Linking Cognitive Integrity to Working Memory Dynamics in the Aging Human Brain.

Aging is accompanied by a decline of working memory, an important cognitive capacity that involves stimulus-selective neural activity that persists after stimulus presentation. Here, we unraveled working memory dynamics in older human adults (male and female) including those diagnosed with mild cognitive impairment (MCI) using a combination of behavioral modeling, neuropsychological assessment, and MEG recordings of brain activity. Younger adults (male and female) were studied with behavioral modeling only. Participants performed a visuospatial delayed match-to-sample task under systematic manipulation of the delay and distance between sample and test stimuli. Their behavior (match/nonmatch decisions) was fit with a computational model permitting the dissociation of noise in the internal operations underlying the working memory performance from a strategic decision threshold. Task accuracy decreased with delay duration and sample/test proximity. When sample/test distances were small, older adults committed more false alarms than younger adults. The computational model explained the participants' behavior well. The model parameters reflecting internal noise (not decision threshold) correlated with the precision of stimulus-selective cortical activity measured with MEG during the delay interval. The model uncovered an increase specifically in working memory noise in older compared with younger participants. Furthermore, in the MCI group, but not in the older healthy controls, internal noise correlated with the participants' clinically assessed cognitive integrity. Our results are consistent with the idea that the stability of working memory contents deteriorates in aging, in a manner that is specifically linked to the overall cognitive integrity of individuals diagnosed with MCI.

Appropriate Categorization of Inequality to Inform Policy Decisions: Estimating Distribution of Lifetime Health Using Alternative Approaches to Socioeconomic Stratification.

OBJECTIVES: Estimation of gradients in lifetime health, notably quality-adjusted life expectancy (QALE), has largely focused on index of multiple deprivation to categorize the population by socioeconomic position. In this article, we estimate QALE using alternate, individual- rather than area-level, indicators of socioeconomic position. METHODS: Building on previous research methods, the distribution of QALE is estimated across education and income groups based on data from the Health Survey for England and the Office for National Statistics. QALE is estimated for each group by combining multivariate mortality rates and health-related quality of life (HRQL) weights using life tables. HRQL weights were estimated using ordinary least squares and missing data were handled using multiple imputation. RESULTS: The estimated lifetime HRQL weights decreased with increased age, lower educational attainment, and lower income. For example, the QALE at birth for males in the lowest educational attainment group was 61.69 quality-adjusted life-years (QALYs), 1.54 QALYs lower than females in the same group. This is in contrast to 76.58 and 75.89 QALYs for males and females in the highest educational attainment group, respectively. A similar trend was observed across income quintiles albeit the gap was less pronounced. CONCLUSIONS: The use of index of multiple deprivation to assess health inequalities may be masking important information about individual-level variation. Decisions makers should consider this alongside the merits of using area-level approaches to categorizing the population if individual-level approaches are preferable.

Methods of assessing value for money of UK-based early childhood public health interventions: a systematic literature review.

INTRODUCTION: Economic evaluation has an important role to play in the demonstration of value for money of early childhood public health interventions; however, concerns have been raised regarding their consistent application and relevance to commissioners. This systematic review of the literature therefore aims to collate the breadth of the existing economic evaluation evidence of these interventions and to identify the approaches adopted in the assessment of value. SOURCE OF DATA: Recently published literature in Medline, EMBASE, EconLit, Health Management Information Consortium, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Health Technology Assessment, NHS EED and Web of Science. AREAS OF AGREEMENT: The importance of the early childhood period on future health and well-being as well as the potential to impact health inequalities making for a strong narrative case for expenditure in early childhood public health. AREAS OF CONTROVERSY: The most appropriate approaches to evaluating value for money of such preventative interventions relevant for UK decision-makers given the evident challenges. GROWING POINTS: The presented review considered inconsistencies across methodological approaches used to demonstrate value for money. The results showed a mixed picture in terms of demonstrating value for money. AREAS TIMELY FOR DEVELOPING RESEARCH: Future resource allocations decisions regarding early childhood public health interventions may benefit from consistency in the evaluative frameworks and health outcomes captured, as well as consistency in approaches to incorporating non-health costs and outcomes, incorporating equity concerns and the use of appropriate time horizons.

