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The key biological "drivers" that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9-transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied., Competing Interests: This study was supported by research funds from the National Institutes of Health (R01HL147968, R01 HL155344), the Veterans Administration (AN # 4345132), and the Wilkinson Foundation to Dr Mann. Dr Diwan was supported by grants from the National Institutes of Health (HL107594, HL143431, and NS094692) and the Department of Veterans Affairs (I01BX004235). Dr Finck was supported by grants from the National Institutes of Health (R01 HL119225, P30 DK05634). Dr Kovacs was supported by grants from the National Institutes of Health (S10 OD028597). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

The role of immune checkpoints in the setting of tissue injury remains unknown. Using an experimental model of isoproterenol (ISO)-induced stress cardiomyopathy, we show that ISO-induced myocardial injury provokes tissue-autonomous up-regulation of the programmed death-1 (PD-1):programmed death ligand (PD-L) axis in cardiac resident innate immune cells and T cells. PD-1 signaling was responsible for modulating the acute inflammatory response, as well as normalization of impaired left ventricular structure and function after ISO injection. Necrotic cardiac extracts were sufficient to increase the expression of PD-1 in macrophages and T cells in vitro. Viewed together these studies suggest that the PD-1:PD-L signaling axis regulates immune responses to cardiac tissue injury and is important for restoring myocardial homeostasis., Competing Interests: This study was supported by research funds from the National Institutes of Health (R01HL147968, R01 HL155344, and S10 OD028597) the Veterans Administration (AN # 4345132), and the Wilkinson Foundation and Elissa and Paul Cahn. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

It is well established that elite football referees possess superior anticipatory skills in specific game scenarios such as when assessing foul situations. Referees might also have better anticipatory skills in other important scenarios such as when observing a long pass. In these often-occurring situations, a referee has to use visual information to anticipate the outcome of the pass, in particular to foresee any potential infringements that might occur when players battle for ball possession. However, little is known about if and how football referees might anticipate outcomes in these scenarios. The aim of the current study was therefore to analyse the visual anticipatory behaviour of football referees when long passes occur during actual football matches. Elite (N = 4) and sub-elite referees (N = 12) officiated an actual football match while wearing a mobile eye-tracker to analyse their gaze behaviour when long passes occurred (N = 196). The results revealed differences in the way that the elite and sub-elite referees tracked the ball and anticipated the outcome of the ball trajectories. The elite referees used a lower search rate (1.3 vs 1.8 fix/s; p < .05) and were more likely to direct their gaze towards the ball during the moment of kick (77 vs 52%; p < .05) and the early flight-phase of the pass (68 vs 45%; p < .05), and subsequently produced earlier anticipatory eye movements to the player(s) receiving the ball (at 50% vs 60% of the ball flight; p < .05). This earlier anticipation may help the elite referees to better pick-up relevant information about the receivers that could be vital in making adjudications about any potential infringement when the ball does arrive. Referee education programs can use the current study to highlight the importance of visual search behaviour and help referees to adapt a strategy that is beneficial for long-pass situations., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed., Methods: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone., Results: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P <0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone., Conclusions: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration.

Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea-hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double-blind, 4 way cross-over, placebo-controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (F Hypopnoea ) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R 2  = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally., Methods: Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs., Results: The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA., Conclusions: The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA., Impact: The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear. Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age. Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age. Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction., Objectives: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction., Methods: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan., Results: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance., Conclusions: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736)., Competing Interests: Funding Support and Author Disclosures Research reported in this publication was supported by the NHLBI of the NIH under award number U10 HL084904 (for the Coordinating Center) and award numbers U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for the Regional Clinical Centers). The NHLBI contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Novartis Pharmaceutical Corporation provided study drug and partial funding through its investigator-initiated trial program CLCZ696BUS04T, but did not contribute to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Neither the NHLBI nor Novartis Pharmaceutical Corporation were involved in manuscript submission. Dr Mann serves on the steering committee for the PARADISE-MI trial for Novartis; and is a member of the Scientific Advisory Board for MyoKardia. Dr Anstrom has received research support from the National Institutes of Health (NIH), Merck, Bayer, and PCORI. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Desvigne-Nickens is an employee of the NHLBI; and is a consultant for Novartis. Dr Hernandez has received research grants and consulting fees from AstraZeneca, Amgen, Bayer, Merck, and Novartis. Dr Braunwald has received research support through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and is a consultant for Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, Novo-Nordisk, and Verve. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study aimed to determine whether elite cricket umpires' decisions contribute to home advantage via leg-before-wicket decisions., Design: Leg-before-wicket decisions (n = 4971) from actual elite level cricket matches in Australia between 2009 and 2016 were analysed using a binomial logistic regression to predict the umpires' leg-before-wicket decisions., Methods: Regressions were performed to determine whether the batter's team (home or away) influenced the likelihood that the umpire would give them out leg-before-wicket., Results: We found no evidence of home advantage in umpires' leg-before-wicket decisions. In fact, we found evidence that umpires in some instances disadvantage the home team., Conclusions: We suggest that the increased professionalism of sports officials, and the scrutiny they are placed under, may lead umpires to reduce or even overcompensate for any existing biases in their decision making., (Copyright © 2022 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

