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Long-term consumption of beetroot juice on efficacy of converting dietary nitrate to plasma nitrate and nitrite was investigated. Adults were randomized to consume either beetroot juice with 380 mg of nitrate (BR) or a beetroot juice placebo (PL) for 12-weeks. Plasma nitrate and nitrite were measured before and 90-minutes after consuming their intervention beverage. Percent change in nitrite across the 90 min was greater in BR (273.2 ± 39.9%) vs. PL (4.9 ± 36.9%). Long-term consumption of nitrate containing beetroot juice increased fasting nitrate and nitrite plasma levels compared to baseline.

Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time.We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg.FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period.This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.

Much of sensory neuroscience focuses on presenting stimuli that are chosen by the experimenter because they are parametric and easy to sample and are thought to be behaviorally relevant to the organism. However, it is not generally known what these relevant features are in complex, natural scenes. This work focuses on using the retinal encoding of natural movies to determine the presumably behaviorally-relevant features that the brain represents. It is prohibitive to parameterize a natural movie and its respective retinal encoding fully. We use time within a natural movie as a proxy for the whole suite of features evolving across the scene. We then use a task-agnostic deep architecture, an encoder-decoder, to model the retinal encoding process and characterize its representation of “time in the natural scene” in a compressed latent space. In our end-to-end training, an encoder learns a compressed latent representation from a large population of salamander retinal ganglion cells responding to natural movies, while a decoder samples from this compressed latent space to generate the appropriate future movie frame. By comparing latent representations of retinal activity from three movies, we find that the retina has a generalizable encoding for time in the natural scene: the precise, low-dimensional representation of time learned from one movie can be used to represent time in a different movie, with up to 17 ms resolution. We then show that static textures and velocity features of a natural movie are synergistic. The retina simultaneously encodes both to establishes a generalizable, low-dimensional representation of time in the natural scene.

State legislatures in the United States began using the legislative veto in 1939 to block rules issued by state agencies. At present, 25 state legislatures possess some form of independent legislative veto authority. This study uses a transaction cost theoretical approach to analyse factors expected to influence the adoption and expansion of legislative veto oversight. Results indicate that such measures are more likely in non-Southern states when a single party controls the state legislature, while legislative size and professionalisation do not substantially affect legislative veto reforms. Empirical analysis differentiating veto power according to whether legislators can nullify or suspend rules shows some differences in the factors affecting the imposition of each oversight type. The most consistent finding is that empowering legislatures with legislative veto authority is more likely to occur with a Republican governor in office.

Background Muscle weakness and impairments in physical functioning are well-recognised sequelae after critical illness. Whether individuals have a higher risk of community falls and a fear of falling has not been examined amongst individuals after critical illness. Objectives The objective of this study was to explore the prevalence of falls, fear of falling, and fall risk in intensive care unit (ICU) survivors over a 6-month period after hospital discharge. Methods This was a nested exploratory study within a medical ICU. Fall prevalence was measured in line with established guidelines over 6 months after ICU discharge. Fear of falling and prediction of fall risk were assessed at 2, 4, and 6 months after discharge. Results Twelve individuals were included. Half of the cohort (n = 6) had at least one fall, with one-third sustaining more than one fall. There were 17 falls reported across the six individuals. Injuries requiring medical intervention were reported with five falls. Almost one-third were classified as ‘moderate’ to ‘severe’ injurious falls. Loss of balance and fatigue were reported as the main contributors to the falls. All individuals who had a fall reported a severe fear of falling at 2 months. Individuals classified as having ‘moderate’ to ‘high’ risk of falls at 2 months were more likely to have at least one fall. Conclusions This study suggests that ICU survivors may have a high fall risk, fear of falling, and fall prevalence, which can result in significant injury.

