Redefining ß-blocker response in heart failure patients with sinus rhythm and atrial fibrillation: a machine learning cluster analysis.

BACKGROUND: Mortality remains unacceptably high in patients with heart failure and reduced left ventricular ejection fraction (LVEF) despite advances in therapeutics. We hypothesised that a novel artificial intelligence approach could better assess multiple and higher-dimension interactions of comorbidities, and define clusters of ß-blocker efficacy in patients with sinus rhythm and atrial fibrillation. METHODS: Neural network-based variational autoencoders and hierarchical clustering were applied to pooled individual patient data from nine double-blind, randomised, placebo-controlled trials of ß blockers. All-cause mortality during median 1·3 years of follow-up was assessed by intention to treat, stratified by electrocardiographic heart rhythm. The number of clusters and dimensions was determined objectively, with results validated using a leave-one-trial-out approach. This study was prospectively registered with ClinicalTrials.gov (NCT00832442) and the PROSPERO database of systematic reviews (CRD42014010012). FINDINGS: 15 659 patients with heart failure and LVEF of less than 50% were included, with median age 65 years (IQR 56-72) and LVEF 27% (IQR 21-33). 3708 (24%) patients were women. In sinus rhythm (n=12 822), most clusters demonstrated a consistent overall mortality benefit from ß blockers, with odds ratios (ORs) ranging from 0·54 to 0·74. One cluster in sinus rhythm of older patients with less severe symptoms showed no significant efficacy (OR 0·86, 95% CI 0·67-1·10; p=0·22). In atrial fibrillation (n=2837), four of five clusters were consistent with the overall neutral effect of ß blockers versus placebo (OR 0·92, 0·77-1·10; p=0·37). One cluster of younger atrial fibrillation patients at lower mortality risk but similar LVEF to average had a statistically significant reduction in mortality with ß blockers (OR 0·57, 0·35-0·93; p=0·023). The robustness and consistency of clustering was confirmed for all models (p<0·0001 vs random), and cluster membership was externally validated across the nine independent trials. INTERPRETATION: An artificial intelligence-based clustering approach was able to distinguish prognostic response from ß blockers in patients with heart failure and reduced LVEF. This included patients in sinus rhythm with suboptimal efficacy, as well as a cluster of patients with atrial fibrillation where ß blockers did reduce mortality. FUNDING: Medical Research Council, UK, and EU/EFPIA Innovative Medicines Initiative BigData@Heart.

Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot survey on Atrial Fibrillation.

AIMS: Sex differences in the epidemiology and clinical management of AF are evident. Of note, females are more symptomatic and if age >65, are at higher risk of thromboembolism if incident AF develops, compared with males. METHODS AND RESULTS: In an analysis from the dataset of the Euro Observational Research Programme on Atrial Fibrillation (EORP-AF) Pilot survey (n = 3119), we examined sex-related differences in presentation, treatment, and outcome of contemporary patients with AF in Europe.Female subjects were older (P < 0.0001), with a greater proportion aged ≥75 years, with more heart failure and hypertension. Heart failure with preserved ejection fraction was more common in females (P < 0.0001), as was valvular heart disease (P = 0.0003). Females were more symptomatic compared with males with a higher proportion being EHRA Class III and IV (P = 0.0012). The more common symptoms that were more prevalent in females were palpitations (P < 0.0001) and fear/anxiety (P = 0.0007). Other symptoms (e.g. dyspnoea, chest pain, fatigue, etc.) were not different between males and females. Health status scores were significantly lower for females overall, specifically for the psychological and physical domains (both P < 0.0001) but not for the sexual activity domain (P = 0.9023). Females were less likely to have electrical cardioversion (18.9 vs. 25.5%, P < 0.0001), and more likely to receive rate control (P = 0.002). Among patients recruited in hospital and discharged alive (n = 2009), documented contraindications to vitamin K antagonist (VKA) were evident in 23.8% of females. A CHA2DS2-VASc score ≥2 was found in 94.7% of females and 74.6% of males (P < 0.0001), with oral anticoagulants being used in 95.3 and 76.2%, respectively (P < 0.0001). A HAS-BLED score of ≥3 was found in 12.2% of females and 14.5% of males. Independent predictors of VKA use in females on multivariate analysis were CHA2DS2-VASc score (P = 0.0007), lower HAS-BLED score (P = 0.0284), and prosthetic mechanical valves (P = 0.0276). CONCLUSION: The EORP-AF Pilot survey provides contemporary data on sex differences in clinical features and management of AF patients participating in the EORP-AF Pilot registry. Female subjects were older and more symptomatic, compared with males, and were more likely to receive rate control. Also, female patients were at higher stroke risk overall, but oral anticoagulation was used in a high proportion of patients.

