In “Missing the Forest for the Trees: Aduhelm, Accelerated Approvals & the Agency,” Dr. Matthew Herder argues that agency capture and politicized discretion drive delays in confirmatory trials of accelerated approval drugs amongst other concerns at US Food and Drug Administration (FDA). In highlighting this important problem and offering nuanced insight into agency workings based in part on interviews with twenty-three unnamed FDA officials and a three-drug case study, Dr. Herder suggests two innovative solutions. However, amidst broader debates balancing agency (...) expertise, data, and delegation, these proposed policy solutions would benefit from more corroborative evidence and consideration of institutional advantages within constitutional limits. (shrink)

Presence: The Key to Mental Excellence is a compilation of author's original articles, essays, poems and journal entries in chronological order from 1981 through 1990. These are simple expressions of a searching mind trying to understand itself and Nature. Such a mind is amazed by the wonder of the humanbeing and the intricate inter-relatedness in Nature. In its wanderings, it stumbles upon the unique peace in itself and is struck by the glory of this amazing experience. A sense of joy (...) and creative happiness dawns on such a mind. The book is an attempt to express this unique wonder of "growing out of oneself" and realizing humanity as truly an integral part of this incredible natural process. This process of "Life" thrives wherever and whenever it can. (shrink)

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon and Lopinavir/ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and viral load. (...) Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection. (shrink)

Compared to our understanding of positive prediction error signals occurring due to unexpected reward outcomes, less is known about the neural circuitry in humans that drives negative prediction errors during omission of expected rewards. While classical learning theories such as Rescorla–Wagner or temporal difference learning suggest that both types of prediction errors result from a simple subtraction, there has been recent evidence suggesting that different brain regions provide input to dopamine neurons which contributes to specific components of this prediction error (...) computation. Here, we focus on the brain regions responding to negative prediction error signals, which has been well-established in animal studies to involve a distinct pathway through the lateral habenula. We examine the activity of this pathway in humans, using a conditioned inhibition paradigm with high-resolution functional MRI. First, participants learned to associate a sensory stimulus with reward delivery. Then, reward delivery was omitted whenever this stimulus was presented simultaneously with a different sensory stimulus, the conditioned inhibitor. Both reward presentation and the reward-predictive cue activated midbrain dopamine regions, insula and orbitofrontal cortex. While we found significant activity at an uncorrected threshold for the CI in the habenula, consistent with our predictions, it did not survive correction for multiple comparisons and awaits further replication. Additionally, the pallidum and putamen regions of the basal ganglia showed modulations of activity for the inhibitor that did not survive the corrected threshold. (shrink)

We argue that Indian speakers’ discourse about reincarnation represents a counterexample to the ordinary-language evidence for the Kripkean thesis of material-origin essentialism. Advocates of the essentiality of origins contend not only that persons have the property of coming from the two particular gametes they actually came from essentially, but also that competent ordinary-language speakers find this view intuitively compelling. We adduce evidence from Indian speakers’ discourse, both ordinary-language remarks and published literature about reincarnation, to disconfirm that contention. We argue that (...) the view that persons are mental entities is clearly coherent, intuitive, and not obviously necessarily false. We consider mental essentialism as an alternative, according to which persons are only accidentally embodied or biological. But we argue against it in favour of a modally relative anti-essentialism: what properties count as essential to an object and what properties count as accidental is not fixed but varies according to pragmatic utility. (shrink)

Language experience clearly affects the perception of speech, but little is known about whether these differences in perception extend to non-speech sounds. In this study, we investigated rhythmic perception of non-linguistic sounds in speakers of French and German using a grouping task, in which complexity was manipulated. In this task, participants grouped sequences of auditory chimeras formed from musical instruments. These chimeras mimic the complexity of speech without being speech. We found that, while showing the same overall grouping preferences, the (...) German speakers showed stronger biases than the French speakers in grouping complex sequences. Sound variability reduced all participants’ biases, resulting in the French group showing no grouping preference for the most variable sequences, though this reduction was attenuated by musical experience. In sum, this study demonstrates that linguistic experience, musical experience, and complexity affect rhythmic grouping of non-linguistic sounds and suggests that experience with acoustic cues in a meaningful context is necessary for developing a robust grouping preference that survives acoustic variability. (shrink)