Nitrate rich beetroot juice (BRJ) can enhance nitric oxide signaling, leading to improved physical function in healthy and diseased populations, but its safety and biologic efficacy have not been evaluated in a critically ill population. We randomized 22 previously functional acute respiratory failure patients to either BRJ or placebo daily until day 14 or discharge. We measured blood nitrate and nitrite levels and quantified strength and physical function at intensive care unit (ICU) and hospital discharge. Participants were predominantly male (54%), aged 68.5 years with an APACHE III score of 62. BRJ increased plasma nitrate (mean 219.2 μM increase, p = 0.002) and nitrite levels (mean 0.144 μM increase, p = 0.02). We identified no adverse events. The unadjusted and adjusted effect sizes of the intervention on the short physical performance battery were small (d = 0.12 and d = 0.17, respectively). In this pilot trial, administration of BRJ was feasible and safe, increased blood nitrate and nitrate levels, but had a small effect on physical function. Future studies could evaluate the clinical efficacy of BRJ as a therapy to improve physical function in survivors of critical illness.

To explore how neural circuits represent novel versus familiar inputs, we presented mice with repeated sets of images with novel images sparsely substituted. Using two-photon calcium imaging to record from layer 2/3 neurons in the mouse primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. This novelty response rapidly emerged, arising with a time constant of 2.6 ± 0.9 s. When a new image set was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which decayed to steady state with a time constant of 1.4 ± 0.4 s. When we increased the number of images in the set, the novelty response's amplitude decreased, defining a capacity to store ∼15 familiar images under our conditions. These results could be explained quantitatively using an adaptive subunit model in which presynaptic neurons have individual tuning and gain control. This result shows that local neural circuits can create different representations for novel versus familiar inputs using generic, widely available mechanisms.

A notable feature of neural activity is sparseness – namely, that only a small fraction of neurons in a local circuit have high activity at any moment. Not only is sparse neural activity observed experimentally in most areas of the brain, but sparseness has been proposed as an optimization or design principle for neural circuits. Sparseness can increase the energy efficiency of the neural code as well as allow for beneficial computations to be carried out. But how does the brain achieve sparse-ness? Here, we found that when neurons in the primary visual cortex were passively exposed to a set of images over several days, neural responses became more sparse. Sparsification was driven by a decrease in the response of neurons with low or moderate activity, while highly active neurons retained similar responses. We also observed a net decorrelation of neural activity. These changes sculpt neural activity for greater coding efficiency.

Objective Chronic pain can have detrimental effects on quality of life and a profound impact on one’s identity. The Pictorial Representation of Illness- and Self-Measure (PRISM), is a visual tool designed to measure the self-illness separation (SIS) that represents the degree of schema-enmeshment (i.e., the degree to which the self-schema and the illness-schema come to overlap). Our aim was to investigate the relationship between schema-enmeshment and pain-related outcomes in patients with fibromyalgia. Methods In this cross-sectional study, 114 patients with fibromyalgia completed self-report assessments of pain catastrophizing, pain severity and interference, impact of symptoms, anxiety, and depression. SIS was assessed using an iPad version of PRISM. Mediation analyses evaluated the mediating role of schema-enmeshment on the association between pain catastrophizing and fibromyalgia impact. Results A higher degree of schema-enmeshment was associated with greater pain catastrophizing, pain severity and interference, impact of symptoms, and depression. Moreover, a mediation analysis revealed that schema-enmeshment significantly mediated the association between pain catastrophizing and fibromyalgia impact (p Conclusions Our results indicate that schema-enmeshment is associated with greater intrusiveness of chronic pain on everyday life, thereby posing significant limitations on the emotional and physical well-being of fibromyalgia patients. Schema-enmeshment also appears to partly account for the deleterious effect of pain catastrophizing on disease impact. The PRISM is a simple tool that may uniquely capture the extent to which chronic pain and illness infiltrates and affects one’s self-concept.

