Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients.

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.

Analysis of the Types of Retracted COVID-19 Articles Published in PubMed-Listed Journals.

OBJECTIVES: Periodically, medical publications are retracted. The reasons vary from minor situations, such as author attributions, which do not undermine the validity of the data or the analysis in the article, to serious reasons, such as fraud. Understanding the reasons for retraction can provide important information for clinicians, educators, researchers, journals, and editorial boards. METHODS: The PubMed database was searched using the term "COVID-19" (coronavirus disease 2019) and the term limitation "retracted publication." The characteristics of the journals with retracted articles, the types of article, and the reasons for retraction were analyzed. RESULTS: This search recovered 196 articles that had been retracted. These retractions were published in 179 different journals; 14 journals had >1 retracted article. The mean impact factor of these journals was 8.4, with a range of 0.32-168.9. The most frequent reasons for retractions were duplicate publication, concerns about data validity and analysis, concerns about peer review, author request, and the lack of permission or ethical violation. There were significant differences between the types of article and the reasons for retraction but no consistent pattern. A more detailed analysis of two particular retractions demonstrates the complexity and the effort required to make decisions about article retractions. CONCLUSIONS: The retraction of published articles presents a significant challenge to journals, editorial boards, peer reviewers, and authors. This process has the potential to provide important benefits; it also has the potential to undermine confidence in both research and the editorial process.

Why did Rubens add a parrot to Titian's The Fall of Man? A pictorial manipulation of joint attention.

Almost 400 years ago, Rubens copied Titian's The Fall of Man, albeit with important changes. Rubens altered Titian's original composition in numerous ways, including by changing the gaze directions of the depicted characters and adding a striking red parrot to the painting. Here, we quantify the impact of Rubens's choices on the viewer's gaze behavior. We displayed digital copies of Rubens's and Titian's artworks-as well as a version of Rubens's painting with the parrot digitally removed-on a computer screen while recording the eye movements produced by observers during free visual exploration of each image. To assess the effects of Rubens's changes to Titian's composition, we directly compared multiple gaze parameters across the different images. We found that participants gazed at Eve's face more frequently in Rubens's painting than in Titian's. In addition, gaze positions were more tightly focused for the former than for the latter, consistent with different allocations of viewer interest. We also investigated how gaze fixation on Eve's face affected the perceptual visibility of the parrot in Rubens's composition and how the parrot's presence versus its absence impacted gaze dynamics. Taken together, our results demonstrate that Rubens's critical deviations from Titian's painting have powerful effects on viewers' oculomotor behavior.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg-1 , and p < 0.001 at 1 mg kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg-1 and 3 mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.

Minimal reporting guideline for research involving eye tracking (2023 edition).

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Eye tracking: empirical foundations for a minimal reporting guideline.

In this paper, we present a review of how the various aspects of any study using an eye tracker (such as the instrument, methodology, environment, participant, etc.) affect the quality of the recorded eye-tracking data and the obtained eye-movement and gaze measures. We take this review to represent the empirical foundation for reporting guidelines of any study involving an eye tracker. We compare this empirical foundation to five existing reporting guidelines and to a database of 207 published eye-tracking studies. We find that reporting guidelines vary substantially and do not match with actual reporting practices. We end by deriving a minimal, flexible reporting guideline based on empirical research (Section "An empirically based minimal reporting guideline").

Mandating Limits on Workload, Duty, and Speed in Radiology.

Research has not yet quantified the effects of workload or duty hours on the accuracy of radiologists. With the exception of a brief reduction in imaging studies during the 2020 peak of the COVID-19 pandemic, the workload of radiologists in the United States has seen relentless growth in recent years. One concern is that this increased demand could lead to reduced accuracy. Behavioral studies in species ranging from insects to humans have shown that decision speed is inversely correlated to decision accuracy. A potential solution is to institute workload and duty limits to optimize radiologist performance and patient safety. The concern, however, is that any prescribed mandated limits would be arbitrary and thus no more advantageous than allowing radiologists to self-regulate. Specific studies have been proposed to determine whether limits reduce error, and if so, to provide a principled basis for such limits. This could determine the precise susceptibility of individual radiologists to medical error as a function of speed during image viewing, the maximum number of studies that could be read during a work shift, and the appropriate shift duration as a function of time of day. Before principled recommendations for restrictions are made, however, it is important to understand how radiologists function both optimally and at the margins of adequate performance. This study examines the relationship between interpretation speed and error rates in radiology, the potential influence of artificial intelligence on reading speed and error rates, and the possible outcomes of imposed limits on both caseload and duty hours. This review concludes that the scientific evidence needed to make meaningful rules is lacking and notes that regulating workloads without scientific principles can be more harmful than not regulating at all.

