Implications of a technician-led pharmacy service on a day case unit in a tertiary oncology centre.

INTRODUCTION: Medicines Management Technicians have been shown to be an underused resource in medicines optimisation and medicines waste. In the United Kingdom, there are national recommendations for the clinical pharmacy service in cancer services ambulatory units, despite these recommendations, there was no clinical pharmacy service on the day case unit at a specialist tertiary centre in England. A lot of the patient pathways had been in place for many years and had not progressed with the changes in the clinical pathways. The main objectives of this study were to analyse how a medicines management technician could reduce medicines waste, improve the current pathway, increase medicines optimisation and ultimately improve the patient experience in an oncology day case unit at a specialist tertiary centre in England. METHODS: A prospective mixed methods study was carried out at Weston Park Hospital. Descriptive statistical analysis was conducted on the quantitative data collected, and thematic analysis was carried out on the qualitative data collected by questionnaire to staff members and patients. RESULTS: This study has shown that a medicines management technician can complete some of the tasks more traditionally done by the chemotherapy nurses on the day case unit, increasing their capacity for more clinically appropriate tasks. A medicines management technician can work as part of the wider multidisciplinary team on a day case unit contributing to medicines optimisation and cost savings for the oncology directorate. CONCLUSIONS: This study has shown that a medicines management technician can act as a valued member of the wider multidisciplinary team, improving communication and patient pathways, improving medicines optimisation and contributing to cost saving initiatives. Further studies are required to assess whether a medicines management technician role can be of the same value on a haematology day case unit.

Case epidemiology from the first three years of a pilot laboratory-based surveillance system for elevated blood-lead concentrations among children in England, 2014-17: implications for public health action.

BACKGROUND: Children incur lead toxicity even at low blood-lead concentrations (BLCs), and testing in England is opportunistic. We described epidemiology of cases notified to a passive laboratory-based surveillance system (SS), the Lead Poisoning in Children (LPIC) SS to inform opportunities to prevent lead exposure in children in England. METHODS: Surveillance population: children <16 years of age and resident in England during the reporting period September 2014-17. Case definition: children with BLC ≥0.48 µmol/l (10 µg/dl). We extracted case demographic/location data and linked it with laboratory, area-level population and socio-economic status (SES) data. We described case BLCs and calculated age-, gender- and SES-specific notification rates, and age-sex standardised regional notification rates. RESULTS: Between 2014 and 2017 there were 86 newly notified cases, giving an annual average notification rate of 2.76 per million children aged 0-15 years. Regionally, rates varied from 0.36 to 9.89 per million. Rates were highest in the most deprived quintile (5.38 per million), males (3.75 per million) and children aged 1-4 years (5.89 per million). CONCLUSIONS: Males, children aged 1-4 years, and children in deprived areas may be at higher risk, and could be targeted for primary prevention. Varied regional notification rates suggest differences in clinician awareness of lead exposure and risk factors; guidelines standardising the indications for BLC-testing may assist secondary prevention.

Age-dependent Pavlovian biases influence motor decision-making.

Motor decision-making is an essential component of everyday life which requires weighing potential rewards and punishments against the probability of successfully executing an action. To achieve this, humans rely on two key mechanisms; a flexible, instrumental, value-dependent process and a hardwired, Pavlovian, value-independent process. In economic decision-making, age-related decline in risk taking is explained by reduced Pavlovian biases that promote action toward reward. Although healthy ageing has also been associated with decreased risk-taking in motor decision-making, it is currently unknown whether this is a result of changes in Pavlovian biases, instrumental processes or a combination of both. Using a newly established approach-avoidance computational model together with a novel app-based motor decision-making task, we measured sensitivity to reward and punishment when participants (n = 26,532) made a 'go/no-go' motor gamble based on their perceived ability to execute a complex action. We show that motor decision-making can be better explained by a model with both instrumental and Pavlovian parameters, and reveal age-related changes across punishment- and reward-based instrumental and Pavlovian processes. However, the most striking effect of ageing was a decrease in Pavlovian attraction towards rewards, which was associated with a reduction in optimality of choice behaviour. In a subset of participants who also played an independent economic decision-making task (n = 17,220), we found similar decision-making tendencies for motor and economic domains across a majority of age groups. Pavlovian biases, therefore, play an important role in not only explaining motor decision-making behaviour but also the changes which occur through normal ageing. This provides a deeper understanding of the mechanisms which shape motor decision-making across the lifespan.