Development of automated neural network prediction for echocardiographic left ventricular ejection fraction.

Introduction: The echocardiographic measurement of left ventricular ejection fraction (LVEF) is fundamental to the diagnosis and classification of patients with heart failure (HF). Methods: This paper aimed to quantify LVEF automatically and accurately with the proposed pipeline method based on deep neural networks and ensemble learning. Within the pipeline, an Atrous Convolutional Neural Network (ACNN) was first trained to segment the left ventricle (LV), before employing the area-length formulation based on the ellipsoid single-plane model to calculate LVEF values. This formulation required inputs of LV area, derived from segmentation using an improved Jeffrey's method, as well as LV length, derived from a novel ensemble learning model. To further improve the pipeline's accuracy, an automated peak detection algorithm was used to identify end-diastolic and end-systolic frames, avoiding issues with human error. Subsequently, single-beat LVEF values were averaged across all cardiac cycles to obtain the final LVEF. Results: This method was developed and internally validated in an open-source dataset containing 10,030 echocardiograms. The Pearson's correlation coefficient was 0.83 for LVEF prediction compared to expert human analysis (p < 0.001), with a subsequent area under the receiver operator curve (AUROC) of 0.98 (95% confidence interval 0.97 to 0.99) for categorisation of HF with reduced ejection (HFrEF; LVEF<40%). In an external dataset with 200 echocardiograms, this method achieved an AUC of 0.90 (95% confidence interval 0.88 to 0.91) for HFrEF assessment. Conclusion: The automated neural network-based calculation of LVEF is comparable to expert clinicians performing time-consuming, frame-by-frame manual evaluations of cardiac systolic function.

Efficacy and safety of intravenous beta-blockers in acute atrial fibrillation and flutter is dependent on beta-1 selectivity: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Intravenous beta-blockers are commonly used to manage patients with acute atrial fibrillation (AF) and atrial flutter (AFl), but the choice of specific agent is often not evidence-based. METHODS: A prospectively-registered systematic review and meta-analysis of randomised trials (PROSPERO: CRD42020204772) to compare the safety and efficacy of intravenous beta-blockers against alternative pharmacological agents. RESULTS: Twelve trials comparing beta-blockers with diltiazem, digoxin, verapamil, anti-arrhythmic drugs and placebo were included, with variable risk of bias and 1152 participants. With high heterogeneity (I2 = 87%; p < 0.001), there was no difference in the primary outcomes of heart rate reduction (standardised mean difference - 0.65 beats/minute compared to control, 95% CI - 1.63 to 0.32; p = 0.19) or the proportion that achieved target heart rate (risk ratio [RR] 0.85, 95% CI 0.36-1.97; p = 0.70). Conventional selective beta-1 blockers were inferior for target heart rate reduction versus control (RR 0.33, 0.17-0.64; p < 0.001), whereas super-selective beta-1 blockers were superior (RR 1.98, 1.54-2.54; p < 0.001). There was no significant difference between beta-blockers and comparators for secondary outcomes of conversion to sinus rhythm (RR 1.15, 0.90-1.46; p = 0.28), hypotension (RR 1.85, 0.87-3.93; p = 0.11), bradycardia (RR 1.29, 0.25-6.82; p = 0.76) or adverse events leading to drug discontinuation (RR 1.03, 0.49-2.17; p = 0.93). The incidence of hypotension and bradycardia were greater with non-selective beta-blockers (p = 0.031 and p < 0.001). CONCLUSIONS: Across all intravenous beta-blockers, there was no difference with other medications for acute heart rate control in atrial fibrillation and flutter. Efficacy and safety may be improved by choosing beta-blockers with higher beta-1 selectivity.

