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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 β-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.

Antibiotic-resistant infections are a pressing global concern, causing millions of deaths each year. Methicillin-resistant

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. Instead of designing and deploying new antibiotics which MRSA would quickly develop resistance to, adjuvants are a key strategy to combatting these bacteria. We have evaluated several small molecule antibiotic adjuvants that have strong potentiation with β-lactam antibiotics and are likely inhibiting a master regulatory kinase, Stk1. Here, we investigated how the lead adjuvant exerts its effects in a more comprehensive manner. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with a β-lactam antibiotic (oxacillin) and the adjuvant (compound 8). 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 with compound 8 and oxacillin compared to oxacillin alone. Gene ontology categories that were significantly enriched among downregulated genes involved phosphotransferase systems. Most of the biochemical pathways enriched with significantly 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.

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.

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.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).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; P0.01). The median cost per patient was $1340 CAD. Evaluation of the primary referrals was costlier than family members ($3096 vs $983; P0.01). 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 (P0.01).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.

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.

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 (

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.

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 β-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 β-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.

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.

This paper reports on recent attempts to develop and test a new type of solid-state neutron detector fabricated from uranium compounds. It has been known for many years that uranium oxide (UO2), triuranium octoxide (U3O8) and other uranium compounds exhibit semiconducting characteristics with a broad range of electrical properties. We seek to exploit these characteristics to make a direct-conversion semiconductor neutron detector. In such a device a neutron interacts with a uranium nucleus, inducing fission. The fission products deposit energy-producing, detectable electron-hole pairs. The high energy released in the fission reaction indicates that noise discrimination in such a device has the potential to be excellent. Schottky devices were fabricated using a chemical deposition coating technique to deposit UO2 layers a few microns thick on a sapphire substrate. Schottky devices have also been made using a single crystal from UO2 samples approximately 500 microns thick. Neutron sensitivity simulations have been performed using GEANT4. Neutron sensitivity for the Schottky devices was tested experimentally using a 252Cf source.