BackgroundImmune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.MethodsWe retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.ResultsAmong patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.ConclusionsRoutine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

We develop an adaptive controller for multi-joint, multi-muscle arm movements based on simplified spinal-like circuits found in the periphery, muscle synergies, and interpretations of gain-field projections from reach related neurons in the Superior Colliculus. The resulting innovation provides a highly robust sensory based controller that can be adapted to systems which require multi-muscle co-ordination. It provides human-like responses during perturbations elicited either internally or by the environment and for simple point-to-point reaching. We simulate limb motion and EMGs in Simulink using Virtual Muscle models and a variety of paradigms, including motion with external perturbations, and varying levels of antagonist muscle co-contractions. The results show that the system can exhibit smooth coordinated motions, without explicit kinematic or dynamic planning even in the presence of perturbations. In addition, we show by varying the level of muscle co-contractions from 0% to 40%, that the effects of external perturbations on joint trajectories can be reduced by up to 42%. The improved controller design is novel providing robust behavior during dynamic events and an automatic adaptive response from sensory-integration.

We use simulations of a controller that adopts a spinal-like network topology for goal-oriented reaching and assess its sensitivity to the dynamics of internal elements that allow context-independent performance. Such internal elements are often referred to as inverse or forward models of the periphery dynamics, depending on the proposed controller theory. Here, the "models" are used in a forward implementation, and we evaluate how the controller's performance would be affected by the nature of the model. For each point-to-point reaching motion experiment, we use forms of internal "efference models" (e.g., full mathematical representations of peripheral dynamics, simple spindle feedback, etc.) driven by motor reafference, then compare hand trajectories and hand path speeds in the presence or absence of external perturbations. It is demonstrated that a simple velocity-based model reduced the effects of dynamic perturbations by as much as 66%. In addition, the 2D hand trajectories varied from a biological reference by only 0.05 cm. Thus, the controller facilitated biological like motions while providing response to dynamic events which are omitted in earlier biomimetic controllers. This research suggests that these spinal-like systems are robust and tunable via gain-fields without the need of context dependent pre-planning.

Induction of neuroplasticity by transcranial direct current stimulation (tDCS) applied to the primary motor cortex facilitates motor learning of the upper extremities in healthy humans. The impact of tDCS on lower limb functions has not been studied extensively so far. In this study, we applied a system identification approach to investigate the impact of anodal transcranial direct current stimulation of the leg area of the motor cortex via the human visuo-myoelectric controller. The visuo-myoelectric reaching task (VMT) involves ballistic muscle contraction after a visual cue. We applied a black box approach using a linear ARX (Auto-regressive with eXogenous input) model for a visuomotor myoelectric reaching task. We found that a 20th order finite impulse response (FIR) model captured the TARGET (single input)—CURSOR (single output) dynamics during a VMT. The 20th order FIR model was investigated based on gain/phase margin analysis, which showed a significant (p < 0.01) effect of anodal tDCS on the gain margin of the VMT system. Also, response latency and the corticomuscular coherence (CMC) time delay were affected (p < 0.05) by anodal tDCS when compared to sham tDCS. Furthermore, gray box simulation results from a Simplified Spinal-Like Controller (SSLC) model demonstrated that the input-output function for motor evoked potentials (MEP) played an essential role in increasing muscle activation levels and response time improvement post-tDCS when compared to pre-tDCS baseline performance. This computational approach can be used to simulate the behavior of the neuromuscular controller during VMT to elucidate the effects of adjuvant treatment with tDCS.

Direct assessment of sunlight exposure can be challenging over extended periods or in multiple remote locations. We optimized liposome formulations that included egg and hydrogenated soy lipids as well as small amounts of a chlorophyll-derived phospholipid (PoP) to confer sunlight reactivity and triggered-release of entrapped dyes. Dye release occurred with PoP-mediated photooxidation of unsaturated phospholipids and could be tuned by varying the unsaturated (egg) to saturated (soy) lipid ratio or by varying the amount of PoP included. Numerous food coloring dyes were entrapped within the liposomes and, when applied onto a polyacrylamide gel, remained intact and immobilized for at least a month in the dark. When exposed to sunlight, the dyes were released and rapidly diffused through the gel, creating a detection system for assessing sunlight exposure by the naked eye based on dye diffusion. Acid Blue 9 and Acid Yellow 23 were particularly effective reporter food dyes in this system. By using liposomes with varying PoP amounts, light-induced dye release could be tuned to coincide with varying amounts of solar exposure. Additionally, exposure-dependent, color-coded release patterns were generated using colloidal mixtures of separately formed liposomes loaded with different dyes. Using customized 3D printed enclosures, a small and readily deployable device was created for visualizing solar-sensitive liposome sunlight reporting. These studies show proof-of-principle that PoP liposomes can serve as simple nonelectric reporters for visually assessing sunlight exposure based on diffusion of entrapped food coloring.