There is a need for alternatives to positive airway pressure for the treatment of obstructive sleep apnea and snoring. Improving upper airway dilator function might alleviate upper airway obstruction. We hypothesized that transoral neuromuscular stimulation would reduce upper airway collapse in concert with improvement in genioglossal muscle function. Subjects with simple snoring and mild OSA (AHI < 15/h on screening) underwent in-laboratory polysomnography with concurrent genioglossal electromyography (EMGgg) before and after 4-6 weeks of twice-daily transoral neuromuscular stimulation. Twenty patients completed the study: Sixteen males, mean ± SD age 40 ± 13 years, and BMI 26.3 ± 3.8 kg/m 2 . Although there was no change in non-rapid eye movement EMGgg phasic (p = 0.66) or tonic activity (p = 0.83), and no decrease in snoring or flow limitation, treatment was associated with improvements in tongue endurance, sleep quality, and sleep efficiency. In this protocol, transoral neurostimulation did not result in changes in genioglossal activity or upper airway collapse, but other beneficial effects were noted suggesting a need for additional mechanistic investigation., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Talent identification in football is complex. Research regarding talent indicators that predict selection into professional academies is increasingly multi-disciplinary, though is typically cross-sectional, failing to consider whether the rate of change of those indicators influences selection. The aim of this study was to determine if longitudinal changes in talent indicators are associated with selection into a professional football academy. A total of 110 Dutch male football players (aged 8-12) playing in a youth development programme of a professional club were included in the study. Players were assessed regularly on their anthropometry, physical fitness, gross motor coordination, technical ability, and psychosocial capacities over four years. A subset of players was then selected into the academy. Cross-sectional and longitudinal analyses revealed the indicators that best predicted selection. The best indicator was the 30 m sprint speed, with prediction not improving when including other predictors or their rate of change. The individuals that the club ultimately selected at age 12 could have been predicted well above chance levels using the sprint speeds at age nine or ten. The relative consistency of the rate of improvement in indicators across participants meant that the rate at which they developed played little role in selections.

Background: The Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes., Methods and Results: HF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan-Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52-5.24; adjusted HR 3.41, 95% CI 1.79-6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14-3.41; adjusted HR 2.11, 95% CI 1.21-3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004)., Conclusions: The HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population., (Copyright © 2021. Published by Elsevier Inc.)

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery., Competing Interests: DG is a biostatistician and has been an employee of Cardiovascular Clinical Studies Foundation LLC (CCSF), the contract research organization (CRO) that has been contracted by LivaNova, United States Incorporated, for ANTHEM-HFrEF Pivotal Study operations. JU is contracted to CCSF as a cardiovascular consultant. JM is contracted to CCSF for statistical consultation. MK is contracted to CCSF and LivaNova, respectively, as a cardiovascular consultant. JA is contracted to LivaNova as a neurocardiology consultant. JB, HK, MK, DM, GD, JP, JT, and JU are contracted to LivaNova as members of the ANTHEM-HFrEF Pivotal Study Steering Committee. IL and LD are employees and shareholders of LivaNova, United States Incorporated. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Konstam, Mann, Udelson, Ardell, De Ferrari, Cowie, Klein, Gregory, Massaro, Libbus, DiCarlo, Butler, Parker and Teerlink.)

