RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

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.

An analysis of retracted COVID-19 articles published by one medical publisher with multiple journals.

Background: The retraction of medical articles periodically occurs in most medical journals and can involve multiple article types. These retractions are beneficial if they remove flawed or fraudulent information from the medical literature. However, retractions may also decrease confidence in the medical literature and require significant amounts of time by editors. Methods: One publisher (Hindawi) announced that it will retract over 1200 articles. Given this, the PubMed database was searched to identify retracted publications on or related to COVID-19, and articles retracted by journals sponsored by the publisher Hindawi were then identified. Results: These journals retracted 25 articles and, in most cases, did not provide an exact explanation about the particular problem(s) resulting in the retraction. The time to retraction was 468.7 ± 109.8 days (median = 446 days). These articles had 9.3 ± 9.9 citations. Conclusion: Analysis of the titles and abstracts of the articles suggests that their removal from the medical literature would have limited effects on the near-term management decisions during the COVID-19 pandemic. Nevertheless, retraction of medical articles creates uncertainty in medical care and science and in the public regarding the validity of medical research and related publications and the level of professionalism of the individuals submitting these articles.

Ambient carbon dioxide concentration correlates with SARS-CoV-2 aerostability and infection risk.

An improved understanding of the underlying physicochemical properties of respiratory aerosol that influence viral infectivity may open new avenues to mitigate the transmission of respiratory diseases such as COVID-19. Previous studies have shown that an increase in the pH of respiratory aerosols following generation due to changes in the gas-particle partitioning of pH buffering bicarbonate ions and carbon dioxide is a significant factor in reducing SARS-CoV-2 infectivity. We show here that a significant increase in SARS-CoV-2 aerostability results from a moderate increase in the atmospheric carbon dioxide concentration (e.g. 800 ppm), an effect that is more marked than that observed for changes in relative humidity. We model the likelihood of COVID-19 transmission on the ambient concentration of CO2, concluding that even this moderate increase in CO2 concentration results in a significant increase in overall risk. These observations confirm the critical importance of ventilation and maintaining low CO2 concentrations in indoor environments for mitigating disease transmission. Moreover, the correlation of increased CO2 concentration with viral aerostability need to be better understood when considering the consequences of increases in ambient CO2 levels in our atmosphere.

A perspective on the evidence for glymphatic obstruction in spaceflight associated neuro-ocular syndrome and fatigue.

Spaceflight associated neuro-ocular syndrome (SANS) alters the vision of astronauts during long-duration spaceflights. Previously, the current authors have discussed the similarities and differences between SANS and idiopathic intracranial hypertension to try to elucidate a possible pathophysiology. Recently, a theory has been advanced that SANS may occur secondary to failure of the glymphatic system caused by venous dilatation within the brain and optic nerves. There is recent evidence to suggest glymphatic obstruction occurs in childhood hydrocephalus, multiple sclerosis and syringomyelia due to venous outflow dilatation similar to that proposed in SANS. The purpose of the current paper is to discuss the similarities and differences between the known CSF and venous pathophysiology in SANS with these other terrestrial diseases, to see if they can shed any further light on the underlying cause of this microgravity-induced disease.

An Evaluation of Messages to Promote Parental Intent to Vaccinate Children Aged <12 Years Against COVID-19.

OBJECTIVES: Effective health communication can increase intent to vaccinate. We compared 8 messages that may influence parents' intent to vaccinate their children against COVID-19. METHODS: In a cross-sectional survey of adults in the United States administered online in August 2021, 1837 parents and legal guardians were exposed to 8 messages (individual choice, gain/practical benefits, nonexpert, health care provider recommendation, altruism/community good, safety/effectiveness, safety, and effectiveness) to determine message reception and influence on intent to vaccinate their children. Parents responded to 10 questions using a Likert scale. We computed odds ratios (ORs) for each message, with an OR >1.0 indicating greater observed odds of participant agreement with the follow-up statement as compared with a reference message. We compared outcomes individually across messages with ordinal logistic regression fit using generalized estimating equations. RESULTS: The individual choice message had the highest odds of agreement for understanding intent (OR = 2.10; 95% CI, 1.94-2.27), followed by the health care provider recommendation message (OR = 1.58; 95% CI, 1.46-1.71). The individual choice message had the highest odds of memorability, relatability, and trustworthiness. The altruism/community good message was at or near second best. The altruism/community good message had the highest or near-highest odds of increasing parents' intent to vaccinate their children, asking friends and family for their thoughts, and searching for additional information. The message that most motivated parents to vaccinate their children depended on parental intent to vaccinate prior to being exposed to the tested messages. CONCLUSIONS: Messages with themes of individual choice, health care provider recommendation, and altruism/community good may be used in future message campaigns. Further research is needed to refine message concepts related to altruism/community good.

