Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: Insights from the SHaRe Registry

Background: The term "end stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized. Methods: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development. Results: From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 1.3-2.8]). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively). Conclusions: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants)

Gravitational Radiation from Compact Binary Pulsars

An outstanding question in modern Physics is whether general relativity (GR) is a complete description of gravity among bodies at macroscopic scales. Currently, the best experiments supporting this hypothesis are based on high-precision timing of radio pulsars. This chapter reviews recent advances in the field with a focus on compact binary millisecond pulsars with white-dwarf (WD) companions. These systems - if modeled properly - provide an unparalleled test ground for physically motivated alternatives to GR that deviate significantly in the strong-field regime. Recent improvements in observational techniques and advances in our understanding of WD interiors have enabled a series of precise mass measurements in such systems. These masses, combined with high-precision radio timing of the pulsars, result to stringent constraints on the radiative properties of gravity, qualitatively very different from what was available in the past.Comment: Short review chapter to appear in "Gravitational Wave Astrophysics" by Springer-Verlag, edited by Carlos F. Sopuerta; v3: a few major corrections and updated references. Comments are welcome

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM

Globular cluster luminosity function as distance indicator

Globular clusters are among the first objects used to establish the distance scale of the Universe. In the 1970-ies it has been recognized that the differential magnitude distribution of old globular clusters is very similar in different galaxies presenting a peak at M_V ~ -7.5. This peak magnitude of the so-called Globular Cluster Luminosity Function has been then established as a secondary distance indicator. The intrinsic accuracy of the method has been estimated to be of the order of ~0.2 mag, competitive with other distance determination methods. Lately the study of the Globular Cluster Systems has been used more as a tool for galaxy formation and evolution, and less so for distance determinations. Nevertheless, the collection of homogeneous and large datasets with the ACS on board HST presented new insights on the usefulness of the Globular Cluster Luminosity Function as distance indicator. I discuss here recent results based on observational and theoretical studies, which show that this distance indicator depends on complex physics of the cluster formation and dynamical evolution, and thus can have dependencies on Hubble type, environment and dynamical history of the host galaxy. While the corrections are often relatively small, they can amount to important systematic differences that make the Globular Cluster Luminosity Function a less accurate distance indicator with respect to some other standard candles.Comment: Accepted for publication in Astrophysics and Space Science. Review paper based on the invited talk at the conference "The Fundamental Cosmic Distance Scale: State of the Art and Gaia Perspective", Naples, May 2011. (13 pages, 8 figures

Search for the decay B0 to gamma gamma

The rare decay B0 -> gamma gamma is searched for in 104 fb^-1 of data, corresponding to 111 x 10^6 BBar pairs, collected with the Belle detector at the KEKB asymmetric-energy e+ e- collider. No evidence for the signal is found, and an upper limit of 6.2 x 10^-7 at 90% confidence level is set for the corresponding branching fraction.Comment: 7 pages, 3 figures, accepted for publication by Phys. Rev.

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design

Importance Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero

Change and continuity in Japanese compensation practices: the case of occupational pensions since the early 2000s

This article analyses changes in the provision of Japanese occupational pensions since the early 2000s. It shows how Japanese companies have followed strategies of cost and risk reduction by creating multi-layered benefit systems that offer a combination of defined benefit (DB) and defined contribution (DC) plans whose benefits are becoming increasingly performance-oriented. Analysing the reasons behind the resilience of DB schemes in Japan, the article concludes that enterprise union behaviour has had less influence than regulatory issues and continued corporate commitment to long-standing employment practices for regular workers. These findings highlight the embeddedness of Japanese employment practices in their institutional context