Age-related changes in working memory and the ability to ignore distraction.

A weakened ability to effectively resist distraction is a potential basis for reduced working memory capacity (WMC) associated with healthy aging. Exploiting data from 29,631 users of a smartphone game, we show that, as age increases, working memory (WM) performance is compromised more by distractors presented during WM maintenance than distractors presented during encoding. However, with increasing age, the ability to exclude distraction at encoding is a better predictor of WMC in the absence of distraction. A significantly greater contribution of distractor filtering at encoding represents a potential compensation for reduced WMC in older age.

Loss of sensory attenuation in patients with functional (psychogenic) movement disorders.

Functional movement disorders require attention to manifest yet patients report the abnormal movement to be out of their control. In this study we explore the phenomenon of sensory attenuation, a measure of the sense of agency for movement, in this group of patients by using a force matching task. Fourteen patients and 14 healthy control subjects were presented with forces varying from 1 to 3 N on the index finger of their left hand. Participants were required to match these forces; either by pressing directly on their own finger or by operating a robot that pressed on their finger. As expected, we found that healthy control subjects consistently overestimated the force required when pressing directly on their own finger than when operating a robot. However, patients did not, indicating a significant loss of sensory attenuation in this group of patients. These data are important because they demonstrate that a fundamental component of normal voluntary movement is impaired in patients with functional movement disorders. The loss of sensory attenuation has been correlated with the loss of sense of agency, and may help to explain why patients report that they do not experience the abnormal movement as voluntary.

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

A Bayesian account of 'hysteria'.

This article provides a neurobiological account of symptoms that have been called 'hysterical', 'psychogenic' or 'medically unexplained', which we will call functional motor and sensory symptoms. We use a neurobiologically informed model of hierarchical Bayesian inference in the brain to explain functional motor and sensory symptoms in terms of perception and action arising from inference based on prior beliefs and sensory information. This explanation exploits the key balance between prior beliefs and sensory evidence that is mediated by (body focused) attention, symptom expectations, physical and emotional experiences and beliefs about illness. Crucially, this furnishes an explanation at three different levels: (i) underlying neuromodulatory (synaptic) mechanisms; (ii) cognitive and experiential processes (attention and attribution of agency); and (iii) formal computations that underlie perceptual inference (representation of uncertainty or precision). Our explanation involves primary and secondary failures of inference; the primary failure is the (autonomous) emergence of a percept or belief that is held with undue certainty (precision) following top-down attentional modulation of synaptic gain. This belief can constitute a sensory percept (or its absence) or induce movement (or its absence). The secondary failure of inference is when the ensuing percept (and any somatosensory consequences) is falsely inferred to be a symptom to explain why its content was not predicted by the source of attentional modulation. This account accommodates several fundamental observations about functional motor and sensory symptoms, including: (i) their induction and maintenance by attention; (ii) their modification by expectation, prior experience and cultural beliefs and (iii) their involuntary and symptomatic nature.

Active inference, sensory attenuation and illusions.

Active inference provides a simple and neurobiologically plausible account of how action and perception are coupled in producing (Bayes) optimal behaviour. This can be seen most easily as minimising prediction error: we can either change our predictions to explain sensory input through perception. Alternatively, we can actively change sensory input to fulfil our predictions. In active inference, this action is mediated by classical reflex arcs that minimise proprioceptive prediction error created by descending proprioceptive predictions. However, this creates a conflict between action and perception; in that, self-generated movements require predictions to override the sensory evidence that one is not actually moving. However, ignoring sensory evidence means that externally generated sensations will not be perceived. Conversely, attending to (proprioceptive and somatosensory) sensations enables the detection of externally generated events but precludes generation of actions. This conflict can be resolved by attenuating the precision of sensory evidence during movement or, equivalently, attending away from the consequences of self-made acts. We propose that this Bayes optimal withdrawal of precise sensory evidence during movement is the cause of psychophysical sensory attenuation. Furthermore, it explains the force-matching illusion and reproduces empirical results almost exactly. Finally, if attenuation is removed, the force-matching illusion disappears and false (delusional) inferences about agency emerge. This is important, given the negative correlation between sensory attenuation and delusional beliefs in normal subjects--and the reduction in the magnitude of the illusion in schizophrenia. Active inference therefore links the neuromodulatory optimisation of precision to sensory attenuation and illusory phenomena during the attribution of agency in normal subjects. It also provides a functional account of deficits in syndromes characterised by false inference and impaired movement--like schizophrenia and Parkinsonism--syndromes that implicate abnormal modulatory neurotransmission.