Data processing pipeline for cardiogenic shock prediction using machine learning.

Introduction: Recent advances in machine learning provide new possibilities to process and analyse observational patient data to predict patient outcomes. In this paper, we introduce a data processing pipeline for cardiogenic shock (CS) prediction from the MIMIC III database of intensive cardiac care unit patients with acute coronary syndrome. The ability to identify high-risk patients could possibly allow taking pre-emptive measures and thus prevent the development of CS. Methods: We mainly focus on techniques for the imputation of missing data by generating a pipeline for imputation and comparing the performance of various multivariate imputation algorithms, including k-nearest neighbours, two singular value decomposition (SVD)-based methods, and Multiple Imputation by Chained Equations. After imputation, we select the final subjects and variables from the imputed dataset and showcase the performance of the gradient-boosted framework that uses a tree-based classifier for cardiogenic shock prediction. Results: We achieved good classification performance thanks to data cleaning and imputation (cross-validated mean area under the curve 0.805) without hyperparameter optimization. Conclusion: We believe our pre-processing pipeline would prove helpful also for other classification and regression experiments.

Breaking the Cycle of Heart Failure With Preserved Ejection Fraction and Atrial Fibrillation.

Heart failure with preserved ejection fraction (HFpEF) and AF are two common cardiovascular conditions that are inextricably linked to each other's development and progression, often in multimorbid patients. Current management is often directed to specific components of each disease without considering their joint impact on diagnosis, treatment and prognosis. The result for patients is suboptimal on all three levels, restricting clinicians from preventing major adverse events, including death, which occurs in 20% of patients at 2 years and in 45% at 4 years. New trial evidence and reanalysis of prior trials are providing a glimmer of hope that adverse outcomes can be reduced in those with concurrent HFpEF and AF. This will require a restructuring of care to integrate heart failure and AF teams, alongside those that manage comorbidities. Parallel commencement and non-sequential uptitration of therapeutics across different domains will be vital to ensure that all patients benefit at a personal level, based on their own needs and priorities.

Systematic approach to outcome assessment from coded electronic healthcare records in the DaRe2THINK NHS-embedded randomized trial.

Aims: Improving the efficiency of clinical trials is key to their continued importance in directing evidence-based patient care. Digital innovations, in particular the use of electronic healthcare records (EHRs), allow for large-scale screening and follow up of participants. However, it is critical these developments are accompanied by robust and transparent methods that can support high-quality and high clinical value research. Methods and results: The DaRe2THINK trial includes a series of novel processes, including nationwide pseudonymized pre screening of the primary-care EHR across England, digital enrolment, remote e-consent, and 'no-visit' follow up by linking all primary- and secondary-care health data with patient-reported outcomes. DaRe2THINK is a pragmatic, healthcare-embedded randomized trial testing whether earlier use of direct oral anticoagulants in patients with prior or current atrial fibrillation can prevent thromboembolic events and cognitive decline (www.birmingham.ac.uk/dare2think). This study outlines the systematic approach and methodology employed to define patient information and outcome events. This includes transparency on all medical code lists and phenotypes used in the trial across a variety of national data sources, including Clinical Practice Research Datalink Aurum (primary care), Hospital Episode Statistics (secondary care), and the Office for National Statistics (mortality). Conclusion: Co-designed by a patient and public involvement team, DaRe2THINK presents an opportunity to transform the approach to randomized trials in the setting of routine healthcare, providing high-quality evidence generation in populations representative of the community at risk.

International Prospective Registry of Acute Coronary Syndromes in Patients With COVID-19.