Objective Limited data exists on the quantification of activity levels and functional status in critically ill patients as they transition from the intensive care unit (ICU) to the wards and subsequently, back into the community. We characterize the physical activity of critically ill patients from their ICU stay until seven days after hospital discharge, as well as correlate physical activity levels with an objective measure of physical function. Methods This prospective observational study of previously independent adults age 55 or older, undergoing mechanical ventilation for up to 7 days, recruited participants at the time of spontaneous breathing trials or Results Twenty-two participants received accelerometers; 15 were suitable for analysis. Participants were 68 ± 9.6 years old; 47% female. Step counts (mean and 95% CI) were 95 [15–173] in the 3 days before ICU discharge, 257 [114–400] before hospital discharge, 1223 [376–2070] in the first 3 days at home and 1278 [349–2207] between day 4 and 6 post-hospital discharge. Physical activity was significantly higher post- compared to pre-hospital discharge. Short Physical Performance Battery scores (SPPB) were poor at ICU and hospital discharge; however, correlated moderately with physical activity levels immediately upon return home. Conclusions Physical activity remained low as survivors of critical illness transitioned from ICU to hospital wards, but significantly increased upon return to the community. Despite poor SPPB scores at both ICU and hospital discharge, participants were significantly more active immediately after discharge than in their last 3 days of hospitalization. This may represent rapid functional improvement or conversely, constrained physical activity in hospital. Impact This study highlights the need for further evaluation of physical activity constraints in hospital and ways to augment physical activity and function upon discharge. Lay summary Physical activity (step counts) increased modestly as survivors of critical illness transitioned from ICU to hospital wards, but significantly increased upon return to the community. This study highlights the need for further evaluation of physical activity constraints in the hospital setting and ways to augment physical activity and function post-discharge.

This study investigates whether differences in learning styles exist between students in online and face-to-face (FTF) sections of political science courses taught by three instructors. Som...

Purpose To examine relationships between self-report and performance-based measures of physical function in ICU patients randomized to standardized rehabilitation therapy (SRT) or usual care (UC). Methods Physical function was assessed in 257 ICU patients using self-report (physical functioning scale of the SF-36 (SF-36 PFS)) and the functional performance inventory-short form (FPI-SF) as well as performance-based measures (Short Physical Performance Battery (SPPB)) and muscular strength (MS). Assessments were at hospital discharge, 2, 4, and 6 months. Results Correlations between self-report and performance-based measures were not significantly different between the two groups. When examining the entire cohort, a significant, but weak, correlation (r = 0.286) was found between the SF-36 PFS and the SPPB. At 2 months, moderate correlations were found between self-report and performance-based measures. The SF-36 PFS and FPI were significantly correlated with the SPPB (r = 0.536 and 0.553, respectively) and muscular strength (r = 0.413 and 0.431, respectively). Similar associations were seen at 4 and 6 months in both groups. Conclusion Self-report and performance-based measures of physical function appear to assess different constructs at hospital discharge. Following recovery, these measures converge, but indicate different constructs are being assessed. As such, both self-report and performance-based measures of physical function should be used with ICU patients.

Purpose Patients with acute respiratory failure (ARF) show changes in skeletal muscle structure and strength. The purpose of this study was to examine the relationship between muscle thickness, echogenicity, and strength in patients with ARF. Methods Thirteen (6 females, 7 males) patients with ARF participated in the study. Knee extensor strength was measured via a handheld dynamometer and quadriceps images were obtained via ultrasonography at hospital discharge. The ultrasonograms were used to obtain muscle thickness and both mean ± SD echogenicity of the rectus femoris, vastus lateralis, and vastus medialis. Partial correlations, controlling for age, body mass index, and fluid intake were used to describe the relationships among knee extensor strength and echogenicity and muscle thickness. Results Knee extensor strength and vastus lateralis SD echogenicity were significantly correlated when controlling for age, body mass index, and fluid intake (r = 0.69, P = .029). Knee extensor strength and vastus lateralis echogenicity were 19.1 ± 8.0 kg and 19.8 ± 5.4 units, respectively. No other correlations between strength and ultrasound measures were found to be significant. Conclusion These results show skeletal muscle echogenicity to be significantly correlated with skeletal muscle strength in patients with ARF. As such, it may be useful in identifying muscle weakness in these patients when they are unable or unwilling to perform voluntary strength testing.