Dynamic causal modelling of precision and synaptic gain in visual perception - an EEG study.

Estimating the precision or uncertainty associated with sensory signals is an important part of perception. Based on a previous computational model, we tested the hypothesis that increasing visual contrast increased the precision encoded in early visual areas by the gain or excitability of superficial pyramidal cells. This hypothesis was investigated using electroencephalography and dynamic causal modelling (DCM); a biologically constrained modelling of the cortical processes underlying EEG activity. Source localisation identified the electromagnetic sources of visually evoked responses and DCM was used to characterise the coupling among these sources. Bayesian model selection was used to select the most likely connectivity pattern and contrast-dependent changes in connectivity. As predicted, the model with the highest evidence entailed increased superficial pyramidal cell gain in higher-contrast trials. As predicted theoretically, contrast-dependent increases were reduced at higher levels of the hierarchy. These results demonstrate that increased signal-to-noise ratio in sensory signals produce (or are represented by) increased superficial pyramidal cell gain, and that synaptic parameters encoding statistical properties like sensory precision can be quantified using EEG and dynamic causal modelling.

Differential retention of pollen grains on clothing and the effectiveness of laboratory retrieval methods in forensic settings.

Forensic palynology has been important in criminal investigation since the 1950s and often provides evidence that is vital in identifying suspects and securing convictions. However, for such evidence to be used appropriately, it is necessary to understand the factors affecting taphonomic variability (i.e. the variability in the fate of pollen grains before they are found during forensic examination). Here, we test the relative amount of pollen retained on clothing after a period of simulated light or heavy wear based on pollen and fabric characteristics. We also test the efficiency of forensic laboratory protocols for retrieving pollen from fabrics for analysis. There was no statistically significant difference in retention of fresh or dried pollen on any fabric type. There was a substantial difference in pollen retention according to wear intensity, with considerably more pollen being retained after light wear than after heavy wear. Pollen from insect-pollinated species was retained at higher concentrations than pollen from wind-pollinated species. This pattern was consistent regardless of wear intensity but pollination type explained more of the variability in pollen retention after light wear. Fabric type was significantly related to pollen retention, but interacted strongly with plant species such that patterns were both complex and highly species-specific. The efficiency of removing pollen with the standard washing protocol differed substantially according to plant species, fabric type, and the interaction between these factors. The average efficiency was 67.7% but this ranged from 21% to 93%, demonstrating that previous assumptions on the reliability of the technique providing a representative sample for forensic use should be reviewed. This paper highlights the importance of understanding pollen and fabric characteristics when creating a pollen profile in criminal investigations and to ensure that evidence used in testimony is accurate and robust.

Development of a browser application to foster research on linking climate and health datasets: Challenges and opportunities.

BACKGROUND: Improved data linkages between diverse environment and health datasets have the potential to provide new insights into the health impacts of environmental exposures, including complex climate change processes. Initiatives that link and explore big data in the environment and health arenas are now being established. OBJECTIVES: To encourage advances in this nascent field, this article documents the development of a web browser application to facilitate such future research, the challenges encountered to date, and how they were addressed. METHODS: A 'storyboard approach' was used to aid the initial design and development of the application. The application followed a 3-tier architecture: a spatial database server for storing and querying data, server-side code for processing and running models, and client-side browser code for user interaction and for displaying data and results. The browser was validated by reproducing previously published results from a regression analysis of time-series datasets of daily mortality, air pollution and temperature in London. RESULTS: Data visualisation and analysis options of the application are presented. The main factors that shaped the development of the browser were: accessibility, open-source software, flexibility, efficiency, user-friendliness, licensing restrictions and data confidentiality, visualisation limitations, cost-effectiveness, and sustainability. CONCLUSIONS: Creating dedicated data and analysis resources, such as the one described here, will become an increasingly vital step in improving understanding of the complex interconnections between the environment and human health and wellbeing, whilst still ensuring appropriate confidentiality safeguards. The issues raised in this paper can inform the future development of similar tools by other researchers working in this field.