The HealthyFood program offers members up to 25% cash back monthly on healthy food purchases. In this randomized controlled trial, we tested the efficacy of financial incentives combined with text messages in increasing healthy food purchases among HF members. Members receiving the lowest cash back level were randomized to one of six arms: Arm 1 : 10% cash back, no weekly text, standard monthly text; Arm 2: 10% cash back, generic weekly text, standard monthly text; Arm 3: 10% cash back, (...) personalized weekly text, standard monthly text; Arm 4: 25% cash back, personalized weekly text, standard monthly text; Arm 5: 10 + 15%NET cash back, personalized weekly text, standard monthly text; and, Arm 6: 10 + 15%NET cash back, personalized weekly text, unbundled monthly text. In the 10 + 15%NET cash back, the cash back amount was the baseline 10% plus 15% of the net difference between healthy and unhealthy spending. The generic text included information on HF and healthy eating, while the personalized text had individualized feedback on purchases. The standard monthly text contained the cash back amount. The unbundled monthly text included the amount lost due to unhealthy purchases. The primary outcome was the average monthly percent healthy food spending. Secondary outcomes were the percent unhealthy food spending, and the percent healthy and unhealthy food items. Of the members contacted, 20 opted out, and 2841 met all inclusion criteria. There were no between-arm differences in the examined outcomes. The largest mean difference in percent healthy spending was between Arm 1 and Arm 2, and the largest mean difference in percent unhealthy spending was also between Arm 1 and Arm 2, but no differences were statistically significant after correction for multiple comparisons. None of the tested financial incentive structures or text strategies differentially affected food purchasing. Notably, more than doubling the cash back amount and introducing a financial disincentive for unhealthy purchases did not affect purchasing. These findings speak to the difficulty of changing shopping habits and to the need for innovative strategies to shift complex health behaviors. NCT02486588 Increasing Engagement with a Healthy Food Benefit. The trial was prospectively registered on July 1, 2015. (shrink)

While mass spectrometry (MS)‐based quantification of small molecules has been successfully used for decades, targeted MS has only recently been used by the proteomics community to investigate clinical questions such as biomarker verification and validation. Targeted MS holds the promise of a paradigm shift in the quantitative determination of proteins. Nevertheless, targeted quantitative proteomics requires improvisation in making sample processing, instruments, and data analysis more accessible. In the backdrop of the genomic era reaching its zenith, certain questions arise: is the (...) proteomic era about to come? If we are at the beginning of a new future for protein quantification, are we prepared to incorporate targeted proteomics at the benchside for basic research and at the bedside for the good of patients? Here, an overview of the knowledge required to perform targeted proteomics as well as its applications is provided. A special emphasis is placed on upcoming areas such as peptidomics, proteoform research, and mass spectrometry imaging, where the utilization of targeted proteomics is expected to bring forth new avenues. The limitations associated with the acceptance of this technique for mainstream usage are also highlighted. (shrink)

Heart disease is the leading cause of death amongst adult Americans and has recently become a top killer worldwide. The direct costs of cardiovascular disease are projected to triple in the next 20 years, from $272.5 billion to $818.1 billion (Heidenreich et al. 2011). Although there has been a decreased incidence and prevalence of ischemic heart disease over the past several decades in the United States, heart failure remains a major cause of morbidity and mortality. In the United States, approximately (...) 500,000 to 700,000 new cases are identified each year (Lloyd-Jones et al. 2009). Heart failure is now the number one diagnosis leading to hospitalization. As such, it is an increasingly heavy economic burden on .. (shrink)

Yoga is a popular and beneficial evidence-based health practice. This book addresses the origins, explores yoga's evolution, and outlines current scientific research as well as contemporary discussions related to the possibilities as well as the politicization of this ancient Indian practice.

