Cerebral Embolic Protection Devices for Transcatheter Aortic Valve Replacement: Review of the Literature and Future Perspectives.

PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) has been a revolutionary therapy in the treatment of aortic valve stenosis. The risk of stroke associated with TAVR has decreased significantly since its introduction; however, it remains a devastating complication when it does occur. RECENT FINDINGS: Many of the strokes associated with TAVR occur peri-procedurally and are thought to be due to embolic debris entering the cerebrovascular circulation. A number of different cerebral embolic protection devices (CEPD) have been developed and are in various stages of testing and use. The results from clinical trials evaluating the role for CEPD to reduce the risk of stroke have been mixed. As a result, their uptake has been very heterogeneous. This review provides a summary of the diverse CEPD devices available for use and outlines the clinical evidence available to date.

"I realized I was not alone": A mixed-methods investigation of the implementation of Ubuntu groups to reduce burnout and social isolation in an allopathic medical School in the Southeastern United States.

PURPOSE/BACKGROUND: Healthcare providers experience higher rates of workplace burnout, a reality highlighted by the COVID-19 pandemic. In response, small groups, inspired by South African philosophy, Ubuntu, were introduced to decrease burnout and social isolation and build community and belonging. This study examines how participation in these groups can impact these measures. METHODS: In this mixed-methods study, trained facilitators led small groups that utilized story-sharing to foster connections within the group and broader community. Quantitative and qualitative data were analyzed separately and merged to identify convergence. RESULTS: Three main qualitative themes emerged: 1) seeking and building connections and community, 2) curiosity, learning, and growing, and 3) open-hearted and thriving. These themes were linked to quantitative outcomes, showing a statistically significant decrease in social isolation among staff/faculty and students. Furthermore, faculty/staff exhibited reduced burnout compared to students, while students reported increased feelings of belonging. CONCLUSION: Participation in Ubuntu groups positively influenced students' sense of belonging, reduced faculty/staff burnout, and alleviated social isolation for all participants. Future research should explore the potential of this intervention to further promote wellness on medical campuses. Programs emphasizing the well-being of individuals, including faculty, staff, and students, are crucial for supporting the overall health of medical communities and the wider society.

Stroke Severity among Men and Women Acute Ischemic Stroke Patients in the Telestroke Network.

INTRODUCTION: This study investigates gender differences among stroke patients treated in the telestroke network using specific risk factors that contribute to stroke severity. METHODS: We examined gender differences in stroke severity among 454 patients hospitalized with acute ischemic stroke (AIS). The logistic regression model was used to predict clinical risk factors associated with stroke severity in men and women AIS patients. RESULTS: In the adjusted analysis among women patients, increasing age (odds ratio [OR] = 1.05, 95% CI: 1.017-1.085, p = 0.003) and higher heart rate (OR = 1.031, 95% CI: 1.005-1.058, p = 0.021) were associated with worsening neurological functions, while direct admission (OR = 0.191, 95% CI: 0.079-0.465, p < 0.001) was associated with improving neurologic functions. Among men, hypertension (OR = 3.077, 95% CI: 1.060-8.931, p = 0.039) and higher international normalized ratio (INR) (OR = 21.959, 95% CI: 1.489-323.912, p = 0.024) were associated with worsening neurologic functions, while Caucasian (OR = 0.181, 95% CI: 0.062-0.526, p = 0.002) and obesity (OR = 0.449, 95% CI: 0.203-0.99, p = 0.047) were associated with neurologic improvement. CONCLUSION: Increasing age and heart rate in women, hypertension and greater INR in men contribute to worsening neurologic functions. There is a need to develop strategies to improve the care of both men and women in the telestroke network.

Brominated Carbazole with Antibiotic Adjuvant Activity Displays Pleiotropic Effects in MRSA's Transcriptome.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic-resistant bacterial infections acquired during hospital stays have increased. Antibiotic adjuvants are a key strategy to combat these bacteria. We have evaluated several small molecule antibiotic adjuvants that have strong potentiation with ß-lactam antibiotics and are likely inhibiting a master regulatory kinase, Stk1. Here, we investigated how the lead adjuvant (compound 8) exerts its effects in a more comprehensive manner. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with oxacillin and the adjuvant. Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up- and downregulated, respectively, in response to cotreatment. Gene ontology categories and biochemical pathways that were significantly enriched with downregulated genes involved carbohydrate utilization, such as the citrate cycle and the phosphotransferase system. One of the most populated pathways was S. aureus infection. Results from an interaction network constructed with affected gene products supported the hypothesis that Stk1 is a target of compound 8. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect due to Stk1 inhibition. These results point to this antibiotic adjuvant having potential broad therapeutic use in combatting MRSA.

Identification and Evaluation of Brominated Carbazoles as a Novel Antibiotic Adjuvant Scaffold in MRSA.

