Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework

Neurosurgical interventions for psychiatric disorders have a long and troubled history (1, 2) but have become much more refined in the last few decades due to the rapid development of neuroimaging and robotic technologies (2). These advances have enabled the design of less invasive techniques, which are more focused, such as deep brain stimulation (DBS) (3). DBS involves electrode insertion into specific neural targets implicated in pathological behavior, which are then repeatedly stimulated at adjustable frequencies. DBS has been used for Parkinson's disease and movement disorders since the 1960s (4-6) and over the last decade has been applied to treatment-refractory psychiatric disorders, with some evidence of benefit in obsessive-compulsive disorder (OCD), major depressive disorder, and addictions (7). Recent consensus guidelines on best practice in psychiatric neurosurgery (8) stress, however, that DBS for psychiatric disorders remains at an experimental and exploratory stage. The ethics of DBS-in particular for psychiatric conditions-is debated (1, 8-10). Much of this discourse surrounds the philosophical implications of competence, authenticity, personality, or identity change following neurosurgical interventions, but there is a paucity of applied guidance on neuroethical best practice in psychiatric DBS, and health-care professionals have expressed that they require more (11). This paper aims to redress this balance by providing a practical, applied neuroethical gold standard framework to guide research ethics committees, researchers, and institutional sponsors. We will describe this as applied to our protocol for a particular research trial of DBS in severe and enduring anorexia nervosa (SE-AN) (https://clinicaltrials.gov/ct2/show/NCT01924598, unique identifier NCT01924598), but believe it may have wider application to DBS in other psychiatric disorders

Qualitative evaluation of media device orchestration for immersive spatial audio reproduction

The challenge of installing and setting up dedicated spatial audio systems can make it difficult to deliver immersive listening experiences to the general public. However, the proliferation of smart mobile devices and the rise of the Internet of Things mean that there are increasing numbers of connected devices capable of producing audio in the home. \Media device orchestration" (MDO) is the concept of utilizing an ad hoc set of devices to deliver or augment a media experience. In this paper, the concept is evaluated by implementing MDO for augmented spatial audio reproduction using object-based audio with semantic metadata. A thematic analysis of positive and negative listener comments about the system revealed three main categories of response: perceptual, technical, and content-dependent aspects. MDO performed particularly well in terms of immersion/envelopment, but the quality of listening experience was partly dependent on loudspeaker quality and listener position. Suggestions for further development based on these categories are given

Behavioural stress responses predict environmental perception in European sea bass (Dicentrarchus labrax)

Individual variation in the response to environmental challenges depends partly on innate reaction norms, partly on experience-based cognitive/emotional evaluations that individuals make of the situation. The goal of this study was to investigate whether pre-existing differences in behaviour predict the outcome of such assessment of environmental cues, using a conditioned place preference/avoidance (CPP/CPA) paradigm. A comparative vertebrate model (European sea bass, Dicentrarchus labrax) was used, and ninety juvenile individuals were initially screened for behavioural reactivity using a net restraining test. Thereafter each individual was tested in a choice tank using net chasing as aversive stimulus or exposure to familiar conspecifics as appetitive stimulus in the preferred or non preferred side respectively (called hereafter stimulation side). Locomotor behaviour (i.e. time spent, distance travelled and swimming speed in each tank side) of each individual was recorded and analysed with video software. The results showed that fish which were previously exposed to appetitive stimulus increased significantly the time spent on the stimulation side, while aversive stimulus led to a strong decrease in time spent on the stimulation side. Moreover, this study showed clearly that proactive fish were characterised by a stronger preference for the social stimulus and when placed in a putative aversive environment showed a lower physiological stress responses than reactive fish. In conclusion, this study showed for the first time in sea bass, that the CPP/CPA paradigm can be used to assess the valence (positive vs. negative) that fish attribute to different stimuli and that individual behavioural traits is predictive of how stimuli are perceived and thus of the magnitude of preference or avoidance behaviour.European Commission [265957]; Portuguese Fundacao para a Ciencia e Tecnologia (FCT) [FRH/BPD/72952/2010]; FCT [SFRH/BD/80029/2011