In this essay, the author presents the Martinican intellectual Edouard Glissant's Poétique de la Relation in a new frame by reading his text as it accomplishes a type of grand-scale theorizing. The notion of Relation in Glissant is followed in its various connections to a Marxian notion of dynamic totality. The Marxian/Hegelian subtext of Poétique is seen as productively revealing for reading Glissant both historically and theoretically. Glissant's theorizing of difference is shown to be an important contribution to contemporary revisions (...) of Marxian-informed thought. (shrink)

The half-century, which is the time that has elapsed since the publication of Wretched of the Earth , seems such a short period when one imagines its author in all his intellectual magnificence, his anguish, and the many details we all know of his short-lived reality. Dare one say, after the concept has long been declared “dead” that we imagine him as having been a live “author”? As I write this, the idea of various notable intellectuals and revolutionary movements could (...) come to mind in order for them to serve as interesting comparisons as we discuss and remember Fanon, his analyses of the colonial aftermath, and his many predictions, both explicit and implicit. However, the “death” of the author is, in fact, as Barthes’ polemical essay showed, a premise that empowers the text in its full potentiality well beyond the deism by which the identity of the author becomes the authority. Here, the liberation of the text joins up the enunciation with its “content” so to speak, or in Barthes’ words, reveals how Fanon “made of his very life a work for which his book was a model.” It is from this idea that I wish to see Fanon as incomparable. The reason to do so does not stem from some esoteric form of admiration, but rather a conviction that Fanon’s narration itself is both indicative and exemplary of a process of thinking that, for me, remains unparalleled in theorizing the role of the intellectual. Such a conviction requires us to read beyond the content of Wretched and be “reborn” in the Barthesian sense as readers. In essence, it is to simply follow the way Fanon himself allows us to actually trace how he dreams of “the native” or “the people” and thus accomplishes an affective leap, arguably, more completely than any other intellectual. This reading is, thus, an invitation to dream – even momentarily – of Fanon. (shrink)

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The (...) animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions. (shrink)

What parameters determine brain size? This question is of particular interest for humans because our large brains confer outstanding cognitive abilities. The answer has long been sought in comparative analyses of brain size relative to body size (herein termed ‘brain size’) in our fellow homeothermic vertebrates – namely other mammals and birds. Unfortunately, brain size is an idiosyncratic trait corresponding to a seemingly miscellaneous collection of traits ranging from gestation length to deception behaviour. Some order can be established by attributing (...) brain size correlates to categories of constraint (‘what traits permit or limit increased brain sizes?’) and selection (‘what traits select for increased brain sizes?. Even so, the vast number of potential correlates has lead to a plethora of (frequently mutually exclusive) hypotheses regarding avian and mammalian brain size evolution. This confusion has recently prompted calls for better integration of brain size correlates. In this article we argue that the latest advances in the field of brain size constraints, combined with modern techniques for tracing brain development, put an integrated framework of brain size evolution within our reach. (shrink)

The dissociation between statistical prediction and scientific explanation advanced by Bowers et al. for studies of vision using deep neural networks is also observed in several other domains of behavior research, and is in fact unavoidable when fitting large models such as deep nets and other supervised learners, with weak theoretical commitments, to restricted samples of highly stochastic behavioral phenomena.

Despite a growing focus on processes to promote gender equity, women remain significantly underrepresented in leadership positions in the Global South. In the present study we focus on the role of familial experiences in shaping and contesting gender ideologies of Pakistani women in the workplace. We specifically examine the reciprocal ways in which women leaders and their family members shape each other’s gender ideologies regarding the workplace. Data collected and analyzed for this study were semi-structured interviews with eight women in (...) positions of leadership in Lahore, Pakistan, and interviews with one family members of each of the women leaders. Using thematic narrative analysis, we identified three thematic phases: learning gender expectations, resistance, and familial transformation. These phases reflect the progression of developing, resisting, and influencing individual and familial gender ideologies. We document the manifestation of these phases in three specific domains: education, marriage and motherhood, and the workplace. We then discuss how these findings contribute to understanding the experiences of women leaders and perceptions of their family members regarding women’s role in the workplace. Findings from our research provide novel insights into the ways globalization and capitalism continue to shape the socio-cultural context for women leaders in the Global South. (shrink)