Antibiotic-resistant infections are a pressing global concern, causing millions of deaths each year. Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections in healthcare settings and is increasingly responsible for community-acquired infections that are often more difficult to treat. Antibiotic adjuvants are small molecules that potentiate antibiotics through nontoxic mechanisms and show excellent promise as novel therapeutics. Screening of low-molecular-weight compounds was employed to identify novel antibiotic adjuvant scaffolds for further elaboration. Brominated carbazoles emerged from this screening as lead compounds for further evaluation. Lead carbazoles were able to potentiate several ß-lactam antibiotics in three medically relevant strains of MRSA. Gene expression studies determined that these carbazoles were dampening the transcription of key genes that modulate ß-lactam resistance in MRSA. The lead brominated carbazoles represent novel scaffolds for elaboration as antibiotic adjuvants.

Initially unexplained cardiac arrest in children and adolescents: A national experience from the Canadian Pediatric Heart Rhythm Network.

BACKGROUND: Unexplained cardiac arrest (UCA) is rare in children. Despite investigations, the etiology in up to one-half of patients remains unknown. OBJECTIVE: The purpose of this study was to assess the management and outcomes of pediatric UCA survivors through the Canadian Pediatric Heart Rhythm Network. METHODS: A retrospective case series of children (age 1-19 years) who presented with UCA between January 1, 2004, and November 1, 2017, was conducted. Patients with known heart disease pre-UCA were excluded. UCA details, investigations, genetic test results, treatment, implantable cardioverter-defibrillator (ICD) data, subsequent diagnoses, and family screening data were collected. RESULTS: Forty-six patients (61% male) were survivors of sudden unexpected death and met inclusion criteria at 8 participating sites. Median age at UCA was 13.8 years (interquartile range [IQR] 9-16 years). Baseline retrievable investigations included electrocardiogram (96%), echocardiogram (85%), exercise stress test (73%), and cardiac magnetic resonance imaging (57%). The presumed etiology for the UCA was identified in 24 (52%), mainly long QT syndrome or catecholaminergic polymorphic ventricular tachycardia. Genetic testing was performed in 33 of 46 (72%), with pathogenic/likely pathogenic variants identified in 13 of 33 (39%) and variants of uncertain significance in 8 of 33 (24%). ICDs were implanted in 35 of 46 (76%). Over median follow-up of 36 months (IQR 17-57 months), 8 of 35 had arrhythmia events captured on device interrogation. Families of 26 of 46 patients(57%) underwent screening, leading to a cardiac diagnosis in 6 of 26 families. CONCLUSION: A cause for UCA was not identified in nearly 50% of patients despite extensive investigations, including cascade screening. A large proportion (75%) of ICD shocks occurred in patients without a diagnosis.

The accessibility and utilization of genetic testing for inherited heart rhythm disorders: a Canadian cross-sectional survey study.

The genetic basis of many sudden death-related conditions has been elucidated. These include inherited arrhythmias and arrhythmogenic cardiomyopathies, termed inherited heart rhythm disorders (IHRD). Advising on and interpreting genetic testing is challenging for the general cardiologist. This has led to the development of interdisciplinary clinics for IHRD in varying stages of establishment in Canada. We sought the viewpoints and patterns of practice of Canadian IHRD experts, and assessed their ability to access genetic testing for IHRD using a national cross-sectional survey. Of 56 participants, most were physicians (68%) or genetic counselors (19%). Despite working collaboratively, most genetic counselors (59%) were either not satisfied or only somewhat satisfied with their relationships with physicians. Ninety percent of participants were involved in offering genetic evaluation, including 80% who felt that testing was usually/always accessible. Most offered genetic testing to confirm clinical diagnosis and/or direct family screening. Post-mortem genetic analysis was sought by 69% of respondents; however, a lack of retained tissue and/or poor tissue preparation hindered this process. Family screening was usually recommended in the setting of a pathogenic/likely pathogenic variant. The most commonly perceived barrier to genetic testing was cost to the healthcare system. More than a quarter of patients waited ≥ 6 months for funding. An ability to engage at-risk relatives was rated as limited/poor by 34% of participants. Despite the establishment of several interdisciplinary clinics, timely access to affordable testing, supported by strong team communication, continues to be a barrier to genetic testing in Canada.

The Safety and Effectiveness of Flecainide in Children in the Current Era.

This retrospective study sought to determine the safety and effectiveness of flecainide in children with normal hearts and those with congenital heart disease (CHD) or cardiomyopathy (CMO). Baseline and follow-up data at two pediatric cardiology sites were queried (2000-2015); a total of 175 patients (20 with CHD and two with CMO) receiving flecainide were assessed. When comparing patients with CHD to those with normal hearts, patients with CHD were younger at diagnosis (median age 19 days; IQR 3-157.5 days vs normal heart patients median age 21 days; IQR 7-172 days, p = 0.4) and severe cardiac dysfunction was more prevalent (30% in CHD patients vs 8% in normal heart patients, p = 0.009). Treatment duration did not differ between the two groups (CHD patients median duration 52 weeks; IQR 27-91.5 weeks vs normal heart patients median duration 55 weeks; IQR 32-156 weeks, p = 0.5). Cardiac dysfunction resulting in flecainide discontinuation occurred in two patients (1%), one with CHD and one without. Three patients experienced proarrhythmia (2%) and there were no cardiac arrests during follow-up. There was one death in this cohort in a patient with severe CHD and an RSV infection (<1%). Arrhythmia control did not differ between the groups (90% in CHD patients vs 77% in normal heart patients, p = 0.2). Flecainide was well tolerated in this cohort, with fewer than 3% discontinuing medication due to flecainide-associated adverse events. Contrary to adult studies, there was no difference in the incidence of adverse events between patients with normal hearts and patients with CHD. Flecainide is a safe and effective antiarrhythmic medication, even for children with underlying CHD.