Effects of Secondary Dopant Anions on Emissivity and Related Properties of Poly(3,4-ethylenedioxythiophene).

Smart materials that are energy efficient and take up less space are crucial in the development of new technologies. Electrochromic polymers (ECPs) are one such class of materials that actively change their optical behavior in both visible and infrared parts of the electromagnetic spectrum. They show promise in a wide range of applications, from active camouflage to smart displays/windows. The full capabilities of ECPs are still yet to be explored, for while their electrochromic properties are well established, their Infrared (IR) modulation is less reported on. This study addresses the potential of ECPs in active IR modulating devices by optimization of Vapor Phase Polymerized poly(3,4-ethylenedioxythiophene) (PEDOT) thin films via the substitution of its dopant anion. Dynamic ranges denoting emissivity changes between reduced and oxidized states of PEDOT are found across dopants of tosylate, bromide, sulfate, chloride, perchlorate, and nitrate. Relative to the emissivity of reduced (neutral) PEDOT, a range of ±15% is achieved from the doped PEDOT films, and a maximum dynamic range of 0.11 across a 34% change is recorded for PEDOT doped with perchlorate.

Optogenetic therapy restores retinal activity in primate for at least a year following photoreceptor ablation.

All retina-based vision restoration approaches rely on the assumption that photoreceptor loss does not preclude reactivation of the remaining retinal architecture. Whether extended periods of vision loss limit the efficacy of restorative therapies at the retinal level is unknown. We examined long-term changes in optogenetic responsivity of foveal retinal ganglion cells (RGCs) in non-human primates following localized photoreceptor ablation by high-intensity laser exposure. By performing fluorescence adaptive optics scanning light ophthalmoscopy (AOSLO) of RGCs expressing both the calcium indicator GCaMP6s and the optogenetic actuator ChrimsonR, it was possible to track optogenetic-mediated calcium responses in deafferented RGCs over time. Fluorescence fundus photography revealed a 40% reduction in ChrimsonR fluorescence from RGCs lacking photoreceptor input over the 3 weeks following photoreceptor ablation. Despite this, in vivo imaging revealed good cellular preservation of RGCs 3 months after the loss of photoreceptor input, and histology confirmed good structural preservation at 2 years. Optogenetic responses of RGCs in primate persisted for at least 1 year after the loss of photoreceptor input, with a sensitivity index similar to optogenetic responses recorded in intact retina. These results are promising for all potential therapeutic approaches to vision restoration that rely on preservation and reactivation of RGCs.

A six-year teaching life supportive first aid program to eventually generate peer trainer pupils: a prospective case control study.

BACKGROUND: Out of hospital cardiac arrest is a life-threatening condition. To improve the chances of survival, lay-person cardio-pulmonary-resuscitation (CPR) is a crucial factor. Many bystanders fail to react appropriately, even if life supporting first aid (LSFA) programs and campaigns including CPR tried to increase the handling of basic cardiac life support. To achieve an enhanced learning of CPR a pupil's grade after grade teaching program was established in a school with medical students. METHODS: The learning of CPR was investigated in a prospective, case-controlled study at an international school. Pupils (12 ± 3 years old) joining our LSFA courses (n = 538, female: 243, attendance for evaluation: 476) were compared to a control group (n = 129, female: 52, attendance for evaluation: 102). Surveys and quality of CPR (QCPR%) through a computer linked "Resusci Anne" dummy were compared with Chi-squared tests, t-tests pair wisely, and by one-way ANOVA. RESULTS: Knowledge and skills on the "Resusci Anne" were significantly better in trained grade 9 pupils compared to the control group (QCPR, 59 vs. 25%). The number of LSFA courses each grade 9 student had, correlated with improved practical performance (r2 = 0.21, p < 0.001). The willingness to deliver CPR to strangers increased with improved practical performance. Attitudes towards performing CPR were high in all participating grades. CONCLUSION: Repetitive teaching LSFA to grade 5-9 pupil's grade after grade by medical students has been successfully established. Pupils who finish the program will eventually be able to teach LSFA to younger students. This is furthermore a good way of sharing a "learning by teaching" role and it enables to have more pupils as trainers who can provide instruction to a larger number of pupils with the purpose of having a better-trained population in LSFA.