People who habituate to stress show a repetition-induced response attenuation—neuroendocrine, cardiovascular, neuroenergetic, and emotional—when exposed to a threatening environment. But the exact dynamics underlying stress habituation remain obscure. The free energy principle offers a unifying account of self-organising systems such as the human brain. In this paper, we elaborate on how stress habituation can be explained and modelled using the free energy principle. We introduce habituation priors that encode the agent’s tendency for stress habituation and incorporate them in the agent’s (...) decision-making process. Using differently shaped goal priors—that encode the agent’s goal preferences—we illustrate, in two examples, the optimising behaviour of agents. We show that habituation minimises free energy by reducing the precision of goal preferences. Reducing the precision of goal priors means that the agent accepts adverse states. Acceptance or tolerance of adverse outcomes may explain why habituation causes people to exhibit an attenuation of the stress response. Given that stress habituation occurs in brain regions where goal priors are encoded, i.e., in the ventromedial prefrontal cortex and that these priors are encoded as sufficient statistics of probability distributions, our approach seems plausible from an anatomical-functional and neuro-statistical point of view. The ensuing formal and generalisable account—based on the free energy principle—further motivate our novel treatment of stress habituation. Our analysis suggests that stress habituation has far-reaching consequences, protecting against the harmful effects of toxic stress, but on the other hand making the acceptability of precarious living conditions and the development of the obese type 2 diabetes mellitus phenotype more likely. (shrink)

Perceptual grouping is fundamental to many auditory processes. The Iambic–Trochaic Law (ITL) is a default grouping strategy, where rhythmic alternations of duration are perceived iambically (weak‐strong), while alternations of intensity are perceived trochaically (strong‐weak). Some argue that the ITL is experience dependent. For instance, French speakers follow the ITL, but not as consistently as German speakers. We hypothesized that learning about prosodic patterns, like word stress, modulates this rhythmic grouping. We tested this idea by training French adults on a German‐like (...) stress contrast. Individuals who showed better phonological learning had more ITL‐like grouping, particularly over duration cues. In a non‐phonological condition, French adults were trained using identical stimuli, but they learned to attend to acoustic variation that was not linguistic. Here, no learning effects were observed. Results thus suggest that phonological learning can modulate low‐level auditory grouping phenomena, but it is constrained by the ability of individuals to learn from short‐term training. (shrink)

The essay looks into the pedagogical role of philosophy in shaping the practice of dissent. Drawing on Gilles Deleuze and Felix Guattari’s radical understandings of philosophy as a machinic assemblage, it redeploys philosophy as a pedagogical tool which gathers traction from social events and remains invested in a dissensual politics. As a machinic assemblage committed to a dissensual politics philosophy works alongside collective modalities of enunciation that operate outside conventional structures of the academia. Such assemblages of enunciation often inhabit a (...) zone of critical inarticulacy brimming with the promise of new kinds of knowledge. How does philosophy critically interact with spaces of dissent along lines of gender, caste, ethnicity and nationalism to enable novel critical interventions? Deleuze and Guattari’s answer redirects us to a pragmatic engagement with philosophy which involves the manufacture of new pedagogical concepts as part of a schizoanalytic apparatus of protest. These concepts often emerge out of a visceral response to events unfolding around us. Needless to emphasize that such a philosophy which emerges out of a praxial encounter with life cannot be framed as an institutional staple, but takes shape as part of a visceral politics of the now. What then is the role of pedagogy in shaping an ethics of dissent and how can such a pedagogy mobilize plebeian acts of resistance in the sphere of the everyday? (shrink)

