Citations

BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health–funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18–25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57–1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67–2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02549664.

This cross-sectional study estimates the number of average-risk colorectal cancer screening–eligible individuals in the US since the US Preventive Services Task Force updated its recommendations in 2021.

AbstractBackgroundEmpirical evidence regarding the development of sensory responsivity in young children at high likelihood to develop autism spectrum disorder (ASD) remains relatively limited. It is unclear how sensory responsivity behaviors may change over time and impact later developmental outcomes. The goals of this study were to (a) characterize developmental trajectories of sensory responsivity across infancy (∼12 months), toddlerhood (∼24 months), and school age (6–11 years) in children at high and low familial likelihood for ASD; and (b) determine if sensory responsivity in infancy predicts adaptive and cognitive functioning at school age among children with ASD.MethodsGeneralized linear mixed effects models were used to examine scores from the Sensory Experiences Questionnaire in three groups of children including high‐likelihood children later diagnosed with ASD (HL‐ASD; n = 30), high‐likelihood children without ASD (HL‐Neg; n = 150), and low‐likelihood control children not meeting ASD diagnostic criteria (LL‐Neg; n = 94). Hierarchical linear regression was then used to examine the association between sensory responsivity scores in infancy and functional adaptive and cognitive outcomes at school age for children at high likelihood of ASD.ResultsDevelopment of sensory responsivity from infancy to later childhood is best estimated by the effects of chronological age and Group for Sensory Seeking and Hypo responsivity and the additional effect of the interaction of Group and chronological age for Total and Hyper responsivity. Early elevated Hypo responsivity and Sensory Seeking scores are negatively associated with later adaptive behavior but not cognitive level.ConclusionOverall, higher degrees of Sensory Seeking and Hypo sensory responsivity are detectable in autistic children's behavioral repertoires by 12 months of age and associate with reduced adaptive functioning in middle childhood. These results point to the potential importance of early detection and treatment implications of early sensory behaviors.

Abstract Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections.

AbstractIn this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.

Abstract Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

An inscription over the north entrance of what today is the Mayo Medical School Student Center reads “Non multa sed bona,” which translates to “Not many but good.” One might enjoy “a quickening of the homiletic pulse” while reflecting on the productive careers of surgeons William J. Mayo, Charles H. Mayo, Donald Guthrie, William L. Estes, Jr., and Harold L. Foss, their influences on each other and surgery in general, and the appropriateness of this Latin aphorism as a tribute to them and to what they as unique achievers accomplished in the practice of medicine—relatively few in numbers, but excellent.