The dysconnection hypothesis (2016).

Twenty years have passed since the dysconnection hypothesis was first proposed (Friston and Frith, 1995; Weinberger, 1993). In that time, neuroscience has witnessed tremendous advances: we now live in a world of non-invasive neuroanatomy, computational neuroimaging and the Bayesian brain. The genomics era has come and gone. Connectomics and large-scale neuroinformatics initiatives are emerging everywhere. So where is the dysconnection hypothesis now? This article considers how the notion of schizophrenia as a dysconnection syndrome has developed - and how it has been enriched by recent advances in clinical neuroscience. In particular, we examine the dysconnection hypothesis in the context of (i) theoretical neurobiology and computational psychiatry; (ii) the empirical insights afforded by neuroimaging and associated connectomics - and (iii) how bottom-up (molecular biology and genetics) and top-down (systems biology) perspectives are converging on the mechanisms and nature of dysconnections in schizophrenia.

Risk Taking for Potential Reward Decreases across the Lifespan.

The extent to which aging affects decision-making is controversial. Given the critical financial decisions that older adults face (e.g., managing retirement funds), changes in risk preferences are of particular importance [1]. Although some studies have found that older individuals are more risk averse than younger ones [2-4], there are also conflicting results, and a recent meta-analysis found no evidence for a consistent change in risk taking across the lifespan [5]. There has as yet been little examination of one potential substrate for age-related changes in decision-making, namely age-related decline in dopamine, a neuromodulator associated with risk-taking behavior. Here, we characterized choice preferences in a smartphone-based experiment (n = 25,189) in which participants chose between safe and risky options. The number of risky options chosen in trials with potential gains but not potential losses decreased gradually over the lifespan, a finding with potentially important economic consequences for an aging population. Using a novel approach-avoidance computational model, we found that a Pavlovian attraction to potential reward declined with age. This Pavlovian bias has been linked to dopamine, suggesting that age-related decline in this neuromodulator could lead to the observed decrease in risk taking.

Proactive and Reactive Response Inhibition across the Lifespan.

One expression of executive control involves proactive preparation for future events, and this contrasts with stimulus driven reactive control exerted in response to events. Here we describe findings from a response inhibition task, delivered using a smartphone-based platform, that allowed us to index proactive and reactive inhibitory self-control in a large community sample (n = 12,496). Change in stop-signal reaction time (SSRT) when participants are provided with advance information about an upcoming trial, compared to when they are not, provides a measure of proactive control while SSRT in the absence of advance information provides a measure of reactive control. Both forms of control rely on overlapping frontostriatal pathways known to deteriorate in healthy aging, an age-related decline that occurs at an accelerated rate in men compared to women. Here we ask whether these patterns of age-related decline are reflected in similar changes in proactive and reactive inhibitory control across the lifespan. As predicted, we observed a decline in reactive control with natural aging, with a greater rate of decline in men compared to women (~10 ms versus ~8 ms per decade of adult life). Surprisingly, the benefit of preparation, i.e. proactive control, did not change over the lifespan and women showed superior proactive control at all ages compared to men. Our results suggest that reactive and proactive inhibitory control partially rely on distinct neural substrates that are differentially sensitive to age-related change.

Crowdsourcing for cognitive science--the utility of smartphones.

By 2015, there will be an estimated two billion smartphone users worldwide. This technology presents exciting opportunities for cognitive science as a medium for rapid, large-scale experimentation and data collection. At present, cost and logistics limit most study populations to small samples, restricting the experimental questions that can be addressed. In this study we investigated whether the mass collection of experimental data using smartphone technology is valid, given the variability of data collection outside of a laboratory setting. We presented four classic experimental paradigms as short games, available as a free app and over the first month 20,800 users submitted data. We found that the large sample size vastly outweighed the noise inherent in collecting data outside a controlled laboratory setting, and show that for all four games canonical results were reproduced. For the first time, we provide experimental validation for the use of smartphones for data collection in cognitive science, which can lead to the collection of richer data sets and a significant cost reduction as well as provide an opportunity for efficient phenotypic screening of large populations.

The functional anatomy of attention: a DCM study.

