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To determine age-matched death rates of current and retired elite male Australian football players (Australian and/or Victorian Football League) with the general population. Analysis of publicly-available birth, debut and death data for all Australian Victorian Football/Victorian Football League players who debuted prior to (and were still alive at) the start of 1971 or debuted 1971–2020. Wikipedia was used to source the dates of death (or record that the player was alive in 2021) for the cohort. New players became part of the cohort for analysis on debut and existing cohort members left it at death. Actual death rates (per year and per decade) were then compared to expected deaths, based on age-specific population death rates. There were 5400 players and ex-players in the cohort at the start of 1971 (average age 47.3) and a further 4532 players debuted between 1971 and 2020 inclusive (a total of 9932 players). The expected deaths for the cohort in this 50-year period were 4955, but only 3914 deaths occurred (Standardized Mortality Ratio 0.79, 95 %CI 0.76–0.82). For younger members of the cohort (age <50) the discrepancy between expected (222) and actual (98) deaths was also significant (Standardized Mortality Ratio 0.44, 95 %CI 0.35–0.56). We conclude that the death rates of elite male Australian footballers are lower than the reference general population, similar to other studies of elite athletes. Some of this may be explained by “healthy cohort” selection bias, a limitation which affects almost all studies in this genre.

Abstract Background While athletes are generally very fit, intense exercise can increase the risk of atrial fibrillation. Moreover, other arrhythmias such as atrial flutter or supraventricular tachycardia can cause distressing, exercise-related symptoms. Given symptoms are infrequent and may occur during intense exertion, traditional monitoring devices are often impractical to use during exercise. Smartphone electrocardiograms (ECGs) such as the Alivecor Kardia device may be the portable and reliable tool required to help identify arrhythmias in this challenging population. This case series highlights the use of such devices in aiding the diagnosis of arrhythmias in the setting of exercise-related symptoms in athletes. Case summary The six cases in this series included one elite non-endurance athlete, two elite cricketers, one amateur middle-distance runner, and two semi-elite ultra-endurance runners, with an age range of 16–48 years. An accurate diagnosis of an arrhythmia was obtained in five cases (atrial fibrillation/flutter and supraventricular tachycardias) using the smartphone ECG, which helped guide definitive treatment. No arrhythmia was identified in the final case despite using the device during multiple symptomatic events. Discussion The smartphone ECG was able to accurately detect arrhythmias and provide a diagnosis in cases where traditional monitoring had not. The utility of detecting no arrhythmia during symptoms in one case was also highlighted, providing the athlete with the confidence to continue exercising. This reassurance and confidence across all cases is perhaps the most valuable aspect of this device, where clinicians and athletes can be more certain of reaching a diagnosis and undertaking appropriate management.

To report the compliance and results of an electrocardiogram (ECG) cardiac screening program in male and female elite Australian cricketers. cross-sectional study. Elite cricketers were offered screening in accordance with Cricket Australia policy. Players who consented provided a personal and family history, physical examination and resting 12-lead ECG. An audit (1 February 2019) examined all cardiac screening records for male and female players in all Australian Cricket state squads from 16 years upwards. Data extracted from the Cricket Australia database included the number of players who underwent screening; signed waivers opting out; and had follow-up tests. ECGs were re-reviewed according to the International Criteria. 710 players were included in the cohort (mean age 20.4±4.9 years, 62% male). 692 (97.5%) players underwent recommended cardiac screening or signed a waiver opting out (1.1%). 173 (24.4%) players were screened (or signed a waiver) more than once. Follow-up testing was conducted for 59 (6.9%) cases. No players were excluded from sport due to a cardiac problem and no major cardiac incidents occurred to any player in the audit cohort. Review of 830 ECGs showed benign athlete heart changes, including sinus bradycardia (33.5%), left ventricular hypertrophy (16.3%), and incomplete/partial right bundle branch block (8.4%), were common but abnormal screening ECGs were uncommon (2.0%). An audit of a cardiac screening program in elite Australian cricketers found excellent compliance. A small proportion required follow-up testing and no player was excluded from sport due to a cardiac problem. ECG analysis suggested cricket is a sport of moderate cardiac demands, with benign athlete heart changes common.

Background One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as “genetic constraint”. Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. Methods We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. Results We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. Conclusions Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2 −/− animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2 −/− animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival. In vitro studies have suggested that the ubiquitin ligase, Nedd4-2, regulates several proteins, including the epithelial sodium channel. Here by examining Nedd4-2-deficient mice, the authors demonstrate that Nedd4-2 is essential for epithelial sodium channel regulation, fetal and postnatal lung function and animal survival.

Keywords: Cardiac Magnetic Resonance, Aortic Stenosis, Late Gadolinium Enhancement, Outflow Tract, Hypertrophic Cardiomyopathy

Background: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. Methods: We present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets. Results: CardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant variant classification. Conclusions: We demonstrate that a disease-specific variant pathogenicity prediction tool outperforms state-of-the-art genome-wide tools for the classification of rare missense variants of uncertain significance for inherited cardiac conditions. To facilitate evaluation of CardioBoost, we provide pre-computed pathogenicity scores for all possible rare missense variants in genes associated with cardiomyopathies and arrhythmias (https://www.cardiodb.org/cardioboost/). Our results also highlight the need to develop and evaluate variant classification tools focused on specific diseases and clinical application contexts. Our proposed model for assessing variants in known disease genes, and the use of application-specific evaluations, is broadly applicable to improve variant interpretation across a wide range of Mendelian diseases.

A typical can of energy drink contains up to 300 milligrams of caffeine, from added caffeine and natural sources such as guarana, but importantly, in volumes far less than a litre - usually 200 millilitres or less. This includes \"energy shots\", which clearly also don't meet the requirements of Standard 2.6.4. Many energy drinks are also marketed as \"dietary supplements\" or \"conventional foods\" in an attempt to circumvent standard requirements of both the FDA and FSANZ.