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Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.

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Objective To highlight the role of interventional radiology (IR) in the treatment of patients hospitalized with coronavirus disease 2019 (COVID-19). Methods Retrospective review of hospitalized patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and had one or more IR procedures at a tertiary referral hospital in New York City during a 6-week period in April and May of 2020. Results Of the 724 patients admitted with COVID-19, 92 (12.7%) underwent 124 interventional radiology procedures (79.8% in IR suite, 20.2% at bedside). The median age of IR patients was 63 years (range 24–86 years); 39.1% were female; 35.9% in the intensive care unit. The most commonly performed IR procedures were central venous catheter placement (31.5%), inferior vena cava filter placement (9.7%), angiography/embolization (4.8%), gastrostomy tube placement (9.7%), image-guided biopsy (10.5%), abscess drainage (9.7%), and cholecystostomy tube placement (6.5%). Thoracentesis/chest tube placement and nephrostomy tube placement were also performed as well as catheter-directed thrombolysis of massive pulmonary embolism and thrombectomy of deep vein thrombosis. General anesthesia (10.5%), monitored anesthesia care (18.5%), moderate sedation (29.8%), or local anesthetic (41.1%) was utilized. There were 3 (2.4%) minor complications (SIR adverse event class B), 1 (0.8%) major complication (class C), and no procedure-related death. With a median follow-up of 4.3 months, 1.1% of patients remain hospitalized, 16.3% died, and 82.6% were discharged. Conclusion Interventional radiology participated in the care of hospitalized COVID-19 patients by performing a wide variety of necessary procedures.