Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells' electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca 2+ transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation. Here, we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived experimental tissues.

Individually personalized computational models of heart mechanics can be used to estimate important physiological and clinically‐relevant quantities that are difficult, if not impossible, to directly measure in the beating heart. Here, we present a novel and efficient framework for creating patient‐specific biventricular models using a gradient‐based data assimilation method for evaluating regional myocardial contractility and estimating myofiber stress. These simulations can be performed on a regular laptop in less than 2 h and produce excellent fit between measured and simulated volume and strain data through the entire cardiac cycle. By applying the framework using data obtained from 3 healthy human biventricles, we extracted clinically important quantities as well as explored the role of fiber angles on heart function. Our results show that steep fiber angles at the endocardium and epicardium are required to produce simulated motion compatible with measured strain and volume data. We also find that the contraction and subsequent systolic stresses in the right ventricle are significantly lower than that in the left ventricle. Variability of the estimated quantities with respect to both patient data and modeling choices are also found to be low. Because of its high efficiency, this framework may be applicable to modeling of patient specific cardiac mechanics for diagnostic purposes.

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The objective of this transformative action research project was to explore and develop sustainable methods to promote female empowerment through science education in rural, disadvantaged sectors of South Africa. In an attempt to achieve this we collaborated with local community members to develop and implement a contextualized science curriculum at a school in the aforementioned setting. As soon as the project was launched it became increasingly clear that although the ideology of 'empowerment through science education' seemed a promising venture, it could also be an extremely complex and often frustrating undertaking. This was especially true when working within an unfamiliar cultural setting. Numerous challenges, such as the lack of teacher motivation, malnutrition amongst the learners, and conflicts stemming from differences between the indigenous knowledge and the western concept of science, greatly impeded the delivery of quality education in the area. These challenges had to be addressed both in pedagogical and practical terms before any attempt towards libratory education could be made. This article sheds light on the complex inter-relationship between the human factor and the organizational and physical infrastructure at a school. It begins with a brief description of the local context and goes on to identify the theoretical underpinnings and chosen methodology for the project. The article concludes with a review of the complexities involved in possible attempts to initiate and foster educational and social transformations in a rural South African setting. We contend that it is essential to first be thoroughly familiar with the background, culture, and needs of any community before any attempts are made towards social justice.

Cardiomyocytes derived from human induced pluripotent stem cells hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of cells' electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for mature cells based on changes in optical measurements of action potentials and Ca 2+ transients made in stem cell derived cardiac microtissues. This methodology quantifies ion channel changes through the inversion of data into a mathematical model, and maps this response to a mature phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation.Here we utilize an updated action potential model to represent both immature and mature cells, apply an IC50-based model of dosedependent drug effects, and introduce a continuation-based optimization algorithm for analysis of dose escalation measurements using five 1 drugs with known effects. The improved methodology can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodology is a step towards employing computational procedures to elucidate drug effects in mature cardiomyocytes for new drugs using stem cell-derived experimental tissues. Flux Description J sl s Flux through the RyRs from the jSR to the SL J n c Flux through the SERCA pumps from the bulk cytosol to the nSR J c d Passive diffusion flux between the dyad and the bulk cytosol J c sl Passive diffusion flux between the SL and the bulk cytosol J s n Passive diffusion flux between the nSR and the jSR J b d Free Ca 2+ binding to a buffer in the dyad J b sl Free Ca 2+ binding to a buffer in the SL J b c Free Ca 2+ binding to a buffer in the bulk cytosol J b s Free Ca 2+ binding to a buffer in the jSR J CaL Ca 2+ -flux through the L-type Ca 2+ channels from the extracellular space to the dyad J bCa Background Ca 2+ flux from the extracellular space to the SL J pCa Ca 2+ flux through the Ca 2+ pump between the extracellular space and the SL J NaCa Ca 2+ flux through the Na + -Ca 2+ exchanger between the extracellular space and the SL J sl e Total Ca 2+ flux from the extracellular space to the SL, defined as J sl e = J bCa + J pCa + J NaCa .

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH ( n = 12) and controls ( n = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements. The optimized parameters were compared with clinical metrics to find usable indicators associated with the underlying mechanical changes. Peak contractility of the RV free wall (RVFW) γRVFW,max was found to be strongly correlated and had an inverse relationship with the RV and left ventricle (LV) end-diastolic volume ratio (i.e., RVEDV/LVEDV) (RVEDV/LVEDV)+ 0.44, R2 = 0.77). Correlation with RV ejection fraction ( R2 = 0.50) and end-diastolic volume index ( R2 = 0.40) were comparatively weaker. Patients with with RVEDV/LVEDV > 1.5 had 25% lower γRVFW,max ( P < 0.05) than that of the control. On average, RVFW passive stiffness progressively increased with the degree of remodeling as indexed by RVEDV/LVEDV. These results suggest a mechanical basis of using RVEDV/LVEDV as a clinical index for delineating disease severity and estimating RVFW contractility in patients with PAH. NEW & NOTEWORTHY This article presents patient-specific data assimilation of a patient cohort and physical description of clinical observations.

Despite global efforts, it took 7 months between the proclamation of global SARS-CoV-2 pandemic and the first FDA-approved treatment for COVID-19. During this timeframe, clinicians focused their efforts on repurposing drugs, such as hydroxychloroquine (HCQ) or azithromycin (AZM) to treat hospitalized COVID-19 patients. While clinical trials are time-consuming, the exponential increase in hospitalizations compelled the FDA to grant an emergency use authorization for HCQ and AZM as treatment for COVID-19, although there was limited evidence of their combined efficacy and safety. The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially ineffective or unsafe therapeutics, while diverting resources from screening of effective drugs. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to rapidly identify clinically relevant cardiac liabilities associated with HCQ and AZM. The cardiac MPS is a microfabricated fluidic system in which cardiomyocytes derived from human induced pluripotent stem cells self-arrange into a uniaxially beating tissue. The drug response was measured using outputs that correlate with clinical measurements such as action potential duration (proxy for clinical QT interval) and drug-biomarker pairing. The cardiac MPS predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities in tissues treated with HCQ. We found no change in QT interval upon acute exposure to AZM, while still observing a significant increase in arrhythmic events. These results suggest that this MPS can not only predict arrhythmias, but it can also identify arrhythmias even when QT prolongation is absent. When exposed to HCQ and AZM polytherapy, this MPS faithfully reflected clinical findings, in that the combination of drugs synergistically increased QT interval when compared to single drug exposure, while not worsening the overall frequency of arrhythmic events. The high content cardiac MPS can rapidly evaluate the cardiac safety of potential therapeutics, ultimately accelerating patients’ access to safe and effective treatments.

Only a handful of FDA Emergency Use Authorizations exist for drug and biologic therapeutics that treat SARS-CoV-2 infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock Phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements such as QT interval (action potential duration) and drug-biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onwards, and arrhythmias were observed at days 8 and 10.Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4-8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients' serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe COVID-19 therapeutics.