Trisha Greenhalgh and colleagues argue that it is time to apply the precautionary principle

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The fundamental basis of muscle contraction ‘the sliding filament model’ (Huxley and Niedergerke, 1954; Huxley and Hanson, 1954) and the ‘swinging, tilting crossbridge-sliding filament mechanism’ (Huxley, 1969; Huxley and Brown, 1967) nucleated a field of research that has unearthed the complex and fascinating role of myosin structure in the regulation of contraction. A recently discovered energy conserving state of myosin termed the super relaxed state (SRX) has been observed in filamentous myosins and is central to modulating force production and energy use within the sarcomere. Modulation of myosin function through SRX is a rapidly developing theme in therapeutic development for both cardiovascular disease and infectious disease. Some 70 years after the first discoveries concerning muscular function, modulation of myosin SRX may bring the first myosin targeted small molecule to the clinic, for treating hypertrophic cardiomyopathy (Olivotto et al., 2020). An often monogenic disease HCM afflicts 1 in 500 individuals, and can cause heart failure and sudden cardiac death. Even as we near therapeutic translation, there remain many questions about the governance of muscle function in human health and disease. With this review, we provide a broad overview of contemporary understanding of myosin SRX, and explore the complexities of targeting this myosin state in human disease.This article has an associated Future Leaders to Watch interview with the authors of the paper.

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Rationale: Calcium transient analysis is central to understanding inherited and acquired cardiac physiology and disease. While the development of novel calcium reporters enables assays of CRISPR/Cas-9 genome edited pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and primary adult cardiomyocytes, existing calcium-detection technologies are often proprietary and require specialist equipment, while open source workflows necessitate considerable user expertise and manual input. Objective: We aimed to develop an easy to use open source, adaptable, and automated analysis pipeline for measuring cellular calcium transients, from image stack to data output, inclusive of cellular identification, background subtraction, photobleaching correction, calcium transient averaging, calcium transient fitting, data collation and aberrant behavior recognition. Methods and Results: We developed CalTrack, a MatLab based algorithm, to monitor fluorescent calcium transients in living cardiomyocytes, including isolated single cells or those contained in 3-dimensional tissues or organoids and to analyze data acquired using photomultiplier tubes or employing line scans. CalTrack uses masks to segment cells allowing multiple cardiomyocyte transients to be measured from a single field of view. After automatically correcting for photobleaching, CalTrack averages and fits a string of transients and provides parameters that measure time to peak, time of decay, tau, F max /F 0 and others. We demonstrate the utility of CalTrack in primary and iPSC-derived cell lines in response to pharmacological compounds and in phenotyping cells carrying hypertrophic cardiomyopathy variants. Conclusions: CalTrack, an open source tool that runs on a local computer, provides automated high-throughput analysis of calcium transients in response to development, genetic or pharmacological manipulations, and pathological conditions. We expect that CalTrack analyses will accelerate insights into physiologic and abnormal calcium homeostasis that influence diverse aspects of cardiomyocyte biology.

Objective: To explore if regional cerebral tissue oxygen saturation monitoring by near-infrared spectroscopy (NIRS) is feasible during neonatal resuscitation of very low birth weight (VLBW) infants after birth.Study Design: Cerebral tissue oxygen saturation was measured by NIRS in 51 VLBW infants (mean gestational age: 27.8 weeks) during the first 10 min after delivery.Result: A regional cerebral tissue oxygen saturation signal was available after a median (interquartile range) age of 52 (44 to 68) s. In three infants the signal was obtained after 10 min of age. After delivery cerebral tissue oxygen saturation rose continuously from 37 (31 to 49) % at 1 minute of age and reached a steady state in the range of 61 to 84% B7 min after birth. Percentiles of cerebral tissue oxygen saturation of this cohort of preterm infants are given. Conclusion:Cerebral tissue oxygen saturation monitoring is feasible during neonatal resuscitation of VLBW infants within the first minutes of life.

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