Background: Paralympic swimmers with vision impairment (VI) currently compete in one of the three classes depending on their visual acuity (VA) and/or visual field. However, there is no evidence to suggest that a three-class system is the most legitimate approach for classification in swimming, or that the tests of VA and visual field are the most suitable. An evidence-based approach is required to establish the relationship between visual function and performance in the sport. Therefore, the aim of this study was to establish the relationship between visual function and performance in VI Para swimming. The swimming performance of 45 elite VI swimmers was evaluated during international competitions by measuring the total race time, start time, clean swim velocity, ability to swim in a straight line, turn time, and finish time. Visual function was measured using a test battery that included VA, contrast sensitivity, light sensitivity, depth perception, visual search, and motion perception., Results: Results revealed that VA was the best predictor of total race time (r = 0.40, p < 0.01), though the relationship was not linear. Decision tree analysis suggested that only two classes were necessary for legitimate competition in VI swimming, with a single cut-off between 2.6 and 3.5 logMAR. No further significant association remained between visual function and performance in either of the two resulting classes (all |rs|< 0.11 and ps > 0.54)., Conclusions: Results suggest that legitimate competition in VI swimming requires one class for partially sighted and another for functionally blind athletes., (© 2022. The Author(s).)

When using a bimanual tool to strike an object, most people place their preferred hand closer to the striking end. In sports, a player is deemed to adopt a "right- or left-handed" stance depending on the hand that is lower on the club or bat. Research has suggested there is an advantage in going against this convention by placing the preferred hand at the top in a "reversed-stance". This study aimed to establish if the reversed-stance advantage exists in golf, whether it is underpinned by the preferred hand or dominant eye, and why players adopt such a stance. We tested hand preference, eye dominance, and full swing stance in 150 golfers (30 for each handicap category) and conducted follow-up interviews with 12 reversed-stance players. Professional or category 1 golfers were 21.5 times more likely to adopt a reversed-stance. The advantage could not be explained by ambidexterity or the dominant eye but could be explained by the position of the preferred hand. Reversed-stance players cited a variety of reasons for adopting it and were more likely to display a left-hand preference. Findings offer initial evidence of a reversed-stance advantage in golf and can inform work identifying its origins and mechanisms.

Introduction: Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory., Methods: REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook., Results: Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p = .006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p = .006) during the year after Early Relook., Conclusions: Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies., Competing Interests: Disclosure P.S. reports the following grant support: American Heart Association/Enduring Hearts Scientist Development Grant, Merck, Haemonetrics, and Medtronic. Consulting: NuPulse CV and Ortho Clinical Diagnostics. K.D.A. reports the following related to the submitted work: the National Institutes of Health/National Heart, Lung, and Blood Institute (contract) and outside the submitted work: Medtronic (research support and consultant [Independent Physician Quality Panel member]), Abbott (research support), Procyrion (consultant), NuPulseCV (consultant), Bioventrix (research support). M.K., A.V.A., S.P., J.T., N.A.G., G.A.E., J.S., M.P., J.D.E., J.T.B., W.T.P., T.M.C., N.J., L.W.S., D.L.M., G.C.S., M.Y., B.R., and S.K have no conflicts of interest to disclose., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population., Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms., Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk., Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy., Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy., Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns., Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels., Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.

Mitochondria are essential for cardiac myocyte function, but damaged mitochondria trigger cardiac myocyte death. Although mitophagy, a lysosomal degradative pathway to remove damaged mitochondria, is robustly active in cardiac myocytes in the unstressed heart, its mechanisms and physiological role remain poorly defined. We discovered a critical role for TRAF2, an innate immunity effector protein with E3 ubiquitin ligase activity, in facilitating physiological cardiac myocyte mitophagy in the adult heart, to prevent inflammation and cell death, and maintain myocardial homeostasis., Competing Interests: This study was supported by National Institutes of Health (NIH) grant HL107594 and by the Hope Center Viral Vectors Core at Washington University School of Medicine. Experiments were performed in part through the use of Washington University Center for Cellular Imaging supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital grants CDI-CORE-2015-505 and CDI-CORE-2019-813; and the Foundation for Barnes-Jewish Hospital grants 3770 and 4642. Dr Rawnsley is supported by NIH grant T32 HL007081. Dr Javaheri is supported by NIH grants K08HL138262 and 1R01HL155344; by the Children's Discovery Institute of Washington University (MC-FR-2020-919) and St. Louis Children's Hospital, as well as the Diabetes Research Center grant P30DK020579; and the Nutrition Obesity Research Center at Washington University grant P30DK056341. Dr Mani was supported by a Seed Grant from the St. Louis VA Medical Center and by a Pilot and Feasibility grant from the Diabetes Research Center at Washington University (NIDDK grant No. P30 DK020579). Dr Abhinav Diwan is supported by NIH grants HL143431 and NS094692, and the Department of Veterans Affairs grant I01BX004235. Dr Mani serves as a member of the Cardiovascular Scientific Advisory Board at Dewpoint Therapeutics. Dr Abhinav Diwan provides consulting services to ERT systems for interpretation of echocardiograms in clinical trials; and serves as a member of the Cardiovascular Scientific Advisory Board at Dewpoint Therapeutics. These interests are not related to and did not influence the current study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Study Objectives: The presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep., Methods: A library of 117,871 breaths (N = 40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen's ƙ); and overnight flow limitation frequency (R2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive., Results: The model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ = 0.572, p < 0.001) and minimal error (overnight flow limitation frequency R2 = 0.86, error = 7.2%). Flow limitation frequency was largely independent of AHI (R2 = 0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI > 15/h, N = 22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R2 = 0.26-0.29; R2 < 0.01 AHI v. drive)., Conclusions: Our method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive. Clinical trial registration: The current observational physiology study does not qualify as a clinical trial., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking., Methods: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first., Results: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group., Conclusions: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.)., (Copyright © 2021 Massachusetts Medical Society.)