Pulmonary arterial hypertension (PAH) is characterized by impaired pulmonary vascular structure and function and is commonly associated with symptoms of dyspnea, fatigue, and potentially syncope. With chronic exposure to elevated pulmonary pressures, dramatic right ventricular dysfunction is common, thereby compromising cardiorespiratory fitness and increasing the risk of mortality. Collective investigative efforts, both at the preclinical and clinical levels, have established the safety and efficacy of regular exercise training in improving quality of life, cardiorespiratory fitness, and the physiologic profile of patients with PAH. Although the total volume of exercise training studies in patients with PAH pales in comparison with other chronic conditions, evidence for the optimal training recommendations is emerging. This review aims to provide a synopsis of the current exercise training literature in patients with PAH and provide preliminary training recommendations that can be implemented in rehabilitation programs.

Rationale: Survivorship from critical illness has improved; however, factors mediating the functional recovery of persons experiencing a critical illness remain incompletely understood. Objectives: To identify groups of acute respiratory failure (ARF) survivors with similar patterns of physical function recovery after discharge and to determine the characteristics associated with group membership in each physical function trajectory group. Methods: We performed a secondary analysis of a randomized controlled trial, using group-based trajectory modeling to identify distinct subgroups of patients with similar physical function recovery patterns after ARF. Chi-square tests and one-way analysis of variance were used to determine which variables were associated with trajectory membership. A multinomial logistic regression analysis was performed to identify variables jointly associated with trajectory group membership. Results: A total of 260 patients enrolled in a trial evaluating standardized rehabilitation therapy in patients with ARF and discharged alive (NCT00976833) were included in this analysis. Physical function was quantified using the Short Physical Performance Battery at hospital discharge and 2, 4, and 6 months after enrollment. Latent class analysis of the Short Physical Performance Battery scores identified four trajectory groups. These groups differ in both the degree and rate of physical function recovery. A multinomial logistic regression analysis was performed using covariates that have been previously identified in the literature as influencing recovery after critical illness. By multinomial logistic regression, age (P

BACKGROUNDVenous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. In England, reporting the percentage of patients with a completed VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance (an assessment and action) is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems(EPS) can mandate guideline-compliant actions. We hypothesised that EPS-based interventions would increase full VTE guideline compliance more than other interventions.METHODSAll admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011-2020. The proportion of patients who received a fully compliant risk assessment and action was assessed over time. Interventions included face-to-face feedback based on measured performance (an individual approach) and mandatory risk assessment and prescribing rules into an EPS (a systems approach).RESULTSData from all 235,005 admissions and all 5503 prescribers were included in the analysis. Face-to-face feedback improved full VTE guideline concordance from 70% to 77% (p=DISCUSSION/ CONCLUSIONAn EPS-systems approach was more effective in improving sustained guideline-compliant VTE prevention. Non-compliance was still not eradicated despite this mandated system and requires further research.FUNDINGHDR-UK Hub PIONEERSummary BoxWhat is already known?Hospitalised patients are at an increased risk of venous thromboembolism (VTE), which can lead to significant morbidity and mortality. Risk factors for VTE are well known, there are established screening criteria and there is an effective prophylactic therapy, using low molecular weight heparin where indicated. Since 2010, NHS England has mandated the reporting of the percentage of patients with a completed VTE risk assessment. However, it does not automatically follow that completing a risk assessment leads to the appropriate action (prescribing and administering VTE prophylaxis where indicated). Currently it is unclear what percentage of patients have a guideline compliant VTE risk assessment and an associated action, or how full guideline compliance can be improved.What does this paper add?First, this paper describes that a VTE risk assessment does not always lead to full VTE guideline compliance (an appropriate prescription and administration of heparin where indicated). This is currently not part of mandated reporting but potentially could lead to patient harm. Second, that Electronic Health Systems (EHS) can capture and interrogate guideline-associated risk assessments and prescribing, and be used to improve full guideline compliance, through a combination of individual feedback to prescribing outliers and mandated prescribing rules. These EPS-assisted systems are robust, and sustain guideline compliance through personnel and formulary changes.

