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Summary: Background: In 2015, Mexico implemented regulatory changes and an electronic system to improve access to prescription opioids. We aimed to investigate trends in opioid dispensing after the implementation of these changes and assess how opioid dispensing varied geographically and by socioeconomic status. Methods: In this retrospective analysis of prescription medication surveillance data, we analysed dispensing data for group 1 medications (all opioids, including morphine, methadone, hydromorphone, oxycodone, tapentadol, fentanyl, sufentanil, and remifentanil) obtained from the Federal Commission for the Protection against Sanitary Risk database for 32 states and six large metropolitan areas in Mexico. We calculated crude annual opioid prescriptions per 10 000 people at the national, state, and municipal levels. Adapting methods from the report of the Lancet Commission on Palliative Care and Pain Relief, we calculated the need for palliative opioids by state, and then assessed the observed opioid dispensing rates as a percentage of expected need by geographical socioeconomic status. Within the six major metropolitan areas, we mapped the geocoded location of opioid prescriptions and assessed the association between opioid dispensing and socioeconomic status as well as the association between opioid dispensing and time to US border crossing for areas on the US–Mexico border. Findings: Between June 25, 2015, and Oct 7, 2019, opioid dispensing rates increased by an average of 13% (95% CI 6·8–19·6) per quarter (3 months). The overall national opioid dispensing rate during the study period was 26·3 prescriptions per 10 000 inhabitants. States with a higher socioeconomic status had higher opioid dispensing rates than states with lower socioeconomic status (rate ratio [RR] 1·88, 95% CI 1·33–2·58, p=0·00016) after controlling for the estimated opioid requirement per state, the presence of methadone clinics, and the presence of tertiary hospitals and cancer centres. The same association between opioid dispensing and socioeconomic status was observed in the metropolitan areas, and in those metropolitan areas on the US–Mexico border a 20% decrease (RR 0·80, 95% CI 0·75–0·86) in opioid dispensation was observed per each SD increase (SD 17·1 min) in travel time to the border. Interpretation: Measures introduced by the Mexican federal Government to increase opioid access for patients with palliative care needs were only marginally successful in raising opioid prescription rates. Opioid access should be improved for patients with palliative care needs who live in geographical areas of lower socioeconomic status. Funding: US National Institutes of Health.

State militaries have strong interests in developing enhanced warfighters: taking otherwise healthy service personnel (soldiers, marines, pilots, etc.) and pushing their biological, physiological, and cognitive capacities beyond their individual statistical or baseline norm. However, the ethical and regulatory challenges of justifying research into these kinds of interventions to demonstrate the efficacy and safety of enhancements in the military has not been well explored. In this paper, we offer, in the context of the US Common Rule and Institutional Review Board framework, potential justifications for justifying research into enhancing warfighters on the grounds of (i) individual and group risk reduction; (ii) protection of third parties such as civilians; and (iii) military effectiveness., (© The Author(s) 2024. Published by Oxford University Press on behalf of Duke University School of Law, Harvard Law School, Oxford University Press, and Stanford Law School.)

The resurgent sodium current (I NaR ) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, I NaR is thought to drive high rates of repetitive neuronal firing. However, I NaR is often studied in combination with the persistent or noninactivating portion of sodium currents (I NaP ). We used dynamic clamp to test how I NaR and I NaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned I NaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold I NaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed I NaP and I NaR 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 I NaP and Purkinje neuron repetitive firing rates., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

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 Ca 2+ 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., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Competing Interests: Declaration of competing interest The authors have no competing interests to declare.