Objectives: The visibility of the pink ball used in day/night Test cricket has been under scrutiny, with recent research suggesting cricketers find the pink ball less visible at dusk under floodlights. With increasing interest in this match format, this study sought to investigate elite umpires' opinions pertaining to the visibility of the pink cricket ball during day/night matches., Design: Purposeful sampling of a cross-section of elite umpires with experience adjudicating matches played using a pink cricket ball., Methods: Twenty-seven international/first-class umpires completed a questionnaire consisting of Likert scale and free text responses covering perceptions of the pink cricket ball, with a particular emphasis on visibility., Results: The pink ball when viewed at night under floodlights was rated as being significantly more visible than the red ball during natural lighting (ps<0.050). Umpires who actively participated in training reported a significantly higher rating of the visibility of the pink ball (mean -3.14) at night under floodlights compared to those who didn't (mean p=0.010). No significant difference was reported in visibility in natural light or dusk under floodlights. Free text responses (n=10) revealed the following themes: use of eyewear (coverage 0.30), and adjustment to positioning (coverage 0.20) to improve visibility of the pink ball., Conclusions: Umpires report the visibility of the pink ball is equal to the red in natural light and at dusk but is significantly better at night. Preference for the pink ball is likely due to the predominantly perceptual nature of visual tasks performed by umpires., (Copyright © 2021 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Classification within the sport of vision impairment (VI) shooting is based upon the athlete's visual function. This study aimed to determine whether more than one class of competition is needed within VI shooting on the basis of visual field loss. Qualification scores of 23 elite athletes were obtained at World Championship events in prone and standing shooting disciplines. Visual field data were obtained from classification data and from assessment at events. A standardized scoring protocol determined whether athletes had function (≥10 dB) or no function (<10 dB) at locations between 0-60 degrees eccentricity along 10 meridia. Visual field function was not associated with shooting performance in prone or standing disciplines (p > 0.05). Having measurable visual field function beyond 30 degrees made no difference to athletes' ability to shoot competitively in prone (p = 0.65) or standing disciplines (p = 0.47), although a potential impact on qualification was observed in the standing discipline. There was no evidence that loss of visual field function at any specific location adversely affected ability to shoot competitively. There is currently no evidence to consider visual fields in classification within prone or standing VI shooting, although further research is needed as the sport grows.

This study aimed to establish the optimal cut-off point(s) between classes in a new, evidence-based classification system for VI judo. We collected results from international VI judo competitions held between 2012 and 2018. Data on visual acuity (VA) and visual field (VF) measured during classification were obtained. Performance was determined by calculating a win ratio for each athlete. VA was significantly associated with judo performance (r = -.33, p <.001), VF was not (r =.30, p =.15). Decision tree analysis suggested to split the data into two groups with a VA cut-off of 2.5 logMAR units. Stability assessment using bootstrap sampling suggested a split into two groups, but showed considerable variability in the cut-off point between 2.0 and 3.5 logMAR. We conclude that to minimise the impact of impairment on the outcome of competition, VI judo should be split into two sport classes to separate partially sighted from functionally blind athletes. To establish an exact cut-off point and to decide if other measures of visual function need to be included, we argue for continued research efforts together with careful evaluation of research results from a multidisciplinary perspective.

