelling inversions introduced recently. This MLE functions as a corrected distance: in particular, we show that because of the way sequences of inversions interact with each other, it is quite possible for minimal distance and MLE distance to differently order the distances of two genomes from a third. This has obvious implications for the use of minimal distance in phylogeny reconstruction. The work also tackles the above problem allowing free rotation of the genome. Generally a frame of reference is locked, and all computation made accordingly. This work incorporates the action of the dihedral group so that distance estimates are free from any a priori frame of reference.Comment: 21 pages, 7 figures. To appear in the Journal of Theoretical Biolog

Coronary covered stents

Covered stents offer an effective bail-out strategy in vessel perforations, are an alternative to surgery for the exclusion of coronary aneurysms, and have a potential role in the treatment of friable embolisation-prone plaques. The aim of this manuscript is to offer an overview of currently available platforms and to report results obtained in prior studies

Near-infrared spectroscopy-intravascular ultrasound: Scientific basis and clinical applications

Coronary angiography underestimates the magnitude of the atherosclerotic burden and cannot detect the presence of disease in the early phases. Recognition of these inherent limitations of angiography has been an impetus for the development of other coronary imaging techniques. The novel near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) catheters can detect and quantify the presence of lipid core in the atherosclerotic plaque and associate it with other features such as lumen size and plaque architecture. Lipid-rich plaques are known to pose a higher risk of distal embolization during interventions and plaque disruption. The aim of this manuscript is the review of the potential clinical and research applications of this technology as highlighted by recent studies

Absorb bioresorbable vascular scaffold: What have we learned after 5 years of clinical experience?

Bioresorbable scaffolds have the potential to introduce a paradigm shift in interventional cardiology, a true anatomical and functional "vascular restoration" instead of an artificial stiff tube encased by persistent metallic foreign body. Early clinical studies using the first commercially available drug-eluting bioresorbable vascular scaffold (BVS) reported very promising safety and efficacy outcomes, comparable to best-in-class second-generation drug-eluting metal stent. To date, more than 60,000 Absorb BVSs have been implanted with only the interim analysis of one randomized trial (ABSORB II RCT) available. Recent registries have challenged the initial claim that BVS is immune from Scaffold Thrombosis (ST). However, suboptimal device expansion and insufficient intracoronary imaging guidance can explain higher than expected ST, especially in complex lesions. The aim of this review article is to critically evaluate the results of the available Absorb BVS studies and discuss the lessons learned to optimize lesion selection and implantation technique of such devices

Optical coherence tomography guidance for percutaneous coronary intervention with bioresorbable scaffolds

Background The effect of optical coherence tomography (OCT) guidance on the implantation strategy during all phases of percutaneous coronary intervention (PCI) with bioresorbable vascular scaffolds (BVSs) in a real-world scenario has been poorly investigated. Methods Consecutive patients undergoing BVS implantation at our institution were included in this registry. Frequency-domain OCT pullbacks were performed at the operator's discretion during all phases of BVS implantation procedures to optimize preparation of lesions, confirm BVS size, and optimize expansion and apposition of scaffolds. Results Between September 2012 and July 2015, 203 BVSs were implanted in 101 consecutive patients at our institution (2.01 BVSs/patient). In 66 patients, the procedure was performed under OCT guidance. In the OCT subgroup, 66 (77.6%) of the 85 treated lesions were complex (B2/C AHA/ACC type). Overall, 147 OCT pullbacks were performed and 72/147 (49.0%) pullbacks indicated the need for changing strategy. After angiography-only-guided optimisation of BVS in 27 (31.8%) lesions, an OCT examination prompted performance of a second post-expansion. This resulted in an increase in the minimal scaffold area (5.5 to 6.3\ua0mm2, p\ua0=\ua00.004) and a decrease in the incomplete scaffold apposition area (1.1 to 0.6\ua0mm2, p\ua0=\ua00.082), with no new stent fractures. When the population was divided according to the time of BVS implantation, an initial learning adaptation became evident, with the number of OCT-guided changes in strategy significantly decreasing between the initial and final time periods (p\ua0=\ua00.017). Conclusions OCT guidance for BVS implantation significantly affects the procedural strategy, with favourable effects on acute results and the learning curve

A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia

Aims Inappropriate Sinus Tachycardia (IST), a syndrome characterized by abnormally fast sinus rates and multisystem symptoms, is still poorly understood. Because of the relevance of HCN4 channels to pacemaker activity, we used a candidate-gene approach and screened IST patients for the presence of disease-causing HCN4 mutations. Methods and results Forty-eight IST patients, four of whom of known familial history, were enrolled in the study. We initially identified in one of the patients with familial history the R524Q mutation in HCN4. Investigation extended to the family members showed that the mutation co-segregated with IST-related symptoms. The R524Q mutation is located in the C-linker, a region known to couple cAMP binding to channel activation. The functional relevance of the mutation was investigated in heterologous expression systems by patch-clamp experiments. We found that mutant HCN4 channels were more sensitive to cAMP than wild-type channels, in agreement with increased sensitivity to basal and stimulated adrenergic input and with a faster than normal pacemaker rate. The properties of variant channels indicate therefore that R524Q is a gain-of-function mutation. Increased channel contribution to activity was confirmed by evidence that when spontaneously beating rat newborn myocytes were transfected with R524Q mutant HCN4 channels, they exhibited a faster rate than when transfected with wild-type HCN4 channels. Conclusion This is the first report of a gain-of-function HCN4 mutation associated with IST through increased sensitivity to cAMP-dependent activation

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013

How do cardiologists select patients for dual antiplatelet therapy continuation beyond 1 year after a myocardial infarction? Insights from the EYESHOT Post-MI Study

Background: Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). Hypothesis: We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. Methods: We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Results: Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Conclusions: Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI

Potential additive effects of ticagrelor, ivabradine, and carvedilol on sinus node

A 51-year-old male patient presented to the emergency room with an anterior ST-elevation myocardial infarction. After a loading dose of both ticagrelor and aspirin, the patient underwent primary-PCI on the left anterior descending coronary artery with stent implantation. After successful revascularization, medical therapy included beta-blockers, statins, and angiotensin II receptor antagonists. Two days later, ivabradine was also administered in order to reduce heart rate at target, but the patient developed a severe symptomatic bradycardia and sinus arrest, even requiring administration of both atropine and adrenaline. Ivabradine and ticagrelor have been then suspended and this latter changed with prasugrel. Any other similar event was not reported during the following days. This clinical case raised concerns about the safety of the combination of beta-blockers and ivabradine in patients treated with ticagrelor, particularly during the acute phase of an acute coronary syndrome. These two latter drugs, in particular, might interact with the same receptor. In fact, ivabradine directly modulates the If-channel which is also modulated by the cyclic adenosine monophosphate levels. These latter have been shown to increase after ticagrelor assumption via inhibition of adenosine uptake by erythrocytes. Further studies are warrant to better clarify the safety of this association