A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.

The importance of professional responsibility and fetal viability in the management of abortion.

In June 2022, the Dobbs v. Jackson Women's Health Organization Supreme Court decision ended the constitutional right to the professional practice of abortion throughout the United States. The removal of the constitutional right to abortion has significantly altered the practice of obstetricians and gynecologists across the US. It potentially increases risks to pregnant patients, leads to profound changes in how physicians can provide care, especially in states with strict bans or gestational limits to abortion, and has introduced personal challenges, including moral distress and injury as well as legal risks for patients and clinicians alike. The professional responsibility model is based on the ethical concept of medicine as a profession and has been influential in shaping medical ethics in the field of obstetrics and gynecology. It provides the framework for the importance of ethical and professional conduct in obstetrics and gynecology. Viability marks a stage where the fetus is a patient with a claim to access to medical care. By allowing unrestricted abortions past this stage without adequate justifications, such as those concerning the life and health of the pregnant individual, or in instances of serious fetal anomalies, the states may not be upholding the equitable ethical consideration owed to the fetus as a patient. Using the professional responsibility model, we emphasize the need for nuanced, evidence-based policies that allow abortion management prior to viability without restrictions and allow abortion after viability to protect the pregnant patient's life and health, as well as permitting abortion for serious fetal anomalies.

Addressing challenges related to the professional practice of abortion post-Roe.

The landmark Roe vs Wade Supreme Court decision in 1973 established a constitutional right to abortion. In June 2022, the Dobbs vs Jackson Women's Health Organization Supreme Court decision brought an end to the established professional practice of abortion throughout the United States. Rights-based reductionism and zealotry threaten the professional practice of abortion. Rights-based reductionism is generally the view that moral or ethical issues can be reduced exclusively to matters of rights. In relation to abortion, there are 2 opposing forms of rights-based reductionism, namely fetal rights reductionism, which emphasizes the rights for the fetus while disregarding the rights and autonomy of the pregnant patient, and pregnant patient rights reductionism, which supports unlimited abortion without regards for the fetus. The 2 positions are irreconcilable. This article provides historical examples of the destructive nature of zealotry, which is characterized by extreme devotion to one's beliefs and an intolerant stance to opposing viewpoints, and of the importance of enlightenment to limit zealotry. This article then explores the professional responsibility model as a clinically ethically sound approach to overcome the clashing forms of rights-based reductionism and zealotry and to address the professional practice of abortion. The professional responsibility model refers to the ethical and professional obligations that obstetricians and other healthcare providers have toward pregnant patients, fetuses, and the society at large. It provides a more balanced and nuanced approach to the abortion debate, avoiding the pitfalls of reductionism and zealotry, and allows both the rights of the woman and the obligations to pregnant and fetal patients to be considered alongside broader ethical, medical, and societal implications. Constructive and respectful dialogue is crucial in addressing diverse perspectives and finding common ground. Embracing the professional responsibility model enables professionals to manage abortion responsibly, thereby prioritizing patients' interests and navigating between absolutist viewpoints to find balanced ethical solutions.

Identification of structures for ion channel kinetic models.

Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori.

Autonomy and Social Responsibility: The Post-Pandemic Challenge.

Over the last 80 years, a series of critical events has led to reconsideration of the basic premises of medical ethics. One of these events was the recognition of horrific medical experiments performed by German medical scientists in World War II concentration camps, resulting in intensified emphasis on a consent requirement, later understood as grounded in the bioethical principle of respect for autonomy, as well as on the moral accountability of the experimenter. Another important event that is forcing a reconsideration of respect for autonomy in medicine and health care is the COVID-19 pandemic. But this time the matter pulls in a different direction, from respect for autonomy to social responsibility, represented in problems as disparate as the wearing of masks, vaccination requirements, and equity in vaccine access and distribution. How can modern bioethics, in part a creature of the response to Nazi crimes, accommodate the intensified sensitivity about public health needs that has accompanied the shock of the pandemic? The responses of European medical ethics to the Nazi era provide tools for bioethics as it faces the challenge now at hand. This article uses historical context from postwar Europe to argue that, in light of the pandemic experience, respect for autonomy must systematically incorporate a commitment to social responsibility.

John Stuart Mill is relevant to COVID-19 vaccination in pregnancy today.

The scientific evidence about COVID-19 and pregnancy is conclusive: COVID-19 infections increase the risk of stillbirths and preterm births, and pregnant and postpartum patients are more likely to get severely ill with COVID-19 and die when compared with people who are not pregnant. Getting a COVID-19 vaccine protects from severe illness from COVID-19 and risk of death. COVID-19 vaccination is recommended for pregnant patients, those trying to conceive, and who are breastfeeding, or might become pregnant in the future. The justification for government involvement in public health measures that restrict personal liberty that we are so familiar with today emanated from a philosophical source at the same time as the progress in managing infectious disease. John Stuart Mill (1806-1873), an empiricist and a utilitarian, was not specifically addressing the ethics of public health in his classic On Liberty (1859), but his arguments have become the reference point for liberal democracies and public health measures. Mill was in search of a philosophical principle that could justify constraints on personal freedom. John Stuart Mill gives direct guidance to our approach supporting not only strong recommendations for pregnant patients to accept vaccinations against COVID-19 but also for those working in healthcare setting to be required to be vaccinated. This approach is respectful to our patient's liberty while doing all that's reasonable to protect them from harm. Based on our professional experience we recognize that some physicians and patients have fixed false beliefs. Physicians espousing fixed false beliefs against COVID-19 vaccines should be censured.

Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.