The International Paralympic Committee (IPC) and individual sports federations have established the need to develop evidence-based systems of classification for athletes with vision impairment (VI) that may differ depending on the visual demands of each sport. As a consequence, research has been conducted that led to a new classification system for athletes competing in VI shooting. The purpose of this study was to canvas the experiences of key stakeholders (athletes, coaches and classifiers) when the new system of classification was implemented. Twenty-eight participants (17 athletes, 7 coaches and 4 classifiers) completed a questionnaire to rate their experiences of the previous and new classification systems and were interviewed to gain richer insights into their opinions. It was apparent that the changes to the classification system were not adequately communicated to the athletes in particular, and that the classifiers may require a better understanding of the principles of evidence-based classification. The new system was perceived to be significantly more specific for VI shooting and intentional misrepresentation was observed to be significantly less likely than when using the old system. This research provides valuable insights into both the positive and negative experiences of key stakeholders experiencing change in a classification system.

In Paralympic judo for athletes with vision impairment (VI judo) all eligible athletes (i.e. B1, B2 and B3 classes) compete against each other in the same competition. Evidence suggests that athletes with more impairment may be disadvantaged, but that more sensitive measures of performance are necessary to understand the impact of impairment on performance. The aim of this study was to investigate the relationship between Para sport class and technical variation, time-motion variables, and performance in Paralympic judo. All 175 judo matches from the Rio 2016 Paralympic Games were analysed across 129 competitors (82 male and 47 female). The main results indicated that athletes who demonstrated less technical variation also experienced less competitive success, with the functionally blind athletes (class B1) demonstrating less technical variation than partially sighted (class B2 and B3) athletes (p < 0.05). There was no difference in the time-motion variables between sport classes (p > 0.05). We conclude that measures of technical variation are sensitive to differences in impairment and are suitable for studies that investigate the impairment-performance relationship in VI judo. Results further confirm that some athletes with impairment are disadvantaged under the current rules of VI judo.

In Para sport, the aim of classification is to minimize the impact of impairment on the outcome of competition. Despite requirements of the International Paralympic Committee Athlete Classification Code for classification to be evidence-based and sport-specific, sports for athletes with VI, including football, use the same generic classes across almost all sports. The aim of this study was to consult with experts to establish the needs and challenges for developing a code-compliant system of classification for VI football. A panel of 18 experts with international experience in VI football (16.8 ± 10.2 years) took part in a three-round Delphi study using online surveys. Results showed that the panel did not think that the current system completely fulfils the aim of classification. The panel identified measures of visual function they considered to be relevant but are not currently measured during classification including dynamic acuity, depth and motion perception, and contrast and light sensitivity. Moreover, they identified technical skills such as ball control, dribbling and passing, as well as perceptual-cognitive skills, as most likely to be affected by vision impairment. Findings outline the need for change and offer a framework for future research to develop an evidence-based classification for VI football.

Background Heart failure (HF) imposes significant burden on patients and caregivers. Longitudinal data on caregiver health-related quality of life (HRQOL) and burden in ambulatory advanced HF are limited. Methods and Results Ambulatory patients with advanced HF (n=400) and their participating caregivers (n=95) enrolled in REVIVAL (Registry Evaluation of Vital Information for VADs [Ventricular Assist Devices] in Ambulatory Life) were followed up for 24 months, or until patient death, left ventricular assist device implantation, heart transplantation, or loss to follow-up. Caregiver HRQOL (EuroQol Visual Analog Scale) and burden (Oberst Caregiving Burden Scale) did not change significantly from baseline to follow-up. At time of caregiver enrollment, better patient HRQOL by Kansas City Cardiomyopathy Questionnaire was associated with better caregiver HRQOL ( P =0.007) and less burden by both time spent ( P <0.0001) and difficulty ( P =0.0007) of caregiving tasks. On longitudinal analyses adjusted for baseline values, better patient HRQOL ( P =0.034) and being a married caregiver ( P =0.016) were independently associated with better caregiver HRQOL. Patients with participating caregivers (versus without) were more likely to prefer left ventricular assist device therapy over time (odds ratio, 1.43; 95% CI, 1.03-1.99; P =0.034). Among patients with participating caregivers, those with nonmarried (versus married) caregivers were at higher composite risk of HF hospitalization, death, heart transplantation or left ventricular assist device implantation (hazard ratio, 2.99; 95% CI, 1.29-6.96; P =0.011). Conclusions Patient and caregiver characteristics may impact their HRQOL and other health outcomes over time. Understanding the patient-caregiver relationship may better inform medical decision making and outcomes in ambulatory advanced HF.

