Lifelike Transformative Materials for Biohybrid Implants: Inspired by Nature, Driven by Technology.

Today's living world is enriched with a myriad of natural biological designs, shaped by billions of years of evolution. Unraveling the construction rules of living organisms offers the potential to create new materials and systems for biomedicine. From the close examination of living organisms, several concepts emerge: hierarchy, pattern repetition, adaptation, and irreducible complexity. All these aspects must be tackled to develop transformative materials with lifelike behavior. This perspective article highlights recent progress in the development of transformative biohybrid systems for applications in the fields of tissue regeneration and biomedicine. Advances in computational simulations and data-driven predictions are also discussed. These tools enable the virtual high-throughput screening of implant design and performance before committing to fabrication, thus reducing the development time and cost of biomimetic and biohybrid constructs. The ongoing progress of imaging methods also constitutes an essential part of this matter in order to validate the computation models and enable longitudinal monitoring. Finally, the current challenges of lifelike biohybrid materials, including reproducibility, ethical considerations, and translation, are discussed. Advances in the development of lifelike materials will open new biomedical horizons, where perhaps what is currently envisioned as science fiction will become a science-driven reality in the future.

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner.

Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play an important role in this evolution, as they can be programmed to direct cell behavior and fate by controlling the activity of bioactive molecules and material properties. Using nature as an inspiration, scientists are creating materials that incorporate specific biological processes observed during human organogenesis and tissue regeneration. This article presents the reader with state-of-the-art developments in the field of in vitro tissue engineering and the challenges related to the design, production, and translation of these transformative materials. Advances regarding (stem) cell sources, expansion, and differentiation, and how novel responsive materials, automated and large-scale fabrication processes, culture conditions, in situ monitoring systems, and computer simulations are required to create functional human tissue models that are relevant and efficient for drug discovery, are described. This paper illustrates how these different technologies need to converge to generate in vitro life-like human tissue models that provide a platform to answer health-based scientific questions.

ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia.

Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.

Responsibility, second opinions and peer-disagreement: ethical and epistemological challenges of using AI in clinical diagnostic contexts.

In this paper, we first classify different types of second opinions and evaluate the ethical and epistemological implications of providing those in a clinical context. Second, we discuss the issue of how artificial intelligent (AI) could replace the human cognitive labour of providing such second opinion and find that several AI reach the levels of accuracy and efficiency needed to clarify their use an urgent ethical issue. Third, we outline the normative conditions of how AI may be used as second opinion in clinical processes, weighing the benefits of its efficiency against concerns of responsibility attribution. Fourth, we provide a 'rule of disagreement' that fulfils these conditions while retaining some of the benefits of expanding the use of AI-based decision support systems (AI-DSS) in clinical contexts. This is because the rule of disagreement proposes to use AI as much as possible, but retain the ability to use human second opinions to resolve disagreements between AI and physician-in-charge. Fifth, we discuss some counterarguments.

Traces of culture: The feedback loop between behavior, brain, and disorder.

Culture is part of an extensive series of feedback loops, which involve multiple organismic levels including social contexts, cognitive mediations, neural processes, and behavior. Recent studies in neuroscience show that culturally contingent social processes shape some neural pathways. Studying the influence of cultural context on neural processes may yield new insights into psychiatric disorders. New methodologies in the neurosciences offer innovative ways to assess the impact of culture on mental health and illness. However, implementing these methodologies raises important theoretical and ethical concerns, which must be resolved to address patient individuality and the complexity of cultural diversity. This article discusses cultural context as a major influence on (and consequence of) human neural plasticity and advocates a culture-brain-behavior (CBB) interaction model for conceptualizing the relationship between culture, brain, and psychiatric disorders. Recommendations are made for integrating neuroscientific techniques into transcultural psychiatric research by taking a systems approach to evaluating disorders.

The adaptive self: Culture and social flexibility in feedback networks.

Culture contextualizes the contents and intentionality of many mental statuses. Cognitive mediation of cultural information shapes these contents and intentionalities, as well as many of the false beliefs of pathology. Flexibility of cognitive mediation processes and resulting beliefs and pathologies may vary by individual, be a key mechanism of the feedback loop, and help characterize network connections.

Addiction and Moralization: the Role of the Underlying Model of Addiction.