COVID-19 Vaccine Hesitancy Among US Adults: Safety and Effectiveness Perceptions and Messaging to Increase Vaccine Confidence and Intent to Vaccinate.

OBJECTIVE: Public health agencies have a critical role in providing effective messaging about mitigation strategies during a public health emergency. The objectives of this study were (1) to understand perceptions of COVID-19 vaccines, including concerns about side effects, safety, and effectiveness and how these perceptions influence vaccine decision-making among US adults and (2) to learn what messages might motivate vaccine uptake. METHODS: In April and May 2021, we conducted 14 online focus groups with non-Hispanic English-speaking and English- and Spanish-speaking Hispanic adults (N = 99) not vaccinated against COVID-19. We oversampled adults aged 18-39 years and rural residents and systematically assessed 10 test messages. Researchers used a standardized guide and an a priori codebook for focus group discussions, coding transcripts, and thematic analysis. RESULTS: Vaccine hesitancy factors included fear of the unknown; long-term side effects, including infertility; and beliefs that the vaccines were developed too quickly and were not sufficiently effective. Motivating factors for receiving vaccination included the ability to safely socialize and travel. Health care providers were considered important trusted messengers. Participants were critical of most messages tested. Messages that came across as "honest" about what is not yet known about COVID-19 vaccines were perceived more positively than other messages tested. Messages were seen as ineffective if perceived as vague or lacking in data and specificity. CONCLUSIONS: Messages that were simple and transparent about what is unknown about vaccines relative to emerging science were viewed most favorably. Health care providers, friends, and family were considered influential in vaccination decision-making. Findings underscore the benefits of research-informed strategies for developing and disseminating effective messages addressing critical issues in a public health emergency.

Article retraction rates in selected MeSH term categories in PubMed published between 2010 and 2020.

BACKGROUND: Academic article retractions occur across all disciplines, though few studies have examined the association between research topics and retraction rates. OBJECTIVES: We assessed and compared the rate of retraction across several important clinical research topics. METHODS: Information about the number of publications, the number of retractions, the retraction rate, and the time to retraction was collected for articles identified by 15 Medical Subject Headings (MeSH) terms. These articles were published between 1 January 2010 and 31 December 2020. The searches took place between 18 September 2021 and 24 October 2021. The MeSH terms were selected based on our clinical experience with the expectation that there will be multiple publications during the timeframe to use for the searches. Additional topics were selected based on the frequency of controversy in the public media and were identified by the Altmetric Top 100 report. RESULTS: The mean number of publications for all categories was 181,975 ± 332,245; the median number of publications was 67,991 [Q1, Q3; 31951.5, 138,981.5]. The mean number of retractions was 100.3 ± 251.3, and the median number of retractions was 22 [Q1, Q3; 6.5, 53]. The mean time to retraction ranged from 114 days to 1,409.5 days; the median was 857.3 days [Q1, Q3; 684.7, 1098.6], depending on the topic. The various MeSH term categories used in this study had significant differences in retraction rate and time to retraction. The "Neoplasms" category had the highest total number of retractions (993) and one of the highest retraction rates (75.4 per 100,000 publications). DISCUSSION: All PubMed categories analyzed in this study had retracted articles. The median time to retraction was 857 days. The long delays in some categories could contribute to potentially misleading information which might have adverse effects on clinical decisions in patient care and on research design. CONCLUSION: Rate of retraction varies across research topics and further studies are needed to explore this relationship.

