Viewpoint Stroke prevention in recent guidelines for the management of patients with atrial fibrillation: An appraisal.

Formal guidelines play an important role in disseminating the best available evidence knowledge and are expected to provide simple and practical recommendations for the most optimal management of patients with various conditions. Such guidelines have important implications for many disease states, which thereby could be more professionally managed in everyday clinical practice by clinicians with divergent educational backgrounds, and also more easily implemented in wards or outpatient clinics eliminating inequalities in health care management. In this brief Viewpoint, we provide an appraisal on the recommendations pertinent to the prevention of atrial fibrillation-related stroke or systemic thromboembolism, as provided in recently published guidelines for the management of this arrhythmia

Antiarrhythmic Medication for Atrial Fibrillation (AIM-AF) study: A physician survey of sotalol use and patient monitoring in the EU and USA

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Sanofi Introduction In the recent 2020 European Society of Cardiology (ESC) guidelines, sotalol was downgraded from a Class IA to a llbA recommendation and advised not to be prescribed in patients with specific co-morbidities. All patients given sotalol should also be closely monitored for proarrhythmic risk factors. To date, American guidelines have not changed. Our study sought to understand the use of sotalol in AF patients and monitoring compliance across the USA and in the EU, with regards to the recent ESC guideline change. Method An online physician survey of cardiologists, cardiac electrophysiologists (EPs) and interventional EPs (N = 569) was conducted in the USA, Germany, Italy and the UK. All respondents were actively treating ≥10 AF patients who received drug therapy and/or who had received or were referred for ablation. This survey included topics on AF types and antiarrhythmic drug (AAD) treatment practices in those with AF +/- co-morbidities (including left ventricular hypertrophy [LVH], LV heart failure, and sinus node dysfunction or renal impairment). Results Sotalol was prescribed across all patient sub-groups, with high use in those with hypertension (49% of physicians) and revascularised coronary artery disease (44%). Sotalol use was consistently higher among US respondents than EU clinicians across co-morbidity categories (heart failure with reduced ejection fraction: 25% vs 14% [guideline deviation]; hypertension: 53% vs 44%; valve disease: 33% vs 23%; recent myocardial infarction [MI]: 44% vs 22%; old MI: 52% vs 31%, respectively). Use was also generally higher among EPs compared with cardiologists, but remained low in patients with minimal or no structural heart disease across all groups. Many respondents prescribed sotalol in those with LVH (35%) or renal impairment (22%), despite guidelines advising against this due to proarrhythmia risk. This contrasts with expressed respondent concerns, as 43% cited ventricular proarrythmia risk as a reason for not using sotalol. Although respondents noted concern over such risks, as per the new guidelines, routine monitoring for these factors was not performed as follows: electrocardiograms (ECG) (19% [US: 23%; EU: 15%]), renal function assessment (42% [US: 36%; EU: 50%]) or electrolyte monitoring (48% [US: 49%; EU: 46%]). Respondents reported sotalol is typically initiated in hospital (45% of patients) or in outpatients with intensive ECG monitoring (37%), but is also being started in non-monitored outpatients (19%). Conclusions Although sotalol use among EU clinicians was lower compared with the USA, which may reflect recent ESC guideline changes, the extent of monitoring practices that would indicate avoidance in those with proarrhythmic risk factors was insufficient. The lack of routine monitoring for specific factors, such as renal impairment or electrolytes, and unmonitored outpatient initiation highlights an ongoing need for further education on maximising safety when using AADs. Abstract Figure

Safety and efficacy of dronedarone from clinical trials to real-world evidence: implications for its use in atrial fibrillation.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment

First report of generalized face processing difficulties in möbius sequence.

Reverse simulation models of facial expression recognition suggest that we recognize the emotions of others by running implicit motor programmes responsible for the production of that expression. Previous work has tested this theory by examining facial expression recognition in participants with Möbius sequence, a condition characterized by congenital bilateral facial paralysis. However, a mixed pattern of findings has emerged, and it has not yet been tested whether these individuals can imagine facial expressions, a process also hypothesized to be underpinned by proprioceptive feedback from the face. We investigated this issue by examining expression recognition and imagery in six participants with Möbius sequence, and also carried out tests assessing facial identity and object recognition, as well as basic visual processing. While five of the six participants presented with expression recognition impairments, only one was impaired at the imagery of facial expressions. Further, five participants presented with other difficulties in the recognition of facial identity or objects, or in lower-level visual processing. We discuss the implications of our findings for the reverse simulation model, and suggest that facial identity recognition impairments may be more severe in the condition than has previously been noted

Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

BACKGROUND AND PURPOSE: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. EXPERIMENTAL APPROACH: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. KEY RESULTS: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. CONCLUSION AND IMPLICATIONS: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection

AIM-AF: A Physician Survey in the United States and Europe.