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The use of metamaterials is a good alternative when looking for structures that can withstand compression forces without increasing their weight. In this sense, using nature as a reference can be an appropriate option to design this type of material. Therefore, in this work, a comparative study of a selection of eight representative models of a wide variety of existing solutions, both bioinspired and proposed by various researchers, is presented. These models have been manufactured using stereolithography (SLA) printing, which allows complex geometries to be obtained in a simple way that would be more complicated to achieve by other procedures. Additionally, the manufacturing cost of each model has been determined. The compression tests of the different models have made it possible to evaluate the breaking force and its corresponding deformation. Likewise, a finite element analysis of the manufactured models has been carried out to simulate their behavior under compression, achieving results very similar to those obtained in the experimental tests. In this way, it has been concluded that, among the three-dimensional patterns, the structure called "3D auxetic" is the one that supports the greatest breaking force due to the topographic characteristics of its bar structure. Similarly, among the two-dimensional patterns, the structure called "Auxetic 1", with a topography based on curves, is capable of supporting the greatest deformation in the compression direction before breaking. Moreover, the highest resistance-force-to-cost ratio has been obtained with a "3D auxetic" structure.

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., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

E-scooter vibrations are a problem recently studied. Theoretical models based on dynamic simulations and also real measurements have confirmed the high impact of e-scooter vibrations on driver comfort and health. Some authors recommend improving e-scooter damping systems, including tyres. However, it has not been suggested nor has any research been published studying how to improve e-scooter frame design for reducing driver vibrations and improving comfort. In this paper, we have modelled a real e-scooter to have a reference. Then, we have developed a multibody dynamic model for running dynamic simulations studying the influence of mass geometry parameters of the e-scooter frame (mass, centre of gravity and inertia moment). Acceleration results have been analysed based on the UNE-2631 standard for obtaining comfort values. Based on results, a qualitative e-scooter frame design guide for mitigating vibrations and increasing the comfort of e-scooter driver has been developed. Some application cases have been running on the multibody dynamic simulation model, finding improvements of comfort levels higher than 9% in comparison with the e-scooter reference model. The dynamic model has been qualitatively validated from real measurements. In addition, a basic sensor proposal and comfort colour scale is proposed for giving feedback to e-scooter drivers.

Background: Perceptual and action systems seem to be related to complex cognitive processes, but the scope of grounded or embodied cognition has been questioned. Zwaan and Yaxley (2003) proposed that cognitive processes of making semantic relatedness judgments can be facilitated when word pairs are presented in ways that their referents maintain their iconic configuration rather than their reverse-iconic configuration (the spatial iconicity effect). This effect has been observed in different semantic categories using specific experiments, but it is known that embodiment is highly dependent on task demands., Method: The present study analyzed the spatial iconicity effect in three semantic categories (physical, abstract, and social) using the same experimental criteria to determine the scope of embodied cognition. In this reaction-time experiment, 75 participants judged the semantic relatedness of 384 word pairs whose experimental items were presented in their iconic or reverse-iconic configurations., Results: Two mixed-effects models with crossed random effects revealed that the interaction between word meaning and spatial position was present only for physical concepts but neither for abstract nor social concepts., Conclusions: Within the framework of strong and weak embodiment theories, the data support weak embodiment theory as the most explicative one., (© 2023 The Authors. Scandinavian Journal of Psychology published by Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Importance: A transdiagnostic treatment, the Unified Protocol, is as effective as single diagnostic protocols in comorbid emotional disorders in clinical populations. However, its effects on posttraumatic stress disorder and other emotional disorders in individuals living in war and armed conflict contexts have not been studied., Objective: To evaluate the efficacy of a cultural and contextual adaptation of the Unified Protocol (CXA-UP) on posttraumatic stress disorder, anxiety, and depression compared to waitlist control in individuals exposed to armed conflict in Colombia., Design, Setting, and Participants: From April 2017 to March 2020, 200 participants 18 years and older were randomly assigned to the CXA-UP or to a waitlist condition. CXA-UP consisted of 12 to 14 twice-a-week or weekly individual 90-minute face-to-face sessions. Outcomes were assessed at baseline, posttreatment, and 3 months following treatment. Analyses were performed and compared for all randomly allocated participants (intent-to-treat [ITT]) and for participants who completed all sessions and posttreatment measures (per protocol [PP]). The study took place at an outpatient university center and included individuals who were registered in the Colombian Victims Unit meeting DSM-5 diagnostic criteria for posttraumatic stress disorder, anxiety, or depression or were severely impaired by anxiety or depression. Individuals who were receiving psychological therapy, were dependent on alcohol or drugs, were actively suicidal or had attempted suicide in the previous 2 months, had psychosis or bipolar disorder, or were cognitively impaired were excluded., Intervention: CXA-UP or waitlist., Main Outcomes and Measures: Primary outcomes were changes in anxiety, depression, and somatic scores on the Patient Health Questionnaire and Posttraumatic Stress Disorder Checklist for DSM-5., Results: Among the 200 participants (160 women [80.0%]; 40 men [20.0%]; mean [SD] age, 43.1 [11.9] years), 120 were randomized to treatment and 80 to waitlist. Results for primary outcomes in the ITT analysis showed a significant pretreatment-to-posttreatment reduction when comparing treatment and waitlist on the posttraumatic stress disorder checklist for DSM-5 scores (slope [SE], -31.12 [3.00]; P < .001; Cohen d, 0.90; 90% CI, 0.63-1.19), 9-item Patient Health Questionnaire (PHQ-9) (slope [SE],-11.94 [1.30]; P < .001; Cohen d, 0.77; 90% CI, 0.52-1.06), PHQ-anxiety (slope [SE], -6.52 [0.67]; P < .001; Cohen d, 0.82; 90% CI, 0.49-1.15), and PHQ-somatic (slope [SE], -8.31 [0.92]; P < .001; Cohen d, 0.75; 90% CI, 0.47-1.04)., Conclusions and Relevance: In this study, significant reductions and large effect sizes in all measures of different emotional disorders showed efficacy of a single transdiagnostic intervention in individuals exposed to armed conflicts., Trial Registration: ClinicalTrials.gov Identifier: NCT03127982.