An audio-visual system for object-based audio : from recording to listening

Object-based audio is an emerging representation for audio content, where content is represented in a reproduction format-agnostic way and, thus, produced once for consumption on many different kinds of devices. This affords new opportunities for immersive, personalized, and interactive listening experiences. This paper introduces an end-to-end object-based spatial audio pipeline, from sound recording to listening. A high-level system architecture is proposed, which includes novel audiovisual interfaces to support object-based capture and listenertracked rendering, and incorporates a proposed component for objectification, that is, recording content directly into an object-based form. Text-based and extensible metadata enable communication between the system components. An open architecture for object rendering is also proposed. The system’s capabilities are evaluated in two parts. First, listener-tracked reproduction of metadata automatically estimated from two moving talkers is evaluated using an objective binaural localization model. Second, object-based scene capture with audio extracted using blind source separation (to remix between two talkers) and beamforming (to remix a recording of a jazz group) is evaluate

Spontaneous infection of a stable mediastinal cystic mass: A case report

Mediastinal cysts have an unpredictable course but can cause complications such as infection or local pressure effects. Persons with mediastinal cysts can be asymptomatic for many years or can develop symptoms as a result of complications of the cyst. There is a lack of consensus on the best approach to managing those patients without symptoms. In this case report, a 56 year old woman with an indolent mediastinal cyst initially managed conservatively suddenly developed symptoms suggestive of an infected mediastinal cyst requiring surgical resection

No evidence for selective follicle abortion underlying primary sex ratio adjustment in pigeons

Primary sex ratio adjustment in birds has been extensively studied, yet the underlying physiological mechanisms are far from understood. Avian females are the heterogametic sex (ZW), and the future sex of the offspring is determined at chromosome segregation during meiosis I, shortly before the oocyte is ovulated. Assuming that the mother can detect the sex of the developing oocyte before ovulation, it has been suggested that a follicle of the un-preferred sex could selectively be induced to become atretic and regress instead of being ovulated (selective follicle abortion). This potential mechanism has been proposed to underlie biased primary sex ratios in birds, including the homing pigeon (Columba livia domestica), which produces a modal clutch size of two eggs. However, without replacement by an additional, already mature follicle, abortion of a preovulatory follicle would most likely result in either reduced clutch sizes or laying gaps, since a not-yet-recruited follicle still needed to undergo the whole maturation phase. In the current study we killed female pigeons, which were adjusting embryo sex of first eggs according to change in body mass. We examined ovaries for signs of follicle abortion but did not find any supporting evidence. All females produced one or two mature follicles but only two out of the 56 experimental birds produced an additional third mature follicle. Therefore, our results do not corroborate the hypothesis that pigeon mothers manipulate primary offspring sex by selectively aborting follicles of the un-preferred sex

Targeting multiple effector pathways in pancreatic ductal adenocarcinoma with a g-quadruplex-binding small molecule

Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers

Micro-pharmacokinetics: quantifying local drug concentration at live cell membranes

Fundamental equations for determining pharmacological parameters, such as the binding afnity of a ligand for its target receptor, assume a homogeneous distribution of ligand, with concentrations in the immediate vicinity of the receptor being the same as those in the bulk aqueous phase. It is, however, known that drugs are able to interact directly with the plasma membrane, potentially increasing local ligand concentrations around the receptor. We have previously reported an infuence of ligand-phospholipid interactions on ligand binding kinetics at the β2-adrenoceptor, which resulted in distinct “micro-pharmacokinetic” ligand profles. Here, we directly quantifed the local concentration of BODIPY630/650-PEG8-S-propranolol (BY-propranolol), a fuorescent derivative of the classical β-blocker propranolol, at various distances above membranes of single living cells using fuorescence correlation spectroscopy. We show for the frst time a signifcantly increased ligand concentration immediatel adjacent to the cell membrane compared to the bulk aqueous phase. We further show a clear role of both the cell membrane and the β2-adrenoceptor in determining high local BY-propranolol concentrations at the cell surface. These data suggest that the true binding afnity of BY-propranolol for the β2-adrenoceptor is likely far lower than previously reported and highlights the critical importance of understanding the “micro-pharmacokinetic” profles of ligands for membrane-associated proteins

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page