Gaze mechanisms enabling the detection of faint stars in the night sky.

For millennia, people have used "averted vision" to improve their detection of faint celestial objects, a technique first documented around 325 BCE. Yet, no studies have assessed gaze location during averted vision to determine what pattern best facilitates perception. Here, we characterized averted vision while recording eye-positions of dark-adapted human participants, for the first time. We simulated stars of apparent magnitudes 3.3 and 3.5, matching their brightness to Megrez (the dimmest star in the Big Dipper) and Tau Ceti. Participants indicated whether each star was visible from a series of fixation locations, providing a comprehensive map of detection performance in all directions. Contrary to prior predictions, maximum detection was first achieved at ~8° from the star, much closer to the fovea than expected from rod-cone distributions alone. These findings challenge the assumption of optimal detection at the rod density peak and provide the first systematic assessment of an age-old facet of human vision.

The Storytelling Brain: How Neuroscience Stories Help Bridge the Gap between Research and Society.

Active communication between researchers and society is necessary for the scientific community's involvement in developing science-based policies. This need is recognized by governmental and funding agencies that compel scientists to increase their public engagement and disseminate research findings in an accessible fashion. Storytelling techniques can help convey science by engaging people's imagination and emotions. Yet, many researchers are uncertain about how to approach scientific storytelling, or feel they lack the tools to undertake it. Here we explore some of the techniques intrinsic to crafting scientific narratives, as well as the reasons why scientific storytelling may be an optimal way of communicating research to nonspecialists. We also point out current communication gaps between science and society, particularly in the context of neurodiverse audiences and those that include neurological and psychiatric patients. Present shortcomings may turn into areas of synergy with the potential to link neuroscience education, research, and advocacy.

Advanced Circuit and Cellular Imaging Methods in Nonhuman Primates.

Novel genetically encoded tools and advanced microscopy methods have revolutionized neural circuit analyses in insects and rodents over the last two decades. Whereas numerous technical hurdles originally barred these methodologies from success in nonhuman primates (NHPs), current research has started to overcome those barriers. In some cases, methodological advances developed with NHPs have even surpassed their precursors. One such advance includes new ultra-large imaging windows on NHP cortex, which are larger than the entire rodent brain and allow analysis unprecedented ultra-large-scale circuits. NHP imaging chambers now remain patent for periods longer than a mouse's lifespan, allowing for long-term all-optical interrogation of identified circuits and neurons over timeframes that are relevant to human cognitive development. Here we present some recent imaging advances brought forth by research teams using macaques and marmosets. These include technical developments in optogenetics; voltage-, calcium- and glutamate-sensitive dye imaging; two-photon and wide-field optical imaging; viral delivery; and genetic expression of indicators and light-activated proteins that result in the visualization of tens of thousands of identified cortical neurons in NHPs. We describe a subset of the many recent advances in circuit and cellular imaging tools in NHPs focusing here primarily on the research presented during the corresponding mini-symposium at the 2019 Society for Neuroscience annual meeting.

What do radiologists look for? Advances and limitations of perceptual learning in radiologic search.

Supported by guidance from training during residency programs, radiologists learn clinically relevant visual features by viewing thousands of medical images. Yet the precise visual features that expert radiologists use in their clinical practice remain unknown. Identifying such features would allow the development of perceptual learning training methods targeted to the optimization of radiology training and the reduction of medical error. Here we review attempts to bridge current gaps in understanding with a focus on computational saliency models that characterize and predict gaze behavior in radiologists. There have been great strides toward the accurate prediction of relevant medical information within images, thereby facilitating the development of novel computer-aided detection and diagnostic tools. In some cases, computational models have achieved equivalent sensitivity to that of radiologists, suggesting that we may be close to identifying the underlying visual representations that radiologists use. However, because the relevant bottom-up features vary across task context and imaging modalities, it will also be necessary to identify relevant top-down factors before perceptual expertise in radiology can be fully understood. Progress along these dimensions will improve the tools available for educating new generations of radiologists, and aid in the detection of medically relevant information, ultimately improving patient health.

Strategies to Address Challenges in Neuroscience Drug Discovery and Development.