Objective: The global trends in myocarditis burden over the past two decades remain poorly understood and might be increasing during the coronavirus disease 2019 (COVID-19) worldwide pandemic. This study aimed to provide comprehensive estimates of the incidence, mortality, and disability-adjusted life years (DALYs) for myocarditis globally from 1990 to 2017. Methods: Data regarding the incidence, mortality, DALY, and estimated annual percentage change (EAPC) between 1990 and 2017 for myocarditis worldwide were collected and calculated from the 2017 Global Burden of Disease study. We additionally calculated the myocarditis burden distribution based on the Socio-Demographic Index (SDI) quintile and Human Development Index (HDI). Results: The incidence cases of myocarditis in 2017 was 3,071,000, with a 59.6% increase from 1990, while the age-standardized incidence rate (ASIR) was slightly decreased. The number of deaths due to myocarditis increased gradually from 27,120 in 1990 to 46,490 in 2017. The middle SDI quintile showed the highest number of myocarditis-related deaths. On the contrary, the global age-standardized death rate (ASDR) decreased with an overall EAPC of -1.4 [95% uncertainty interval (UI) = -1.8 to -1.0]. Similar to ASDR, the global age-standardized DALY rate also declined, with an EAPC of -1.50 (95% UI = -2.30 to -0.8) from 1990 to 2017. However, there was a 12.1% increase in the number of DALYs in the past 28 years; the middle SDI and low-middle SDI quintiles contributed the most to the DALY number in 2017. We also observed significant positive correlations between the EPAC of age-standardized rate and HDI for both death and DALY in 2017. Conclusions: Globally, the ASIR, ASDR, and age-standardized DALY rate of myocarditis decreased slightly from 1990 to 2017. The middle SDI quintile had the highest level of ASIR, ASDR, and age-standardized DALY rate, indicating that targeted control should be developed to reduce the myocarditis burden especially based on the regional socioeconomic status. Our findings also provide a platform for further investigation into the myocarditis burden in the era of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Bu, Wei, Liu, Yang, Mann, Ma and Hayashi.)

Significance: Paralympic judo currently requires all athletes to compete against each other in one class irrespective of their level of vision impairment (VI). Recent evidence suggests that multiple classes are required to enhance fairness, yet it remains unclear how many classes are necessary and what vision tests should be used to define those classes., Purpose: The aim of this study was to quantify the relationship between vision and performance in judo for individuals with VI. The results were expected to inform the development of evidence-based criteria to structure Paralympic judo competition., Methods: The visual function of 53 elite VI judokas was assessed using a test battery that included tests of visual acuity (VA), contrast sensitivity, light sensitivity, depth perception, motion perception, visual search, and central visual field. Performance was assessed by measuring the ratio of fights won across all competitions the participants took part in in the 2 years before and after vision testing. Pearson correlation coefficients and decision tree analyses were used to determine the relationship between vision and performance. Partial correlations were also conducted to determine the unique ability of each measure of visual function to predict judo performance., Results: Visual acuity was the best predictor of judo performance and remained the only visual function related to performance when controlling for correlations between VA and other visual functions. Decision tree analyses suggested to split athletes into two groups for more legitimate competition, using a cutoff point around 2.6 logMAR. Within each of the two resulting subgroups, no correlations remained between any of the visual functions and performance., Conclusions: The results of this study suggest that VI judo competition should be split into separate categories for partially sighted and functionally blind athletes. The inclusion of visual functions in addition to VA does not improve the ability to predict performance in VI judo., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2021 American Academy of Optometry.)

Significance: The two-visual-system hypothesis (TVSH) provides a framework for understanding the nature of the visual information athletes are likely to rely on during competition. If valid, the framework provides a valuable means of evaluating the likely efficacy of different vision training tools that claim to improve the sport performance of athletes.The TVSH has been used to explain that many of the existing methods of testing and training vision may be ineffective to improve on-field sport performance. The TVSH suggests that the visual pathway used to control actions on-field may be different-and rely on different visual information-to the pathway often tested and trained off-field. However, the central claims of the TVSH are increasingly questioned, and this has implications for our understanding of vision and sport performance. The aim of this article is to outline the implications of the TVSH for the visual control of actions in sport. We first provide a summary of the TVSH and outline how the visual information used to control actions might differ from that usually tested. Second, we look at the evidence from studies of sports that are (and are not) consistent with the TVSH and the implications they have for training vision. Finally, we take a wider look at the impact of the TVSH on the sport sciences and other complementary theories that hold implications for training vision to improve sport performance., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2021 American Academy of Optometry.)