Background Guideline recommendations are the accepted reference for selection of therapies for rhythm control of atrial fibrillation (AF). This study was designed to understand physicians' treatment practices and adherence to guidelines. Methods and Results The AIM-AF (Antiarrhythmic Medication for Atrial Fibrillation) study was an online survey of clinical cardiologists and electrophysiologists that was conducted in the United States and Europe (N=629). Respondents actively treated ≥30 patients with AF who received drug therapy, and had received or were referred for ablation every 3 months. The survey comprised 96 questions on physician demographics, AF types, and treatment practices. Overall, 54% of respondents considered guidelines to be the most important nonpatient factor influencing treatment choice. Across most queried comorbidities, amiodarone was selected by 60% to 80% of respondents. Other nonadherent usage included sotalol by 21% in patients with renal impairment; dofetilide initiation (16%, United States only) outside of hospital; class Ic agents by 6% in coronary artery disease; and dronedarone by 8% in patients with heart failure with reduced ejection fraction. Additionally, rhythm control strategies were frequently chosen in asymptomatic AF (antiarrhythmic drugs [AADs], 35%; ablation, 8%) and subclinical AF (AADs, 38%; ablation, 13%). Despite guideline algorithms emphasizing safety first, efficacy (48%) was selected as the most important consideration for AAD choice, followed by safety (34%). Conclusions Despite surveyed clinicians recognizing the importance of guidelines, nonadherence was frequently observed. While deviation may be reasonable in selected patients, in general, nonadherence has the potential to compromise patient safety. These findings highlight an underappreciation of the safe use of AADs, emphasizing the need for interventions to support optimal AAD selection

Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs

Real-world utilization of the pill-in-the-pocket method for terminating episodes of atrial fibrillation: data from the multinational Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey.

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated. METHODS AND RESULTS: The recently published Antiarrhythmic Interventions for Managing Atrial Fibrillation (AIM-AF) survey included questions regarding current PITP usage, stratified by US vs. European countries surveyed, by representative countries within Europe, and by cardiologists vs. electrophysiologists. This manuscript presents the data from this planned sub-study. Our survey revealed that clinicians in both the USA and Europe consider PITP in about a quarter of their patients, mostly for recent-onset AF with minimal or no structural heart disease (guideline appropriate). However, significant deviations exist. See the Graphical abstract for a summary of the data. CONCLUSION: Our findings highlight the frequent use of PITP and the need for further physician education about appropriate and optimal use of this strategy

Isolation and fine mapping of Rps6: An intermediate host resistance gene in barley to wheat stripe rust

A plant may be considered a nonhost of a pathogen if all known genotypes of a plant species are resistant to all known isolates of a pathogen species. However, if a small number of genotypes are susceptible to some known isolates of a pathogen species this plant maybe considered an intermediate host. Barley (Hordeum vulgare) is an intermediate host for Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust. We wanted to understand the genetic architecture underlying resistance to Pst and to determine whether any overlap exists with resistance to the host pathogen, Puccinia striiformis f. sp. hordei (Psh). We mapped Pst resistance to chromosome 7H and show that host and intermediate host resistance is genetically uncoupled. Therefore, we designate this resistance locus Rps6. We used phenotypic and genotypic selection on F2:3 families to isolate Rps6 and fine mapped the locus to a 0.1 cM region. Anchoring of the Rps6 locus to the barley physical map placed the region on two adjacent fingerprinted contigs. Efforts are now underway to sequence the minimal tiling path and to delimit the physical region harbouring Rps6. This will facilitate additional marker development and permit identification of candidate genes in the region

Barley <i>SIX-ROWED SPIKE3</i> encodes a putative Jumonji C-type H3K9me2/me3 demethylase that represses lateral spikelet fertility

The VRS genes of barley control the fertility of the lateral spikelets on the barley inflorescence. Here, Bull et al. show that VRS3 encodes a putative Jumonji C-type histone demethylase that regulates expression of other VRS genes, and genes involved in stress, hormone and sugar metabolism