The paucity of novel drugs for neuropsychiatric indications contrasts with the remarkable recent advances in neuroscience research. We have identified 5 challenges the field needs to address and recommend potential solutions. First, we need to drive discovery efforts based on human data. Second, we need to think more carefully about animal models, embracing them as tools to test pathophysiological alterations. Third, we need to develop strategies to select more homogenous groups of patients in our clinical trials. Fourth, we need to develop and validate translational biomarkers, which can be used for pharmacodynamic assessments as well as for patient selection. Fifth, we need to adopt more reliable and objective measures to capture clinical efficacy. The tools that will allow these solutions to be implemented may already be in place but not routinely adopted or are still being developed. Overall, a change in mindset to adopt science- and data-driven paths is needed.

Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells.

Experimental autoimmune uveitis (EAU), in which CD4+ Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+ T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+ T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid-related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis.

A comparison of head injuries in male and female lacrosse participants seen in US emergency departments from 2005 to 2016.

INTRODUCTION: In the United States there has been a large increase in participation in lacrosse for both males and females. The purpose of this study was to analyze the number of head injuries, injury rates (calculated using the reported number of participants) and types of head injuries that are seen in emergency departments in the United States. METHODS: We compared injuries between male and female lacrosse participants. This was a retrospective study using a publicly available database produced by the US Consumer Product Safety Commission and information about lacrosse participation from US Lacrosse. RESULTS: A linear regression was performed and showed a positive correlation between number of head injuries to males and time from 2002 to 2010 (R2 = 0.823; p = 0.001). While the number of injuries to the head in female lacrosse participants was not significant. There was a negative correlation between the number of head injuries to males from 2010 to 2016 (R2 = 0.800; p = 0.007), but again, there was no significance for female injury count (R2 = 0.417; p = 0.117). Other significant differences between head injuries in males and females included the mechanism of injury and the type of injury recorded. CONCLUSION: The most recent data from 2010 to 2016, suggest that both males and females have had a decrease in injury rate. However the total number of female head injuries is not significantly decreasing and as the sport continues to grow there will likely be more total head injuries and visits to the emergency department.

Work of breathing for cuffed and uncuffed pediatric endotracheal tubes in an in vitro lung model setting.

BACKGROUND: Over the last decade, cuffed endotracheal tubes are increasingly used in pediatric anesthesia and also in pediatric intensive care. However, the smaller inner diameter of cuffed endotracheal tubes and, implicitly, the increased endotracheal tube resistance is still a matter of debate. AIMS: This in vitro study investigated work of breathing and inspiratory airway pressures in cuffed and uncuffed endotracheal tubes and the impact of pressure support ventilation and automatic tube compensation. METHODS: In 5 simulated neonatal and pediatric lung models, the Active Servo Lung 5000 and an intensive care ventilator were used to quantify the differences in work of breathing under spontaneous breathing (with and without pressure support ventilation and automatic tube compensation) between cuffed and uncuffed endotracheal tubes. Additionally, differences in inspiratory airway pressures, measured either proximal or distal of the endotracheal tube, between cuffed and uncuffed endotracheal tubes under mechanical ventilation were investigated. RESULTS: Work of breathing was overall 10.27% [95% confidence interval 9.01-11.94] higher with cuffed than with uncuffed endotracheal tubes and was dramatically reduced by 34.19% [95% confidence interval 31.61-35.25] with the application of pressure support. Automatic tube compensation almost diminished work of breathing differences between the 2 endotracheal tube types in nearly all pediatric lung models. Peak inspiratory and mean airway pressures measured at the proximal endotracheal tube end revealed significantly higher values in cuffed than in uncuffed endotracheal tubes. However, these differences measured at the distal end of the endotracheal tube became minimal. CONCLUSION: This in vitro study confirmed significant differences in work of breathing and inspiratory pressures between cuffed and uncuffed endotracheal tubes. Work of breathing, however, is almost neutralized by pressure support ventilation with automatic tube compensation and distal inspiratory airway pressures that, from a clinical perspective, are not significantly increased.

Occluded information is restored at preview but not during visual search.

Objects often appear with some amount of occlusion. We fill in missing information using local shape features even before attending to those objects-a process called amodal completion. Here we explore the possibility that knowledge about common realistic objects can be used to "restore" missing information even in cases where amodal completion is not expected. We systematically varied whether visual search targets were occluded or not, both at preview and in search displays. Button-press responses were longest when the preview was unoccluded and the target was occluded in the search display. This pattern is consistent with a target-verification process that uses the features visible at preview but does not restore missing information in the search display. However, visual search guidance was weakest whenever the target was occluded in the search display, regardless of whether it was occluded at preview. This pattern suggests that information missing during the preview was restored and used to guide search, thereby resulting in a feature mismatch and poor guidance. If this process were preattentive, as with amodal completion, we should have found roughly equivalent search guidance across all conditions because the target would always be unoccluded or restored, resulting in no mismatch. We conclude that realistic objects are restored behind occluders during search target preview, even in situations not prone to amodal completion, and this restoration does not occur preattentively during search.