Recent formulations of attention-in terms of predictive coding-associate attentional gain with the expected precision of sensory information. Formal models of the Posner paradigm suggest that validity effects can be explained in a principled (Bayes optimal) fashion in terms of a cue-dependent setting of precision or gain on the sensory channels reporting anticipated target locations, which is updated selectively by invalid targets. This normative model is equipped with a biologically plausible process theory in the form of predictive coding, where precision is encoded by the gain of superficial pyramidal cells reporting prediction error. We used dynamic causal modeling to assess the evidence in magnetoencephalographic responses for cue-dependent and top-down updating of superficial pyramidal cell gain. Bayesian model comparison suggested that it is almost certain that differences in superficial pyramidal cells gain-and its top-down modulation-contribute to observed responses; and we could be more than 80% certain that anticipatory effects on post-synaptic gain are limited to visual (extrastriate) sources. These empirical results speak to the role of attention in optimizing perceptual inference and its formulation in terms of predictive coding.

The computational anatomy of psychosis.

This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an inference machine that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes-optimal) account of action and perception that emphasizes probabilistic representations; in particular, the confidence or precision of beliefs about the world. We will consider hallucinosis, abnormal eye movements, sensory attenuation deficits, catatonia, and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision. From a cognitive perspective, this represents a pernicious failure of metacognition (beliefs about beliefs) that can confound perceptual inference. In the embodied setting of active (Bayesian) inference, it can lead to behaviors that are paradoxically more accurate than Bayes-optimal behavior. Crucially, this normative account is accompanied by a neuronally plausible process theory based upon hierarchical predictive coding. In predictive coding, precision is thought to be encoded by the post-synaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling post-synaptic gain - such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using biologically plausible simulations of perceptual synthesis, smooth pursuit eye movements and attribution of agency - that all use the same predictive coding scheme and pathology: namely, a reduction in the precision of prior beliefs, relative to sensory evidence.

Free-energy and illusions: the cornsweet effect.

In this paper, we review the nature of illusions using the free-energy formulation of Bayesian perception. We reiterate the notion that illusory percepts are, in fact, Bayes-optimal and represent the most likely explanation for ambiguous sensory input. This point is illustrated using perhaps the simplest of visual illusions; namely, the Cornsweet effect. By using plausible prior beliefs about the spatial gradients of illuminance and reflectance in visual scenes, we show that the Cornsweet effect emerges as a natural consequence of Bayes-optimal perception. Furthermore, we were able to simulate the appearance of secondary illusory percepts (Mach bands) as a function of stimulus contrast. The contrast-dependent emergence of the Cornsweet effect and subsequent appearance of Mach bands were simulated using a simple but plausible generative model. Because our generative model was inverted using a neurobiologically plausible scheme, we could use the inversion as a simulation of neuronal processing and implicit inference. Finally, we were able to verify the qualitative and quantitative predictions of this Bayes-optimal simulation psychophysically, using stimuli presented briefly to normal subjects at different contrast levels, in the context of a fixed alternative forced choice paradigm.

Active inference, attention, and motor preparation.

Perception is the foundation of cognition and is fundamental to our beliefs and consequent action planning. The Editorial (this issue) asks: "what mechanisms, if any, mediate between perceptual and cognitive processes?" It has recently been argued that attention might furnish such a mechanism. In this paper, we pursue the idea that action planning (motor preparation) is an attentional phenomenon directed toward kinesthetic signals. This rests on a view of motor control as active inference, where predictions of proprioceptive signals are fulfilled by peripheral motor reflexes. If valid, active inference suggests that attention should not be limited to the optimal biasing of perceptual signals in the exteroceptive (e.g., visual) domain but should also bias proprioceptive signals during movement. Here, we investigate this idea using a classical attention (Posner) paradigm cast in a motor setting. Specially, we looked for decreases in reaction times when movements were preceded by valid relative to invalid cues. Furthermore, we addressed the hierarchical level at which putative attentional effects were expressed by independently cueing the nature of the movement and the hand used to execute it. We found a significant interaction between the validity of movement and effector cues on reaction times. This suggests that attentional bias might be mediated at a low level in the motor hierarchy, in an intrinsic frame of reference. This finding is consistent with attentional enabling of top-down predictions of proprioceptive input and may rely upon the same synaptic mechanisms that mediate directed spatial attention in the visual system.