Animals depend on fast and reliable detection of novel stimuli in their environment. Indeed, neurons in multiple sensory areas respond more strongly to novel in comparison to familiar stimuli. Yet, it remains unclear which circuit, cellular and synaptic mechanisms underlie those responses. Here, we show that inhibitory synaptic plasticity readily generates novelty responses in a recurrent spiking network model. Inhibitory plasticity increases the inhibition onto excitatory neurons tuned to familiar stimuli, while inhibition for novel stimuli remains low, leading to a network novelty response. Generated novelty responses do not depend on the exact temporal structure but rather on the distribution of presented stimuli. By including tuning of inhibitory neurons, the network further captures stimulus-specific adaptation. Finally, we suggest that disinhibition can control the amplification of novelty responses. Therefore, inhibitory plasticity provides a flexible, biologically-plausible mechanism to detect the novelty of bottom-up stimuli, enabling us to make numerous experimentally testable predictions.

Pain catastrophizing is prominent in chronic pain conditions such as fibromyalgia and has been proposed to contribute to the development of pain widespreadness. However, the brain mechanisms responsible for this association are unknown. We hypothesized that increased resting salience network (SLN) connectivity to nodes of the default mode network (DMN), representing previously reported pain-linked cross-network enmeshment, would be associated with increased pain catastrophizing and widespreadness across body sites. We applied functional magnetic resonance imaging (fMRI) and digital pain drawings (free-hand drawing over a body outline, analyzed using conventional software for multivoxel fMRI analysis) to investigate precisely quantified measures of pain widespreadness and the associations between pain catastrophizing (Pain Catastrophizing Scale), resting brain network connectivity (Dual-regression Independent Component Analysis, 6-minute multiband accelerated fMRI), and pain widespreadness in fibromyalgia patients (N = 79). Fibromyalgia patients reported pain in multiple body areas (most frequently the spinal region, from the lower back to the neck), with moderately high pain widespreadness (mean ± SD: 26.1 ± 24.1% of total body area), and high pain catastrophizing scale scores (27.0 ± 21.9, scale range: 0-52), which were positively correlated (r = 0.26, P = 0.02). A whole-brain regression analysis focused on SLN connectivity indicated that pain widespreadness was also positively associated with SLN connectivity to the posterior cingulate cortex, a key node of the DMN. Moreover, we found that SLN-posterior cingulate cortex connectivity statistically mediated the association between pain catastrophizing and pain widespreadness (P = 0.01). In conclusion, we identified a putative brain mechanism underpinning the association between greater pain catastrophizing and a larger spatial extent of body pain in fibromyalgia, implicating a role for brain SLN-DMN cross-network enmeshment in mediating this association.

Purpose Nitrate (NO3-), through its conversion to nitrite (NO2-) and nitric oxide, has been shown to increase exercise tolerance in healthy younger adults and older diseased patients. Nitrate’s effect in well-trained middle to older-aged adults has not been studied. Therefore, the purpose of this investigation was to examine the effects of a NO3- rich beverage on submaximal constant work rate exercise time in well-trained middle to older-aged adults. Methods This was a randomized controlled cross-over trial with 15 well-trained middle to older-aged adults, 41–64 year-old, who received one of two treatments (NO3- rich beverage then placebo or placebo then NO3- rich beverage), after which an exercise test at 75 percent of the subject’s maximal work rate was completed. Results The NO3- rich beverage increased plasma NO3- and NO2- levels by 260 μM and 0.47 μM, respectively (p