Race/Ethnic Variations in Quitline Use Among US Adult Tobacco Users in 45 States, 2011-2013.

INTRODUCTION: State quitlines provide free telephone-based cessation services and are available in all states. However, quitlines presently reach 1% of US cigarette smokers. We assessed variations in quitline reach by race/ethnicity across 45 US states included in the National Quitline Data Warehouse, a repository on non-identifiable data reported by state quitlines. METHODS: During 2011 to 2013, we analyzed 1 220 171 records from the National Quitline Data Warehouse. Annual quitline reach was defined as the proportion of cigarette smokers and smokeless tobacco users who utilized quitline services during each year, and was calculated by dividing the number of state-specific quitline registrants in each year by the number of adult cigarette smokers and smokeless tobacco users in the state. RESULTS: Average annual reach ranged from: 0.08% (Tennessee) to 3.42% (Hawaii) among non-Hispanic whites; 0.17% (Tennessee) to 3.85% (Delaware) among non-Hispanic blacks; 0.27% (Nevada) to 9.98% (Delaware) among non-Hispanic American Indians/Alaska Native; 0.03% (Alabama) to 2.43% (Hawaii) among non-Hispanic Asian/Pacific Islanders; and from 0.08% (Tennessee) to 3.18% (Maine) among Hispanics. Average annual reach was highest among non-Hispanic American Indians/Alaska Native in 27 states, non-Hispanic blacks in 14 states, and non-Hispanic whites in four states. CONCLUSIONS: Quitlines appear to be reaching minority populations; however, overall reach remains low and variations in quitline reach exist by race/ethnicity. Opportunities exist to increase the utilization of quitlines and other effective cessation treatments among racial/ethnic minority populations. IMPLICATIONS: Some studies have assessed quitline reach across demographic groups in individual states; however, no studies have provided multistate data about quitline reach across race/ethnic groups. Ongoing monitoring of the use of state quitlines can help guide targeted outreach to particular race/ethnic groups with the goal of increasing the overall proportion and number of tobacco users that use quitlines. These efforts should be complemented by comprehensive tobacco control initiatives that increase cessation including mass media campaigns, smoke-free policies, increased tobacco prices, expansion of health insurance coverage, and health systems change.

Increasing the dose of television advertising in a national antismoking media campaign: results from a randomised field trial.

BACKGROUND: While antismoking media campaigns have demonstrated effectiveness, less is known about the country-level effects of increased media dosing. The 2012 US Tips From Former Smokers (Tips) campaign generated approximately 1.6 million quit attempts overall; however, the specific dose-response from the campaign was only assessed by self-report. OBJECTIVE: Assess the impact of higher ad exposure during the 2013 Tips campaign on quit-related behaviours and intentions, campaign awareness, communication about campaign, and disease knowledge. METHODS: A 3-month national media buy was supplemented within 67 (of 190) randomly selected local media markets. Higher-dose markets received media buys 3 times that of standard-dose markets. We compared outcomes of interest using data collected via web-based surveys from nationally representative, address-based probability samples of 5733 cigarette smokers and 2843 non-smokers. RESULTS: In higher-dose markets, 87.2% of smokers and 83.9% of non-smokers recalled television campaign exposure versus 75.0% of smokers and 73.9% of non-smokers in standard-dose markets. Among smokers overall, the relative quit attempt rate was 11% higher in higher-dose markets (38.8% vs 34.9%; p<0.04). The higher-dose increase was larger in African-Americans (50.9% vs 31.8%; p<0.01). Smokers in higher-dose markets without a mental health condition, with a chronic health condition, or with only some college education made quit attempts at a higher rate than those in standard-dose markets. Non-smokers in higher-dose markets were more likely to talk with family or friends about smoking dangers (43.1% vs 35.7%; p<0.01) and had greater knowledge of smoking-related diseases. CONCLUSIONS: The US 2013 Tips antismoking media campaign compared standard and higher doses by randomisation of local media markets. Results demonstrate the effectiveness of a higher dose for engaging non-smokers and further increasing quit attempts among smokers, especially African-Americans.