Temporal Expectation Hastens Decision Onset But Does Not Affect Evidence Quality.

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory/motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modeling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation but had no effect on its build-up rate. Anticipatory α band power was modulated by temporal expectation and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events.SIGNIFICANCE STATEMENT Temporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We manipulated expectations about the onset of a dim visual target using a temporal cueing paradigm, and probed the locus of the expectation effect with two complementary approaches: drift diffusion modeling (DDM) of behavior, and estimation of the onset and progression of the decision process from a supramodal accumulation-to-bound signal in simultaneously measured EEG signals. Behavioral modeling and neural data provided strong, converging evidence for an account in which temporal expectations enhance perception by speeding up decision onset, without affecting evidence quality.

Appraising the Costs of Genomic Testing for Histology-Independent Technologies: An Illustrative Example for NTRK Fusions.

OBJECTIVES: Histology-independent (HI) technologies are authorized for patients with advanced or metastatic cancer if they express a particular biomarker regardless of its position in the body. Although this represents an important advancement in cancer treatment, genomic testing to identify eligible individuals for HI technologies will require substantial investment and impact their cost-effectiveness. Estimating these costs is complicated by several issues, which affect not only the overall cost of testing but also the distribution of testing costs across tumor types. METHODS: Key issues that should be considered when evaluating the cost of genomic testing to identify those eligible for HI technologies are discussed. These issues are explored in illustrative analyses where costs of genomic testing for NTRK fusions in England for recently approved HI technologies are estimated. RESULTS: The prevalence of mutation, testing strategy adopted, and current testing provision affect the cost of identifying eligible patients. The illustrative analysis estimated the cost of RNA-based next-generation sequencing to identify 1 individual with an NTRK fusion ranged between £377 and £282 258. To improve cost-effectiveness, testing costs could be shared across multiple technologies. An estimated additional ∼4000 patients would need to be treated with other HI therapies for testing in patients with advanced or metastatic cancer to be cost-effective. CONCLUSIONS: The cost of testing to identify individuals eligible for HI technologies affect the drug's cost-effectiveness. The cost of testing across tumor types varies owing to heterogeneity in the mutation's prevalence and current testing provision. The cost-effectiveness of HI technologies may be improved if testing costs could be shared across multiple agents.

Peripheral Tolerance Checkpoints Imposed by Ubiquitous Antigen Expression Limit Antigen-Specific B Cell Responses under Strongly Immunogenic Conditions.

A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached; however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically relevant B cell responses without the use of an engineered BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. In this study, we use a strong adjuvant to provide bystander innate and adaptive signals that promote B cell responsiveness in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more disease-relevant Ags, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

Modified fluid gelatin 4% for perioperative volume replacement in pediatric patients (GPS): Results of a European prospective noninterventional multicenter study.