A birth defect is a structural or chromosomal change present at birth that can affect almost any part or parts of the body. Birth defects can vary from mild to severe. On June 24, 2022, with its Dobbs v Jackson Women's Health Organization decision the Supreme Court of the United States overturned Roe v. Wade, removing the longstanding landmark 1973 ruling that secured a person's constitutional right to an abortion. With this decision individual states can now decide their own abortion laws. In about one-half of the states that continue the legality of pregnancy termination, the process of offering, discussing, and performing terminations of pregnancy remain the same as previously. In states where abortions are not legal, there will be conflicts between the law and the ethical responsibility of physicians to offer and discuss termination of pregnancy for severe anomalies., Competing Interests: Declaration of competing interest None of the authors have any conflicts., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the field of cardiac electrophysiology, modeling has played a central role for many decades. However, even though the effort is well-established, it has recently seen a rapid and sustained evolution in the complexity and predictive power of the models being created. In particular, new approaches to modeling have allowed the tracking of parallel and interconnected processes that span from the nanometers and femtoseconds that determine ion channel gating to the centimeters and minutes needed to describe an arrhythmia. The connection between scales has brought unprecedented insight into cardiac arrhythmia mechanisms and drug therapies. This review focuses on the generation of these models from first principles, generation of detailed models to describe ion channel kinetics, algorithms to create and numerically solve kinetic models, and new approaches toward data gathering that parameterize these models. While we focus on application of these models for cardiac arrhythmia, these concepts are widely applicable to model the physiology and pathophysiology of any excitable cell., Competing Interests: The authors have no conflicts to disclose., (© 2023 Author(s).)