An appealing new principle for neural population codes is that correlations among neurons organize neural activity patterns into a discrete set of clusters, which can each be viewed as a noise-robust population codeword. Previous studies assumed that these codewords corresponded geometrically with local peaks in the probability landscape of neural population responses. Here, we analyze multiple data sets of the responses of approximately 150 retinal ganglion cells and show that local probability peaks are absent under broad, nonrepeated stimulus ensembles, which are characteristic of natural behavior. However, we find that neural activity still forms noise-robust clusters in this regime, albeit clusters with a different geometry. We start by defining a soft local maximum, which is a local probability maximum when constrained to a fixed spike count. Next, we show that soft local maxima are robustly present and can, moreover, be linked across different spike count levels in the probability landscape to form a ridge. We found that these ridges comprise combinations of spiking and silence in the neural population such that all of the spiking neurons are members of the same neuronal community, a notion from network theory. We argue that a neuronal community shares many of the properties of Donald Hebb's classic cell assembly and show that a simple, biologically plausible decoding algorithm can recognize the presence of a specific neuronal community.

Alpha herpesviruses naturally infect the peripheral nervous system, and can spread to the central nervous system causing severe deadly or debilitating disease. Because alpha herpesviruses spread along synaptic circuits, and infected neurons exhibit altered electrophysiology and increased spontaneous firing, we hypothesized that alpha herpesviruses use activity-dependent synaptic vesicle-like regulated secretory mechanisms for egress and spread from neurons. To address this hypothesis, we used a compartmentalized primary neuron culture system to measure egress and spread of pseudorabies virus (PRV), pharmacological and optogenetics approaches to modulate neuronal firing activity, and a live-cell fluorescence microscopy assay to directly visualize the exocytosis of individual virus particles from infected neurons. Using tetrodotoxin to silence neuronal activity, we observed no inhibition of virus spread, and using potassium chloride or optogenetics to elevate neuronal activity, we also show no increase in virus spread. Using a live-cell fluorescence microscopy method to directly measure virus egress from infected neurons, we observed no association between virus particle exocytosis and intracellular Ca2+ signaling. Finally, we observed virus particle exocytosis occurs in association with constitutive secretory Rab GTPases, Rab6a and Rab8a, not Rab proteins that are associated with the Ca2+-regulated secretory pathway in neurons, Rab3a and Rab11a. Therefore, we conclude that alpha herpesvirus egress and spread is independent of neuronal activity and Ca2+ signaling because virus particle exocytosis uses constitutive secretory mechanisms in neurons.Author SummaryAlpha herpesviruses, including important human pathogens Herpes Simplex Virus 1 and 2, and Varicella-Zoster Virus, are among the very few viruses that naturally infect the nervous system. These viruses cause recurrent herpetic and zosteriform lesions, peripheral neuropathies, and deadly or debilitating central nervous system diseases. Many of the molecular and cellular mechanisms of viral egress and spread remain unknown, particularly in the context of specialized neuronal cell biology. Our results indicate that elevated firing activity of infected neurons is not functionally or mechanistically linked to virus egress and spread; therefore, therapies targeting peripheral neuropathic symptoms, elevated neuronal activity, and synaptic vesicle secretory mechanisms are unlikely to affect virus spread in the nervous system.

International audience; Within a given brain region, individual neurons exhibit a wide variety of different feature selectivities. Here, we investigated the impact of this extensive functional diversity on the population neural code. Our approach was to build optimal decoders to discriminate among stimuli using the spiking output of a real, measured neural population and compare its performance against a matched, homogeneous neural population with the same number of cells and spikes. Analyzing large populations of retinal ganglion cells, we found that the real, heterogeneous population can yield a discrimination error lower than the homogeneous population by several orders of magnitude and consequently can encode much more visual information. This effect increases with population size and with graded degrees of heterogeneity. We complemented these results with an analysis of coding based on the Chernoff distance, as well as derivations of inequalities on coding in certain limits, from which we can conclude that the beneficial effect of heterogeneity occurs over a broad set of conditions. Together, our results indicate that the presence of functional diversity in neural populations can enhance their coding fidelity appreciably. A noteworthy outcome of our study is that this effect can be extremely strong and should be taken into account when investigating design principles for neural circuits.