INTRODUCTION: Modified fluid gelatin 4% is approved for use in children, but there is still a surprising lack of clinical studies including large numbers of pediatric patients. Therefore, we performed a European prospective noninterventional multicenter study to evaluate the use of a modified fluid gelatin 4% in saline (sal-GEL) or an acetate-containing balanced electrolyte solution (bal-GEL) in children undergoing major pediatric surgery. AIMS: The primary aim was to assess the indications and dosing of modified fluid gelatin, and the secondary aim was to assess the safety and efficacy, focusing, in particular, on routinely collected clinical parameters. METHODS: Children aged up to 12 years with ASA risk scores of I-III receiving sal-GEL or bal-GEL were followed perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events, and adverse drug reactions were documented using a standardized case report form. RESULTS: 601 children that were investigated at 13 European pediatric centers from May 2015 to March 2020 (sal-GEL 20.1%, bal-GEL 79.9%; mean age 29.1 ± 38.6 (range 0-144) months; body weight 12.1 ± 10.5 (1.4-70) kg) were included in the analysis. The most frequent indications for GEL infusion were hemodynamic instability without bleeding (76.0%), crystalloids alone not being sufficient for hemodynamic stabilization (55.7%), replacement of preoperative deficit (26.0%), and significant bleeding (13.0%). Mean infused GEL volume was 13.0 ± 5.3 (2.4-37.5) ml kg-1 . The total dose was affected by age, with higher doses in younger patients. After gelatin infusion, mean arterial pressure increased (mean change 8.5 ± 7.3 [95% CI: 8 to 9.1] mmHg), and the hemoglobin concentrations decreased significantly (mean change -1.1 ± 1.8 [95% CI: -1.2 to -0.9] g·dL-1 ). Acid-base parameters were more stable with bal-GEL. No serious adverse drug reactions directly related to gelatin (i.e., anaphylactoid reaction, clotting disorders, and renal failure) were observed. CONCLUSION: Moderate doses up to 20 ml kg-1 of modified fluid gelatin were infused most frequently to improve hemodynamic stability in children undergoing major pediatric surgery. The acid-base balance was more stable when gelatin in a balanced electrolyte solution was used instead of saline. No serious adverse drug reactions associated with gelatin were observed.

Fifteen-minute consultation: Intubation of the critically ill child presenting to the emergency department.

Intubation of critically ill children presenting to the emergency department is a high-risk procedure. Our article aims to offer a step-by-step guide as to how to plan and execute a rapid, successful intubation in a way that minimises risk of adverse events and patient harm. We address considerations such as the need for adequate resuscitation before intubation and selection of equipment and personnel. We also discuss drug choice for induction and peri-intubation instability, difficult airway considerations as well as postintubation care. Focus is also given on the value of preintubation checklists, both in terms of equipment selection and in the context of staff role designation and intubation plan clarity. Finally, in cases of failed intubation, we recommend the application of the Vortex approach, highlighting, thus, the importance of avoiding task fixation and maintaining our focus on what matters most: adequate oxygenation.

Epilepsy care during the COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has affected the care of all patients around the world. The International League Against Epilepsy (ILAE) COVID-19 and Telemedicine Task Forces examined, through surveys to people with epilepsy (PWE), caregivers, and health care professionals, how the pandemic has affected the well-being, care, and services for PWE. The ILAE included a link on their website whereby PWE and/or their caregivers could fill out a survey (in 11 languages) about the impact of the COVID-19 pandemic, including access to health services and impact on mental health, including the 6-item Kessler Psychological Distress Scale. An anonymous link was also provided whereby health care providers could report cases of new-onset seizures or an exacerbation of seizures in the context of COVID-19. Finally, a separate questionnaire aimed at exploring the utilization of telehealth by health care professionals since the pandemic began was available on the ILAE website and also disseminated to its members. Seventeen case reports were received; data were limited and therefore no firm conclusions could be drawn. Of 590 respondents to the well-being survey (422 PWE, 166 caregivers), 22.8% PWE and 27.5% caregivers reported an increase in seizure frequency, with difficulty in accessing medication and health care professionals reported as barriers to care. Of all respondents, 57.1% PWE and 21.5% caregivers had severe psychological distress (k score >13), which was significantly higher among PWE than caregivers (p<0.01). An increase in telemedicine use during the COVID-19 pandemic was reported by health care professionals, with 40% of consultations conducted by this method. Although 74.9% of health care providers thought that this impacted positively, barriers to care were also identified. As we move forward, there is a need to ensure ongoing support and care for PWE to prevent a parallel pandemic of unmet health care needs.

A Postdecisional Neural Marker of Confidence Predicts Information-Seeking in Decision-Making.