Beyond the Electrocardiogram: Mutations in Cardiac Ion Channel Genes Underlie Nonarrhythmic Phenotypes.

Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis.

Cost Analysis of Patients Referred for Inherited Heart Rhythm Disorder Evaluation.

BACKGROUND: Inherited heart rhythm disorders (IHRDs) are complex and uncommon arrhythmogenic conditions that can lead to sudden unexpected death in seemingly healthy individuals. Multidisciplinary programs can assist in the diagnostic testing of potentially affected individuals and their family members. METHODS: Patients evaluated in a specialized adult and pediatric IHRD clinic between April 2013 and February 2015 were characterized. The total costs per evaluation and diagnosis were calculated. Patients were divided according to referral indication (primary referral or family member). RESULTS: A total of 618 patients were evaluated (age 36 ± 21 years; 52% male), of which 274 (44%) were primary referrals and 344 (56%) were family members referred for cascade screening. Overall, 47% had at least 1 follow-up visit. Patients had a median of 3 tests; primary referrals required more tests (4 vs 2; P < 0.01). The median cost per patient was $1340 CAD. Evaluation of the primary referrals was costlier than family members ($3096 vs $983; P < 0.01). A definite or probable diagnosis was determined in 464 patients (77%), with no difference according to patient type (P = 0.18). The total cost per diagnosis was $4021 in primary referrals compared with $1277 in family members (P < 0.01). CONCLUSIONS: Clinical evaluation of patients with suspected IHRD results in a high diagnostic yield and costs aligned with other complex disorders involving multidisciplinary clinics. Evaluation costs are expectedly higher in primary referrals compared with targeted family screening.

Advances in the diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia.

Since the sentinel description of exercise-triggered ventricular arrhythmias in 21 children, our recognition and understanding of catecholaminergic polymorphic ventricular tachycardia has improved substantially. A variety of treatments are now available, but reaching a diagnosis before cardiac arrest remains a challenge. Most cases are related to variants in the gene encoding for ryanodine receptor-2 (RyR2), which mediates calcium-induced calcium release. Up to half of cases remain genetically elusive. The condition is presently incurable, but one basic intervention, the universal administration of ß-blockers, has improved survival. In the past, implantable cardioverter-defibrillators (ICDs) were frequently implanted, especially in those with a history of cardiac arrest. Treatment limitations include under-dosing and poor compliance with ß-blockers, and potentially lethal ICD-related electrical storm. Newer therapies include flecainide and sympathetic ganglionectomy. Limited data have suggested that genotype may predict phenotype in catecholaminergic polymorphic ventricular tachycardia, including a higher risk of life-threatening cardiac events in subjects with variants in the C-terminus of ryanodine receptor-2 (RyR2). At present, international efforts are underway to better understand this condition through large prospective registries. The recent publication of gene therapy in an animal model of the recessive form of the disease highlights the importance of improving our understanding of the genetic underpinnings of the disease.

Morbidities in the ultra-athlete and marathoner.

The cardiovascular benefits of habitual exercise are well documented. In the current era, more of the population is exceeding the recommendations for physical activity as the popularity of endurance events increases. Recent data have proposed a U-shaped relationship between exercise intensity and cardiovascular outcomes. Regular participation in endurance activities has been shown to result in structural and functional changes in the heart. This re-modelling may be the substrate for cardiac dysfunction or arrhythmias. The risk of sudden cardiac death may also be elevated; however, in most cases of sudden cardiac death, the cause can be linked to an underlying cardiac pathology where exercise acted as the trigger for a lethal arrhythmia. This article serves to review whether excessive exercise may result in harm in some athletes.

The Current State and Future Potential of Pediatric and Congenital Electrophysiology.

Pediatric electrophysiologists specialize in the diagnosis and treatment of rhythm abnormalities in pediatric, congenital heart disease, and inherited arrhythmia syndrome patients. The field originated out of the unique knowledge base that rhythm management in young patients required. In the 1970s, pediatric electrophysiology was recognized as a distinct cardiac subspecialty and it has evolved rapidly since that time. Despite the considerable growth in personnel, technology, and complexity that the field has undergone, further opportunities to progress pediatric electrophysiology exist. In this review, we highlight some of the clinical focus of pediatric and adult congenital electrophysiologists to date and identify areas within this specialty where the pediatric and congenital electrophysiology community could come together in order to drive improvements in rhythm management for patients.