The separation of visual input into discrete channels begins at the photoreceptor to bipolar cell synapse. Current models of the ON pathway describe the time-varying membrane voltage of ON bipolar cells as a linear function of light fluctuations. While this linearity holds under some visual conditions, stimulating the retina with full-field, high contrast flashes reveals a number of nonlinearities already present in the input current of ON bipolar cells. First, we show that the synaptic input to ON bipolar cells is asymmetric in response to equal flashes of opposite polarity. Next, we show that this asymmetry emerges because the responses to dark flashes increase linearly with contrast, whereas responses to bright flashes are highly rectified. We also describe how the outward current saturates in response to dark flashes of increasing duration. Furthermore, varying the inter-flash interval between a pair of high contrast flashes reveals a rapid, transient form of gain control that modulates both the amplitude and time course of the flash response. We develop a phenomenological model that captures the primary features of the ON bipolar cell response at high contrast. Finally, we discuss the implications of these nonlinearities in our understanding of how retinal circuitry shapes the visual signal.

IntroductionThe number of inconclusive physical rehabilitation randomised controlled trials for patients with critical illness is increasing. Evidence suggests critical illness patient subgroups may exist that benefit from targeted physical rehabilitation interventions that could improve their recovery trajectory. We aim to identify critical illness patient subgroups that respond to physical rehabilitation and map recovery trajectories according to physical function and quality of life outcomes. Additionally, the utilisation of healthcare resources will be examined for subgroups identified.Methods and analysisThis is an individual participant data meta-analysis protocol. A systematic literature review was conducted for randomised controlled trials that delivered additional physical rehabilitation for patients with critical illness during their acute hospital stay, assessed chronic disease burden, with a minimum follow-up period of 3 months measuring performance-based physical function and health-related quality of life outcomes. From 2178 records retrieved in the systematic literature review, four eligible trials were identified by two independent reviewers. Principal investigators of eligible trials were invited to contribute their data to this individual participant data meta-analysis. Risk of bias will be assessed (Cochrane risk of bias tool for randomised trials). Participant and trial characteristics, interventions and outcomes data of included studies will be summarised. Meta-analyses will entail a one-stage model, which will account for the heterogeneity across and the clustering between studies. Multiple imputation using chained equations will be used to account for the missing data.Ethics and disseminationThis individual participant data meta-analysis does not require ethical review as anonymised participant data will be used and no new data collected. Additionally, eligible trials were granted approval by institutional review boards or research ethics committees and informed consent was provided for participants. Data sharing agreements are in place permitting contribution of data. The study findings will be disseminated at conferences and through peer-reviewed publications.PROSPERO registration numberCRD42019152526.

When correlations within a neural population are strong enough, neural activity in early visual areas is organized into a discrete set of clusters. Here, we show that a simple, biologically plausible circuit can learn and then readout in real-time the identity of experimentally measured clusters of retinal ganglion cell population activity. After learning, individual readout neurons develop cluster tuning, meaning that they respond strongly to any neural activity pattern in one cluster and weakly to all other inputs. Different readout neurons specialize for different clusters, and all input clusters can be learned, as long as the number of readout units is mildly larger than the number of input clusters. We argue that this operation can be repeated as signals flow up the cortical hierarchy.