Neural engineering technologies such as implanted deep brain stimulators and brain-computer interfaces represent exciting and potentially transformative tools for improving human health and well-being. Yet their current use and future prospects raise a variety of ethical and philosophical concerns. Devices that alter brain function invite us to think deeply about a range of ethical concerns—identity, normality, authority, responsibility, privacy, and justice. If a device is stimulating my brain while I decide upon an action, am I still the author of the (...) action? Does a device make the interiority of my experience accessible to others? Will the device change the way I think of myself and others think of me? Such fundamental questions arise even when a device is designed for only a relatively circumscribed purpose, such as restoring functioning via a smart prosthetic. We are part of a National Science Foundation-funded Engineering Research Center tasked with investigating philosophical and social implications of neural engineering research and technologies. Neural devices already in clinical use, such as deep brain stimulators for Parkinson's disease or essential tremor, have spurred healthy debate about such implications. Devices currently under development—such as the BrainGate System of implanted brain sensors coupled to robotics in persons with paralysis, exoskeletons for augmented movement, transcranial do-it-yourself stimulators, closed-loop brain stimulating systems, or even brain-to-brain interfacing—promise to extend and deepen these debates. At our center, brain-computer interfaces are the principal focus of work. Even acknowledging that the clinical translation of neural devices and seamless integration by end users may still largely reside in the future, the potential these devices hold calls for careful early analysis. The launching of the Brain Research through Advancing Innovative Neurotechnologies Initiative in April 2013 provides further impetus for this work. (shrink)

There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open: why are psychiatric disorders and immune responses intertwined? To address this would require a (...) step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question: translation, unification, and simulation. To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the immune response and psychiatric illness both be explained in terms of self-organising systems responding to threatening stimuli in their external environment, whether those stimuli happen to be pathogens, predators, or people? Does false inference at an immunological level alter the message passing at a psychological level (or vice versa) through a principled exchange between the two systems? (shrink)

Brain–Computer Interface research is an interdisciplinary area of study within Neural Engineering. Recent interest in end-user perspectives has led to an intersection with user-centered design. The goal of user-centered design is to reduce the translational gap between researchers and potential end users. However, while qualitative studies have been conducted with end users of BCI technology, little is known about individual BCI researchers’ experience with and attitudes towards UCD. Given the scientific, financial, and ethical imperatives of UCD, we sought to gain (...) a better understanding of practical and principled considerations for researchers who engage with end users. We conducted a qualitative interview case study with neural engineering researchers at a center dedicated to the creation of BCIs. Our analysis generated five themes common across interviews. The thematic analysis shows that participants identify multiple beneficiaries of their work, including other researchers, clinicians working with devices, device end users, and families and caregivers of device users. Participants value experience with device end users, and personal experience is the most meaningful type of interaction. They welcome end-user input, but are skeptical of limited focus groups and case studies. They also recognize a tension between creating sophisticated devices and developing technology that will meet user needs. Finally, interviewees espouse functional, assistive goals for their technology, but describe uncertainty in what degree of function is “good enough” for individual end users. Based on these results, we offer preliminary recommendations for conducting future UCD studies in BCI and neural engineering. (shrink)

BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups.ResultsTwelve (...) studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers, 633 intermediate metabolizers, 1,272 normal metabolizers, and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were PM versus NM; weight = –0.07, BMI = 0.40. IM versus NM; weight = 0.09 and BMI = 0.09. UM versus EM; weight = 0.01 and BMI = –0.08.ConclusionOur systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health. (shrink)

Almost all biomedical research to date has relied upon mean measurements from cell populations, however it is well established that what it is observed at this macroscopic level can be the result of many interactions of several different single cells. Thus, the observable macroscopic ‘average’ cannot outright be used as representative of the ‘average cell’. Rather, it is the resulting emerging behaviour of the actions and interactions of many different cells. Single‐cell RNA sequencing (scRNA‐Seq) enables the comparison of the transcriptomes (...) of individual cells. This provides high‐resolution maps of the dynamic cellular programmes allowing us to answer fundamental biological questions on their function and evolution. It also allows to address medical questions such as the role of rare cell populations contributing to disease progression and therapeutic resistance. Furthermore, it provides an understanding of context‐specific dependencies, namely the behaviour and function that a cell has in a specific context, which can be crucial to understand some complex diseases, such as diabetes, cardiovascular disease and cancer. Here, we provide an overview of scRNA‐Seq, including a comparative review of emerging technologies and computational pipelines. We discuss the current and emerging applications and focus on tumour heterogeneity a clear example of how scRNA‐Seq can provide new understanding of a complex disease. Additionally, we review the limitations and highlight the need of powerful computational pipelines and reproducible protocols for the broader acceptance of this technique in basic and clinical research. (shrink)