Theoretical work predicts that decisions made with low confidence should lead to increased information-seeking. This is an adaptive strategy because it can increase the quality of a decision, and previous behavioral work has shown that decision-makers engage in such confidence-driven information-seeking. The present study aimed to characterize the neural markers that mediate the relationship between confidence and information-seeking. A paradigm was used in which 17 human participants (9 male) made an initial perceptual decision, and then decided whether or not they wanted to sample more evidence before committing to a final decision and confidence judgment. Predecisional and postdecisional event-related potential components were similarly modulated by the level of confidence and by information-seeking choices. Time-resolved multivariate decoding of scalp EEG signals first revealed that both information-seeking choices and decision confidence could be decoded from the time of the initial decision to the time of the subsequent information-seeking choice (within-condition decoding). No above-chance decoding was visible in the preresponse time window. Crucially, a classifier trained to decode high versus low confidence predicted information-seeking choices after the initial perceptual decision (across-condition decoding). This time window corresponds to that of a postdecisional neural marker of confidence. Collectively, our findings demonstrate, for the first time, that neural indices of confidence are functionally involved in information-seeking decisions.SIGNIFICANCE STATEMENT Despite substantial current interest in neural signatures of our sense of confidence, it remains largely unknown how confidence is used to regulate behavior. Here, we devised a task in which human participants could decide whether or not to sample additional decision-relevant information at a small monetary cost. Using neural recordings, we could predict such information-seeking choices based on a neural signature of decision confidence. Our study illuminates a neural link between decision confidence and adaptive behavioral control.

Noradrenergic and Cholinergic Modulation of Belief Updating.

To make optimal predictions in a dynamic environment, the impact of new observations on existing beliefs-that is, the learning rate-should be guided by ongoing estimates of change and uncertainty. Theoretical work has proposed specific computational roles for various neuromodulatory systems in the control of learning rate, but empirical evidence is still sparse. The aim of the current research was to examine the role of the noradrenergic and cholinergic systems in learning rate regulation. First, we replicated our recent findings that the centroparietal P3 component of the EEG-an index of phasic catecholamine release in the cortex-predicts trial-to-trial variability in learning rate and mediates the effects of surprise and belief uncertainty on learning rate (Study 1, n = 17). Second, we found that pharmacological suppression of either norepinephrine or acetylcholine activity produced baseline-dependent effects on learning rate following nonobvious changes in an outcome-generating process (Study 1). Third, we identified two genes, coding for α2A receptor sensitivity (ADRA2A) and norepinephrine reuptake (NET), as promising targets for future research on the genetic basis of individual differences in learning rate (Study 2, n = 137). Our findings suggest a role for the noradrenergic and cholinergic systems in belief updating and underline the importance of studying interactions between different neuromodulatory systems.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

UNLABELLED: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

Pseudomonas Quinolone Signal Induces Oxidative Stress and Inhibits Heme Oxygenase-1 Expression in Lung Epithelial Cells.

Pseudomonasaeruginosa causes lung infections in patients with cystic fibrosis (CF). The Pseudomonas quinolone signal (PQS) compound is a secreted P. aeruginosa virulence factor that contributes to the pathogenicity of P. aeruginosa We were able to detect PQS in sputum samples from CF patients infected with P. aeruginosa but not in samples from uninfected patients. We then tested the hypothesis that PQS induces oxidative stress in host cells by determining the ability of PQS to induce the production of reactive oxygen species (ROS) in lung epithelial cells (A549 and primary normal human bronchial epithelial [NHBE]) cells and macrophages (J774A.1 and THP-1). ROS production induced by PQS was detected with fluorescent probes (dichlorodihydrofluorescein diacetate, dihydroethidium, and MitoSOX Red) in conjunction with confocal microscopy and flow cytometry. PQS induced ROS production in lung epithelial (A549 and NHBE) cells and macrophages (J774A.1 and THP-1 cells). NHBE cells were sensitive to PQS concentrations as low as 500 ng/ml. PQS significantly induced early apoptosis (P < 0.05, n = 6) in lung epithelial cells, as measured by annexin/propidium iodide detection by flow cytometry. However, no change in apoptosis upon PQS treatment was seen in J774A.1 cells. Heme oxygenase-1 (HO-1) protein is an antioxidant enzyme usually induced by oxidative stress. Interestingly, incubation with PQS significantly reduced HO-1 and NrF2 expression in A549 and NHBE cells but increased HO-1 expression in J774A.1 cells (P < 0.05, n = 3), as determined by immunoblotting and densitometry. These PQS effects on host cells could play an important role in the pathogenicity of P. aeruginosa infections.