Comparisons between endurance and strength training in chronic obstructive pulmonary disease (COPD) patients have produced equivocal findings when examining physical function and health-related quality of life (HRQL). One reason for these differences may be due to individual patient responses to the different training modalities.To compare changes in physical function and HRQL in a group of COPD patients completing both an endurance and a strength training program.Eleven mildly diseased patients completed a three month endurance training program and, approximately 5 years later, completed a three month strength training program. Changes in 6 minute walk distance (6 MW), time to rise from a chair five times (CRT), and the total score and subscores from the SF-36 and Chronic Respiratory Disease Questionnaire (CRQ) were examined.The forced expiratory volume as a percent of predicted remained relatively constant over the 5 years (61.1 ± 5.9 vs. 60.0 ± 10.3). Endurance and strength training increased 6 MW by 48.2 ± 11.2 (p = 0.008) and 39.8 ± 9.8 (p = 0.001) meters, respectively. Endurance and strength training decreased CRT by 4.8 ± 0.7 (p = 0.001) and 1.3 ± 1.2 (p = 0.056) seconds, respectively. Endurance training resulted in greater improvements in HRQL as compared to strength training.These results show that walk distance improves as a result of participating in either an endurance or a strength training program. However, an endurance training program leads to greater improvements in both general and disease specific measures of HRQL.

Cell phones are nearly ubiquitous in the college classroom. This study asks two primary questions regarding the making and breaking of in-class cell phone policies. In what manner are students using their phones and how can faculty members minimize the potential for phone-related distractions? To answer these questions we analyze original survey data from nearly 400 college students across multiple public and private universities to better understand the students' impulse to use their phones during class. Results from the survey demonstrate that more than 80% of students use their phone at least once per class and that students generally believe this to be an acceptable practice. These student data are supplemented with survey data from close to 100 college faculty to evaluate a range of policy options for dealing with this issue. From this analysis, it is clear that the policies most frequently implemented by instructors are typically perceived by students as the least effective.

U.S. states have led the federal government in instituting policies aimed at promoting renewable energy. Nearly all research on renewable portfolio standards (RPSs) has treated RPS adoption as a binary choice. Given the substantial variation in the renewable energy goals established by RPSs, we propose a new measure of RPS ambition that accounts for the amount of additional renewable energy production needed to reach the RPS goal and the number of years allotted to reach the standard. By measuring RPS policy with more precision, our analysis demonstrates that many factors found to affect whether a state will adopt an RPS do not exert a similar effect on the policy’s ambitiousness. Most notably, our analysis demonstrates that Democratic control of the state legislature is the most consequential factor in determining the ambitiousness of state RPS policies.

To explore theories of predictive coding, we presented mice with repeated sequences of images with novel images sparsely substituted. Under these conditions, mice could be rapidly trained to lick in response to a novel image, demonstrating a high level of performance on the first day of testing. Using 2-photon calcium imaging to record from layer 2/3 neurons in the primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. When a new stimulus sequence was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which then decayed to almost zero activity. The decay time of these transient responses was not fixed, but instead scaled with the length of the stimulus sequence. However, at the same time, we also found a small fraction of the neurons within the population (∼2%) that continued to respond strongly and periodically to the repeated stimulus. Decoding analysis demonstrated that both the transient and sustained responses encoded information about stimulus identity. We conclude that the layer 2/3 population uses a two-channel predictive code: a dense transient code for novel stimuli and a sparse sustained code for familiar stimuli. These results extend and unify existing theories about the nature of predictive neural codes.

Author(s): Berry, Michael J. | Abstract: This year's budgeting is characterized by more uncertainty than in previous years.

By most metrics, Colorado’s economy continues to recover from the recession. State revenues have reached the point where tax refunds mandated under the Taxpayer’s Bill of Rights (TABOR) are a distinct possibility. Governor Hickenlooper’s 2015–2016 budget is generally in line with his previous budgets, while including contingency plans for TABOR rebates. The legalization of recreational marijuana has provided the state with a new revenue stream, although taxes and fees collected in 2014 fell short of initial projections.

Author(s): Berry, Michael J. | Abstract: Restrictions on revenue and spending imposed by the Taxpayer’s Bill of Rights (TABOR) challenge Colorado legislators annually. Despite a generally positive economic environment and increasing population growth providing greater tax revenue, the state is prohibited from spending revenue collected in excess of prior year’s spending after accounting for inflation and population growth. This legislative session witnessed the collapse of a referendum to increase transportation funding, but also the success of a major reform to state revenue collection in the form of the hos-pital provider fees.