Consensus guidelines for improving quality of assessment and training for neuromuscular diseases

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center\u27s expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naïve to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings

Camilla: A Centaur reconnaissance and impact mission concept

Centaurs, minor planets with a semi-major axis between the orbits of Jupiter and Neptune (5–30 AU), are thought to be among the most diverse small bodies in the solar system. These important targets for future missions may have recently been Kuiper Belt Objects (KBOs), which are thought to be chemically and physically primitive remnants of the early solar system. While the Kuiper Belt spans distances of 30–50 AU, making direct observations difficult, Centaurs' proximity to the Earth and Sun make them more accessible targets for robotic missions. Thus, we outline a mission concept designed to reconnoiter 10199 Chariklo, the largest Centaur and smallest ringed body yet discovered. Named for a legendary Centaur tamer, the conceptual Camilla mission is designed to fit under the cost cap of the National Aeronautics and Space Administration (NASA) New Frontiers program, leveraging a conservative payload to support a foundational scientific investigation to these primitive bodies. Specifically, the single flyby encounter utilizes a combined high-resolution camera/VIS-IR mapping spectrometer, a sub-mm point spectrometer, and a UV mapping spectrometer. In addition, the mission concept utilizes a kinetic impactor, which would provide the first opportunity to sample the composition of potentially primitive subsurface material beyond Saturn, thus providing key insights into solar system origins. Such a flyby of the Chariklo system would provide a linchpin in the understanding of small body composition, evolution, and transport of materials in the solar system

Identification of functional differences between recombinant human α and β cardiac myosin motors

The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding

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