Parsing the neural signatures of reduced error detection in older age.

Recent work has demonstrated that explicit error detection relies on a neural evidence accumulation process that can be traced in the human electroencephalogram (EEG). Here, we sought to establish the impact of natural aging on this process by recording EEG from young (18-35 years) and older adults (65-88 years) during the performance of a Go/No-Go paradigm in which participants were required to overtly signal their errors. Despite performing the task with equivalent accuracy, older adults reported substantially fewer errors, and the timing of their reports were both slower and more variable. These behavioral differences were linked to three key neurophysiological changes reflecting distinct parameters of the error detection decision process: a reduction in medial frontal delta/theta (2-7 Hz) activity, indicating diminished top-down input to the decision process; a slower rate of evidence accumulation as indexed by the rate of rise of a centro-parietal signal, known as the error positivity; and a higher motor execution threshold as indexed by lateralized beta-band (16-30 Hz) activity. Our data provide novel insight into how the natural aging process affects the neural underpinnings of error detection.

Catecholaminergic Regulation of Learning Rate in a Dynamic Environment.

Adaptive behavior in a changing world requires flexibly adapting one's rate of learning to the rate of environmental change. Recent studies have examined the computational mechanisms by which various environmental factors determine the impact of new outcomes on existing beliefs (i.e., the 'learning rate'). However, the brain mechanisms, and in particular the neuromodulators, involved in this process are still largely unknown. The brain-wide neurophysiological effects of the catecholamines norepinephrine and dopamine on stimulus-evoked cortical responses suggest that the catecholamine systems are well positioned to regulate learning about environmental change, but more direct evidence for a role of this system is scant. Here, we report evidence from a study employing pharmacology, scalp electrophysiology and computational modeling (N = 32) that suggests an important role for catecholamines in learning rate regulation. We found that the P3 component of the EEG-an electrophysiological index of outcome-evoked phasic catecholamine release in the cortex-predicted learning rate, and formally mediated the effect of prediction-error magnitude on learning rate. P3 amplitude also mediated the effects of two computational variables-capturing the unexpectedness of an outcome and the uncertainty of a preexisting belief-on learning rate. Furthermore, a pharmacological manipulation of catecholamine activity affected learning rate following unanticipated task changes, in a way that depended on participants' baseline learning rate. Our findings provide converging evidence for a causal role of the human catecholamine systems in learning-rate regulation as a function of environmental change.

Moving beyond the rhetoric of patient input in health technology assessment deliberations.

At a health system level, the importance of patient and public input into healthcare decision making is well recognised. Patient and public involvement not only provides a mechanism to legitimise decisions, but also contributes to improved translation of these decisions into practice, ultimately leading to better patient outcomes. Recent reviews in the health technology assessment space have identified the need for, and increased use of, patient input through systematic methodologies. Yet, what does this mean in practical terms? This paper outlines both short- and longer-term options for strengthening patient input into health technology assessment deliberations. This is particularly important given the planned reforms in this area and the commitment to public consultation as part of the reform process.

Unusual Nature of Fingerprints and the Implications for Easy-to-Clean Coatings.

Irrespective of the technology, we now rely on touch to interact with devices such as smart phones, tablet computers, and control panels. As a result, touch screen technologies are frequently in contact with body grease. Hence, surface deposition arises from localized inhomogeneous finger-derived contaminants adhering to a surface, impairing the visual/optical experience of the user. In this study, we examined the contamination itself in order to understand its static and dynamic behavior with respect to deposition and cleaning. A process for standardized deposition of fingerprints was developed. Artificial sebum was used in this process to enable reproducibility for quantitative analysis. Fingerprint contamination was shown to be hygroscopic and to possess temperature- and shear-dependent properties. These results have implications for the design of easily cleanable surfaces.