Background: Phonotimpus pennimani (Araneae, Phrurolithidae) is a small-sized (3-5 mm) spider endemic to the Tacaná volcano in Chiapas, Mexico, where it is found in soil litter of cloud forests and coffee plantations. Its venom composition has so far not been investigated, partly because it is not a species of medical significance. However, it does have an important impact on the arthropod populations of its natural habitat., Methods: Specimens were collected in Southeastern Mexico (Chiapas) and identified taxonomically by morphological characteristics. A partial sequence from the mitochondrial gene coxI was amplified. Sequencing on the Illumina platform of a transcriptome library constructed from 12 adult specimens revealed 25 toxin or toxin-like genes. Transcripts were validated (RT-qPCR) by assessing the differential expression of the toxin-like PpenTox1 transcript and normalising with housekeeping genes., Results: Analysis of the coxI -gene revealed a similarity to other species of the family Phrurolithidae. Transcriptome analysis also revealed similarity with venom components of species from the families Ctenidae, Lycosidae, and Sicariidae. Expression of the toxin-like PpenTox1 gene was different for each developmental stage (juvenile or adult) and also for both sexes (female or male). Additionally, a partial sequence was obtained for the toxin-like PpenTox1 from DNA., Conclusion: Data from the amplification of the mitochondrial coxI gene confirmed that P. pennimani belongs to the family Phrurolithidae. New genes and transcripts coding for venom components were identified., Competing Interests: Competing interests: The authors declare that they have not competing interests.

The Russian invasion of Ukraine has led to the imposition of economic sanctions intended to isolate Russia from much of global commerce, which implicitly includes the medical research enterprise. The prospect of ongoing isolation of Russia's substantial research enterprise raises issues related to but distinct from the more familiar problem of corruption. In this paper, we identify reasons that the culture of research ethics in Russia may have been weak even before the war, contributing to hard questions about its future role in the global clinical research community., (© 2022 by The Hastings Center. All rights reserved.)

Background: The attitudes of others towards the sexuality of people with intellectual disabilities are one of the main perceived barriers to them expressing their sexuality. Research on what influences these attitudes yields heterogeneous results., Method: A systematic review of the literature and a meta-analysis were carried out., Results: Eleven studies using the Attitudes to Sexuality Questionnaire-Individuals with an Intellectual Disability (ASQ-ID) were included. Within the included studies, the country's socio-economic development and level of individualism were associated with attitudes towards the sexual rights, parenting and self-control of adults with intellectual disabilities. General population and staff samples held more favourable attitudes than family samples in terms of sexual rights and parenting. Age and gender did not yield significant results., Conclusions: Variables related to country context may underlie the differences observed between countries and therefore influence the population's general thinking and ideologies. Unexpectedly, no age differences were observed. Gender-related results may reflect rapprochement between genders in sexuality. These findings are relevant for researchers and practitioners, as they suggest the importance of considering contextual factors when developing effective interventions that aim to support adults with disabilities to live their sexuality., (© 2022 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Drugs are often removed from clinical trials or market progression owing to their unforeseen effects on cardiac action potential and calcium handling. Induced pluripotent stem cell-derived cardiomyocytes and tissues fabricated from these cells are promising as screening tools for early identification of these potential cardiac liabilities. In this study, we describe an automated, open-source MATLAB-based analysis software for calculating cardiac action potentials and calcium transients from fluorescent reporters. We first identified the most robust manner in which to automatically identify the initiation point for action potentials and calcium transients in a user-independent manner, and used this approach to quantify the duration and morphology of these signals. We then demonstrate the software by assessing changes to action potentials and calcium transients in our micro-heart muscles after exposure to hydroxychloroquine, an antimalarial drug with known cardiac liability. Consistent with clinical observations, our system predicted mild action potential prolongation. However, we also observed marked calcium transient suppression, highlighting the advantage of testing multiple physiologic readouts in cardiomyocytes rather than relying on heterologous overexpression of single channels such as the human ether-a-go-go -related gene channel. This open-source software can serve as a useful, high-throughput tool for analyzing cardiomyocyte physiology from fluorescence imaging.

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out.

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., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT., Methods: This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers., Results: The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up., Conclusions: The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR., Competing Interests: J.D.M. and B.J.K. were supported by the National Institutes of Health grant T32 HL007081 and the Washington University Physician Scientist Training Program. This project was also supported by intradepartmental funding from the Department of Pathology and Immunology, Washington University in St. Louis. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Computational modeling of ion channels provides key insight into experimental electrophysiology results and can be used to connect channel dynamics to emergent phenomena observed at the tissue and organ levels. However, creation of these models requires substantial mathematical and computational background. This tutorial seeks to lower the barrier to creating these models by providing an automated pipeline for creating Markov models of an ion channel kinetics dataset. We start by detailing how to encode sample voltage-clamp protocols and experimental data into the program and its implementation in a cloud computing environment. We guide the reader on how to build a containerized instance, push the machine image, and finally run the routine on cluster nodes. While providing open-source code has become more standard in computational studies, this tutorial provides unprecedented detail on the use of the program and the creation of channel models, starting from inputting the raw experimental data. © 2022 Wiley Periodicals LLC. Basic Protocol: Creation of ion channel kinetic models with a cloud computing environment Alternate Protocol: Instructions for use in a standard high-performance compute cluster., (© 2022 Wiley Periodicals LLC.)