BACKGROUND: Published data suggest worse outcomes in acute coronary syndrome (ACS) patients and concurrent coronavirus disease 2019 (COVID-19) infection. Mechanisms remain unclear. OBJECTIVES: The purpose of this study was to report the demographics, angiographic findings, and in-hospital outcomes of COVID-19 ACS patients and compare these with pre-COVID-19 cohorts. METHODS: From March 1, 2020 to July 31, 2020, data from 55 international centers were entered into a prospective, COVID-ACS Registry. Patients were COVID-19 positive (or had a high index of clinical suspicion) and underwent invasive coronary angiography for suspected ACS. Outcomes were in-hospital major cardiovascular events (all-cause mortality, re-myocardial infarction, heart failure, stroke, unplanned revascularization, or stent thrombosis). Results were compared with national pre-COVID-19 databases (MINAP [Myocardial Ischaemia National Audit Project] 2019 and BCIS [British Cardiovascular Intervention Society] 2018 to 2019). RESULTS: In 144 ST-segment elevation myocardial infarction (STEMI) and 121 non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients, symptom-to-admission times were significantly prolonged (COVID-STEMI vs. BCIS: median 339.0 min vs. 173.0 min; p < 0.001; COVID NSTE-ACS vs. MINAP: 417.0 min vs. 295.0 min; p = 0.012). Mortality in COVID-ACS patients was significantly higher than BCIS/MINAP control subjects in both subgroups (COVID-STEMI: 22.9% vs. 5.7%; p < 0.001; COVID NSTE-ACS: 6.6% vs. 1.2%; p < 0.001), which remained following multivariate propensity analysis adjusting for comorbidities (STEMI subgroup odds ratio: 3.33 [95% confidence interval: 2.04 to 5.42]). Cardiogenic shock occurred in 20.1% of COVID-STEMI patients versus 8.7% of BCIS patients (p < 0.001). CONCLUSIONS: In this multicenter international registry, COVID-19-positive ACS patients presented later and had increased in-hospital mortality compared with a pre-COVID-19 ACS population. Excessive rates of and mortality from cardiogenic shock were major contributors to the worse outcomes in COVID-19 positive STEMI patients.

Antimicrobial activity of fusidic acid inclusion complexes.

OBJECTIVES: To synthesize and characterize the inclusion complexes of fusidic acid with ß - cyclodextrin, followed by the evaluation of their antimicrobial activity against pure strain (Staphylococcus aureus ATCC 25,923) and isolated Staphylococcus from clinical cases. METHODS: The desired compounds were synthesized using molar ratio of fusidic acid: ß-cyclodextrin of 1:1. Synthesized compounds were analyzed by Fourier Transform Infrared Spectroscopy (FTIR), X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), and Thermal Analysis, and the results confirmed the formation of inclusion compounds by fusidic acid with ß-cyclodextrin. RESULTS: Physical-chemical characterization confirmed the preparation of desired inclusion compounds, and the antimicrobial test confirmed that all compounds obtained have antimicrobial activity. Antimicrobial activity of freeze-drying complex againstS. aureus is similar with pure fusidic acid activity, being better than the cefoxitin one. Similar behavior was observed against methicillin-resistant S. aureus and S. epidermidis. CONCLUSIONS: In the present work, three different inclusion complexes of fusidic acid were prepared using three different preparation methods. All inclusion complexes obtained presented good antimicrobial activity against differentS. aureus strains. Antimicrobial activity of these new prepared compounds was observed to be better than that of cefoxitin.

Intradiploic epidermoid cysts - a series of three cases and our experience with literature data.

Intracranial epidermoid cysts are rare, representing almost 1% of all primary tumors and when are located in the diploe result from entrapped ectodermal embryonic remnants. Because of frequent complications, imaging studies are mandatory for highlighting erosions of both outer and inner table of the calvaria and treatment preparation. We enlisted three female patients within our study, comparing imaging with histopathology aspects. Even though the bone destruction was evident, no atypia or malignant signs were highlighted in serial sections. The interesting fact that we present is that our patients are all females, opposed to what is written in literature. Although the positive diagnosis can be made by imaging, histopathological examination of these cysts is mandatory for identifying malignant behavior.

Atherosclerosis Burden and Therapeutic Challenges Regarding Acute Coronary Syndromes in Chronic Kidney Disease Patients.

The major cause of death in patients with chronic kidney disease is represented by cardiovascular events. Atherosclerosis is usually initiated by the association of traditional and non-traditional risk factors, and the acute thrombotic complications are more frequent in subjects with reduced glomerular filtration rate. The diagnosis of acute coronary syndromes is challenging due to the increased values of cardiac necrosis enzymes correlated with reduced renal function.