RATIONALE: Mutations in the SCN5A gene, encoding the α subunit of the Nav1.5 channel, cause a life-threatening form of cardiac arrhythmia, long QT syndrome type 3 (LQT3). Mexiletine, which is structurally related to the Na+ channel-blocking anesthetic lidocaine, is used to treat LQT3 patients. However, the patient response is variable, depending on the genetic mutation in SCN5A. OBJECTIVE: The goal of this study is to understand the molecular basis of patients' variable responses and build a predictive statistical model that can be used to personalize mexiletine treatment based on patient's genetic variant. METHODS AND RESULTS: We monitored the cardiac Na+ channel voltage-sensing domain (VSD) conformational dynamics simultaneously with other gating properties for the LQT3 variants. To systematically identify the relationship between mexiletine block and channel biophysical properties, we used a system-based statistical modeling approach to connect the multivariate properties to patient phenotype. We found that mexiletine altered the conformation of the Domain III VSD, which is the same VSD that many tested LQT3 mutations affect. Analysis of 15 LQT3 variants showed a strong correlation between the activation of the Domain III-VSD and the strength of the inhibition of the channel by mexiletine. Based on this improved molecular-level understanding, we generated a systems-based model based on a dataset of 32 LQT3 patients, which then successfully predicted the response of 7 out of 8 patients to mexiletine in a blinded, retrospective trial. CONCLUSIONS: Our results imply that the modulated receptor theory of local anesthetic action, which confines local anesthetic binding effects to the channel pore, should be revised to include drug interaction with the Domain III-VSD. Using an algorithm that incorporates this mode of action, we can predict patient-specific responses to mexiletine, improving therapeutic decision making.

Belmont in Context.

Given its outsized influence as a core document in bioethics, it is worth reminding ourselves of the historical context in which the Belmont Report came to be. This article examines the societal forces that helped bring about the Belmont Report and that shaped its conception of ethical research. A product of a public investigation that included many nonscientists and espoused philosophical principles, the Report internalized a growing call in the late 1960s for oversight over the research enterprise, which had long been the private realm of physician-investigators. Belmont helped bring about a regulatory and oversight apparatus to the research enterprise, as well as a language and discipline of bioethics that added a multidisciplinary set of voices and decision-makers to discussions of what constitutes ethical research. Because it reflected the spirit of protectionism engendered by events of the 1960s and 1970s, Belmont also helped emphasize the importance of informed consent and the protection of vulnerable populations. But because the Report was a product of its time, contingent on historical developments and highly publicized events, it is not necessarily responsive to new factors that now condition the research enterprise.

History, Morals, and Medicine.

This essay provides a rational reconstruction of the author's genetically inscribed inclination to do normative ethics with an historical bent and offers some reflections on the value of historical thinking for bioethics.

In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia.

KEY POINTS: The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear. Model predictions suggest that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during ß-adrenergic stimulation. Current treatment strategies include ß-blockade, flecainide and ICD implementation--none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na(+) channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na(+) channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, ß-blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side-effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na(+) channel, and benefit may be gained from an alternative multi-drug regimen.

Acid Brothers: Henry Beecher, Timothy Leary, and the psychedelic of the century.

Henry Knowles Beecher, an icon of human research ethics, and Timothy Francis Leary, a guru of the counterculture, are bound together in history by the synthetic hallucinogen lysergic acid diethylamide (LSD). Both were associated with Harvard University during a critical period in their careers and of drastic social change. To all appearances the first was a paragon of the establishment and a constructive if complex hero, the second a rebel and a criminal, a rogue and a scoundrel. Although there is no evidence they ever met, Beecher's indirect struggle with Leary over control of the 20th century's most celebrated psychedelic was at the very heart of his views about the legitimate, responsible investigator. That struggle also proves to be a revealing bellwether of the increasingly formalized scrutiny of human experiments that was then taking shape.

Neuroscience, ethics, and national security: the state of the art.

National security organizations in the United States, including the armed services and the intelligence community, have developed a close relationship with the scientific establishment. The latest technology often fuels warfighting and counter-intelligence capacities, providing the tactical advantages thought necessary to maintain geopolitical dominance and national security. Neuroscience has emerged as a prominent focus within this milieu, annually receiving hundreds of millions of Department of Defense dollars. Its role in national security operations raises ethical issues that need to be addressed to ensure the pragmatic synthesis of ethical accountability and national security.

Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening.

RATIONALE: The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine. OBJECTIVE: We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure. METHODS AND RESULTS: We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na(+) channels in the setting of normal physiology, long-QT syndrome type 3-linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na(+) channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling. CONCLUSIONS: Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL.

A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.

Giant Left Ventricular Aneurysm With Dynamic Right Ventricular Compression and Subsequent End-Stage Heart Failure.

We report a case of a patient with a missed anterior myocardial infarction and associated ischemic cardiomyopathy. The patient had a massive true left ventricular aneurysm causing dynamic right ventricular compression, with associated cardiogenic shock, for which a heart transplantation was ultimately performed.

Substrate mechanics unveil early structural and functional pathology in iPSC micro-tissue models of hypertrophic cardiomyopathy.

Hypertension is a major cause of morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM), suggesting a potential role for mechanics in HCM pathogenesis. Here, we developed an in vitro physiological model to investigate how mechanics acts together with HCM-linked myosin binding protein C (MYBPC3) mutations to trigger disease. Micro-heart muscles (µHM) were engineered from induced pluripotent stem cell (iPSC)-derived cardiomyocytes bearing MYBPC3+/- mutations and challenged to contract against substrates of different elasticity. µHMs that worked against substrates with stiffness at or exceeding the stiffness of healthy adult heart muscle exhibited several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in MYBPC3+/- µHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+ intake through membrane-embedded channels underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease with iPSC technology.