Addiction appears to be a deeply moralized concept. To understand the entwinement of addiction and morality, we briefly discuss the disease model and its alternatives in order to address the following questions: Is the disease model the only path towards a 'de-moralized' discourse of addiction? While it is tempting to think that medical language surrounding addiction provides liberation from the moralized language, evidence suggests that this is not necessarily the case. On the other hand non-disease models of addiction may seem to resuscitate problematic forms of the moralization of addiction, including, invoking blame, shame, and the wholesale rejection of addicts as people who have deep character flaws, while ignoring the complex biological and social context of addiction. This is also not necessarily the case. We argue that a deficit in reasons responsiveness as basis for attribution of moral responsibility can be realized by multiple different causes, disease being one, but it also seems likely that alternative accounts of addiction as developed by Flanagan, Lewis, and Levy, may also involve mechanisms, psychological, social, and neurobiological that can diminish reasons responsiveness. It thus seems to us that nondisease models of addiction do not necessarily involve moralization. Hence, a non-stigmatizing approach to recovery can be realized in ways that are consistent with both the disease model and alternative models of addiction.

Modernizing Relationship Therapy through Social Thermoregulation Theory: Evidence, Hypotheses, and Explorations.

In the present article the authors propose to modernize relationship therapy by integrating novel sensor and actuator technologies that can help optimize people's thermoregulation, especially as they pertain to social contexts. Specifically, they propose to integrate Social Thermoregulation Theory (IJzerman et al., 2015a; IJzerman and Hogerzeil, 2017) into Emotionally Focused Therapy by first doing exploratory research during couples' therapy, followed by Randomized Clinical Trials (RCTs). The authors thus suggest crafting a Social Thermoregulation Therapy (STT) as enhancement to existing relationship therapies. The authors outline what is known and not known in terms of social thermoregulatory mechanisms, what kind of data collection and analyses are necessary to better understand social thermoregulatory mechanisms to craft interventions, and stress the need to conduct RCTs prior to implementation. They further warn against too hastily applying these theoretical perspectives. The article concludes by outlining why STT is the way forward in improving relationship functioning.

Learning New Sensorimotor Contingencies: Effects of Long-Term Use of Sensory Augmentation on the Brain and Conscious Perception.

Theories of embodied cognition propose that perception is shaped by sensory stimuli and by the actions of the organism. Following sensorimotor contingency theory, the mastery of lawful relations between own behavior and resulting changes in sensory signals, called sensorimotor contingencies, is constitutive of conscious perception. Sensorimotor contingency theory predicts that, after training, knowledge relating to new sensorimotor contingencies develops, leading to changes in the activation of sensorimotor systems, and concomitant changes in perception. In the present study, we spell out this hypothesis in detail and investigate whether it is possible to learn new sensorimotor contingencies by sensory augmentation. Specifically, we designed an fMRI compatible sensory augmentation device, the feelSpace belt, which gives orientation information about the direction of magnetic north via vibrotactile stimulation on the waist of participants. In a longitudinal study, participants trained with this belt for seven weeks in natural environment. Our EEG results indicate that training with the belt leads to changes in sleep architecture early in the training phase, compatible with the consolidation of procedural learning as well as increased sensorimotor processing and motor programming. The fMRI results suggest that training entails activity in sensory as well as higher motor centers and brain areas known to be involved in navigation. These neural changes are accompanied with changes in how space and the belt signal are perceived, as well as with increased trust in navigational ability. Thus, our data on physiological processes and subjective experiences are compatible with the hypothesis that new sensorimotor contingencies can be acquired using sensory augmentation.

Addressing the problem of ADHD medication as neuroenhancements.

The prevalence of attention deficit hyperactivity disorder (ADHD) diagnoses is rising. ADHD is closely linked to its treatment with medications such as methylphenidate and amphetamines, which have popular appeal as neuroenhancement drugs by persons without a neurological disorder. The three main reasons for the increase in ADHD medication demand, production, and consumption are a) the inclusion of milder ADHD diagnoses; b) the vast marketing of ADHD medications by the pharmaceutical industry; and c) the illegal diversion of controlled ADHD medication to consumers seeking stimulants as neuroenhancements. Rapidly rising rates of any neurological disorder - especially a behaviorly-defined disorder closely linked to potent medications currently prescribed to more than 5% of the population - deserves ongoing scrutiny. Major social and ethical problems arise from vague-symptom medicalization, neurological disorder trivialization, medication overuse, and controlled substances diversion to healthy persons for nonmedical purposes. We argue against the 'spectrumization' of ADHD in an effort to curtail further diagnosis creep.

Predictions in the light of your own action repertoire as a general computational principle.

We argue that brains generate predictions only within the constraints of the action repertoire. This makes the computational complexity tractable and fosters a step-by-step parallel development of sensory and motor systems. Hence, it is more of a benefit than a literal constraint and may serve as a universal normative principle to understand sensorimotor coupling and interactions with the world.

Pediatric neuroenhancement: ethical, legal, social, and neurodevelopmental implications.

The use of prescription medication to augment cognitive or affective function in healthy persons-or neuroenhancement-is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor-child-parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.