Choroidal melanoma, unfavorable prognostic factors. Case report and review of literature.

Uveal melanoma is the most common intraocular tumor characterized by increased metastatic potential. The tumor develops from uveal melanocytes that, from an embryological point of view, derive from the cells of the anterior neural crest. The risk factors associated with melanoma development are close related to patient phenotype: light-colored hair and iris, fair skin. Recent studies have shown the link between choroidal melanoma and choroidal pigmentation of white-haired and light-colored eyes individuals. Increased pigmentation of the choroid is associated to marked increase in melanocyte density, which from a histological point of view can be a starting point for choroidal carcinogenesis. This case report is about a 36-year-old patient who presented in an outpatient ophthalmological examination for intermittent vision blurring. The ophthalmological examination revealed a view of 0.8 and nasally from the optic nerve head, a prominent tumor-shaped formation was detected during the fundus examination. The presence of a choroidal melanoma was suspected and eye ultrasound, angio-fluorography, optical coherence tomography (OCT) were performed and confirmed the diagnosis. Due to the small size, a team of three ophthalmologists decided to make brachytherapy. The procedure consisting of brachytherapy was temporarily applied to the scleral wall and was done at Debrecen University Hospital, Hungary, the follow-up monitoring being done at the Clinic in Oradea, Romania. Although the initial prognosis was optimistic, after four years of brachytherapy the tumor recurred, the dimensions found were over 14 mm, which is why enucleation was decided. Prior to enucleation, no computed tomography (CT) metastases were detected. Five months after enucleation, hepatic metastases occurred and after another two months, death occurred.

'Real-world' antithrombotic treatment in atrial fibrillation: The EORP-AF pilot survey.

BACKGROUND: Current guidelines strongly recommend that oral anticoagulation should be offered to patients with atrial fibrillation and ≥1 stroke risk factors. The guidelines also recommend that oral anticoagulation still should be used in the presence of stroke risk factors irrespective of rate or rhythm control. METHODS: In an analysis from the dataset of the EURObservational Research Programme on Atrial Fibrillation Pilot Survey (n = 3119), we examined antithrombotic therapy prescribing, with particular focus on the risk factors determining oral anticoagulation or antiplatelet therapy use. RESULTS: When oral anticoagulation was used among admitted patients in whom no pharmacologic cardioversion, electrical cardioversion, or catheter ablation was performed or planned, vitamin K antagonist therapy was prescribed in the majority (72.2%), whereas novel oral anticoagulants were used in the minority (7.7%). There was no significant difference in bleeding risk factors among the patients treated with the different types of antithrombotic therapies, except for those with chronic kidney disease, in whom oral anticoagulation was less commonly used (P = .0318). Antiplatelet therapy was more commonly used in patients with a high Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly score (≥2) (P < .0001). More oral anticoagulation use was associated with female gender (P = .0245). Less novel oral anticoagulant use was associated with valvular heart disease (P < .0001), chronic heart failure (P = .0010), coronary artery disease (P < .0001), and peripheral artery disease (P = .0092). Coronary artery disease was the strongest reason for combination therapy with oral anticoagulation plus antiplatelet drug (odds ratio, 8.54; P < .0001). When the Congestive heart failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [female] score was used, 95.6% of patients with a score ≥1 received antithrombotic therapy, with 80.5% of patients with a score ≥1 receiving oral anticoagulation. Of note, 83.7% of those with a score ≥2 received antithrombotic therapy. Of the latter, 70.9% of those with a score ≥2 received oral anticoagulation, vitamin K antagonists were used in 64.1%, and novel oral anticoagulants were used in 6.9%. CONCLUSIONS: The EURObservational Research Programme on Atrial Fibrillation Pilot Survey provides contemporary data on oral anticoagulation prescribing by European cardiologists for atrial fibrillation. Although the uptake of oral anticoagulation (mostly vitamin K antagonist therapy) has improved since the Euro Heart Survey a decade ago, antiplatelet therapy is still commonly prescribed, with or without oral anticoagulation, whereas elderly patients are commonly undertreated with oral anticoagulation.