The resurgent component of the voltage-gated sodium current (I NaR ) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of I NaR remain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of I NaR . Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na + influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of I NaR reflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast- and slow-inactivated states, such as the accessory Navβ4 channel subunit, can modulate the amplitude of I NaR ., Competing Interests: JR, JM, DB, JS, JN No competing interests declared, (© 2022, Ransdell et al.)

Purpose: To investigate the use of instruments from the Washington Group on Disability Statistics (WG) to obtain data on hearing disability (HD)., Research Strategies: We conducted searches in the PubMed, Scopus, Science Direct, Web of Science, Lilacs databases and the grey literature. The software "The State of the Art through Systematic Review" and "Mendeley" were used to assist in the bibliographic reference organization, selection, and storage., Selection Criteria: we followed the guidelines proposed by the "Preferred Reporting Items for Systematic Reviews and Meta-Analysis" and we selected studies that met the following inclusion criteria: written in English or Portuguese, within the period of 2001 to 2017 and have used the WG hearing disability question., Data Analysis: The variables analyzed into the studies were: WG module, country and year of data collection, sample size and composition, objective of the study, publication journal, HD estimate of prevalence and accuracy measures., Results: Sixty-five studies are included in the review, conducted with data from 30 countries. The WG Short Set of question was the most often used. Hearing disability prevalence ranged from 0.2 to 2.3% and only three studies estimated the accuracy of the instrument to identify HD., Conclusion: The hearing disability question of WG has been used worldwide and mainly in developing countries. The short variation in the estimated prevalence measurements within studies seems favorable to the WG's goal of generate estimates that allow international comparison. However, the shortage of validity studies indicates the need for further investigations with this purpose.

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.

Surveying the early responses to the Covid-19 pandemic among nation states, one finds a veritable babel of responses, some predictable and some not. Would these results have been different half a century or more ago, when smallpox was eradicated and hopes were high that international cooperation would yield similar results for other infectious diseases? Is this a story about the stability provided by the bipolar postwar world, juxtaposed with the complex geopolitical repositioning that finally followed the collapse of the Soviet Union, or is that too rich an irony? A multipolar world may indeed be less prepared to cope with an international health crisis than a bipolar one. In any case, the patterns of global response are not only reminiscent of the Cold War era itself but also suggestive of a new vaccination cold war., (© 2021 The Hastings Center.)

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., Competing Interests: The authors have declared that no competing interests exist.

In the midst of the Covid-19 pandemic, ethicists, researchers, and journalists have recommended studies that deliberately infect healthy volunteers with the coronavirus as a scientific means of expediting vaccine development. In this essay, we trace the history of infection challenge experiments and reflect on the Nuremberg Code of 1947, issued in response to brutal human experiments conducted by Nazi investigators in concentration camps. We argue that the Code continues to offer valuable guidance for assessing the ethics of this controversial form of research, with respect particularly to the acceptable limits to research risks and the social value of research necessary to justify exposing human participants to these risks., (© 2021 by The Hastings Center. All rights reserved.)

Because of its prevalence and its potential negative consequences, child sexual abuse (CSA) is a public health problem in every country in the world. Knowledge of the characteristics of abuse episodes (victim, abuser, relationship between them, type of sexual contact, duration, threat and/or use of force) is essential to specify the contents of intervention programs for the detection and reduction of the negative consequences of CSA. Starting with an initial sample of 1605 university students of both sexes (70.9% women, 29.1% men), aged between 18 and 26 years ( M = 21.1, SD = 2.2), 90 participants who had suffered an episode of CSA up to age 16 were selected (84.4% women, 15.6% men; M age = 21.1, SD = 2.2). It was found that: (1) there was a higher prevalence of CSA among women and that the victims' average age when they suffered abuse was around 11 years; (2) the abusers were mostly male, close to the victims, and with an average of slightly less than 30 years; and (3) there was a significant proportion (25.6%) of CSA cases with penetration and in which force was used or threatened. These results are relevant, as they show that there is still a noteworthy prevalence of CSA cases on university campuses that needs to be addressed. Knowing the characteristics of these episodes is critical to implementing more effective interventions.

In the view of many, heritable human genome editing (HHGE) harbors the remedial potential of ridding the world of deadly genetic diseases. A Hippocratic obligation, if there ever was one, HHGE is widely viewed as a life-sustaining proposition. The national go/no-go decision regarding the implementation of HHGE, however, must not, in the collective view of the authors, proceed absent thorough public engagement. A comparable call for an "extensive societal dialogue" was recently issued by the International Commission on the Clinical Use of Human Germline Genome Editing. In this communication, the authors lay out the foundational principles undergirding the formation, modification, and evaluation of public opinion. It is against this backdrop that the societal decision to warrant or enjoin the clinical conduct of HHGE will doubtlessly transpire.

In the present study, ozone was applied for the removal of dimethyl phthalate (DMP) from soil. The effect of several experimental parameters was investigated considering, the initial DMP concentration, ozone flow, the type of soil (sand and agricultural soil) and the presence of α-FeOOH as a potential catalyst in the reaction system with sand. The elimination of DMP using ozone is significantly affected by the type of soil. In the case of sand, conventional ozonation was capable to degrade 74% of the initial DMP concentration (0.5 mg g -1 ) after 8 h of the reaction, however, the mineralization degree was below 50%. Under the same experimental conditions, the complete elimination of DMP was achieved when calcined agricultural soil was present reaching a 70% of mineralization. The presence of metal oxides in calcined agricultural soil combined with ozone produced oxidants species which were responsible of incrementing the mineralization degree (around 20% in comparison with the sand). The toxicity tests on lettuce seed demonstrated lower toxicity of DMP byproducts after ozonation. The DMP high removal efficiencies and the lower toxicity of generated byproducts in soil prove the applicability of ozone treatment for soil remediation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Data acquisition is a crucial stage in the execution of condition monitoring (CM) of rotating machinery, by means of vibration analysis. However, the major challenge in the execution of this technique lies in the features of the recording equipment (accuracy, resolution, sampling frequency and number of channels) and the cost they represent. The present work proposes a low-cost data acquisition system, based on Raspberry-Pi, with a high sampling frequency capacity in the recording of up to three channels. To demonstrate the effectiveness of the proposed data acquisition system, a case study is presented in which the vibrations registered in a bearing are analyzed for four degrees of failure.

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.

Antiarrhythmic treatment strategies remain suboptimal due to our inability to predict how drug interactions with ion channels will affect the ability of the tissues to initiate and sustain an arrhythmia. We built a multiscale molecular model of the Na + channel domain III (domain III voltage-sensing domain) to highlight the molecular underpinnings responsible for mexiletine drug efficacy. This model predicts that a hyperpolarizing shift in the domain III voltage-sensing domain is critical for drug efficacy and may be leveraged to design more potent Class I molecules. The model was therefore used to design, in silico, a theoretical mexiletine booster that can dramatically rescue a mutant resistant to the potent antiarrhythmic effects of mexiletine. Our framework provides a strategy for in silico design of precision-targeted therapeutic agents that simultaneously assesses antiarrhythmic markers of success and failure at multiple spatial and time scales. This approach provides a roadmap for the design of novel molecular-based therapy to treat myriad arrhythmia syndromes, including ventricular tachycardia, heart failure arrhythmias, and inherited arrhythmia syndromes., (© 2019 The Authors.)