• Article retractions occurred in all subsets of articles classified by the 15 PubMed MeSH terms used in this study.• The time to retraction and the rate of retraction differed significantly across research topics classified by these MeSH terms. This suggests that research content and visibility affect retraction rates.• As an example, the "Neoplasms" category had the highest total number of retractions (993) and one of the highest retraction rates (75.4 per 100,000 publications).• Readers, editors, and authors need to understand that retractions do occur following publication in the medical literature. These retractions potentially have important consequences and require attention from all individuals involved in the multiple steps needed to create high-quality medical and scientific information.

Syringomyelia Is Associated with a Reduction in Spinal Canal Compliance, Venous Outflow Dilatation and Glymphatic Fluid Obstruction.

The cause of the cystic dilatation of the cord found in syringomyelia has been a source of conjecture for a considerable time. Recent studies have shown that there is a reduction in craniospinal compliance in both childhood hydrocephalus and multiple sclerosis which leads to venous outflow dilatation. Both diseases are associated with glymphatic outflow obstruction. Venous dilatation will narrow the perivenous glymphatic outflow pathway and lead to an increase in glymphatic outflow resistance. Syringomyelia has been shown to be associated with reduced spinal canal compliance. This paper discusses the possibility that venous dilatation and obstructed glymphatic outflow within the cord may be behind the cystic dilatation found within syringomyelia.

TOMM40 '523 Genotype Distinguishes Patterns of Cognitive Improvement for Executive Function in APOEɛ3 Homozygotes.

BACKGROUND: TOMM40 '523 has been associated with cognitive performance and risk for developing Alzheimer's disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. OBJECTIVE: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 '523 for genetic risk for conversion to mild cognitive impairment. METHODS: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. RESULTS: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = -0.088, p = 0.034) and for the executive function domain score (B = -0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. CONCLUSIONS: Our results add to the growing body of evidence that TOMM40, in the absence of APOEɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer's disease risk.

The disappearing act: case of a migrating left renal vein stent.

INTRODUCTION: Nutcracker syndrome (NS) is a rare condition in which the abdominal aorta and superior mesenteric artery compress the left renal vein (LRV). One treatment option is the placement of an endovascular stent into the LRV, which carries the risk of stent migration. CASE REPORT: A 30-year-old female with NS status-post LRV stenting 6 months prior presented to the emergency department with suprapubic pain. An incidental finding on abdominal computed tomography scan noted interval removal of LRV stent, which had not been surgically removed. A subsequent chest radiograph showed the stent lodged in the left pulmonary artery. DISCUSSION: To our knowledge, this is the first documented case of LRV stent migration to the pulmonary artery. This case demonstrates the importance of physician awareness of stent migration as a potential complication after stent placement, and careful review of all imaging findings, even if unrelated to the chief complaint.

Association of Blood Pressure Variability With Death and Discharge Destination Among Critically Ill Patients With and Without Stroke.

BACKGROUND AND OBJECTIVES: It is unclear whether blood pressure variability's (BPV) association with worse outcomes is unique to patients with stroke or a risk factor among all critically ill patients. We (1) determined whether BPV differed between patients with stroke and nonstroke patients, (2) examined BPV's associations with in-hospital death and favorable discharge destination in patients with stroke and nonstroke patients, and (3) assessed how minimum mean arterial pressure (MAP)-a correlate of illness severity and cerebral perfusion-affects these associations. METHODS: This is a retrospective analysis of adult intensive care unit patients hospitalized between 2001 and 2012 from the Medical Information Mart for Intensive Care III database. Confounder-adjusted logistic regressions determined associations between BPV, measured as SD and average real variability (ARV), and (1) in-hospital death and (2) favorable discharge, with testing of minimum MAP for effect modification. RESULTS: BPV was higher in patients with stroke (N = 2,248) compared with nonstroke patients (N = 9,085) (SD mean difference 2.3, 95% CI 2.1-2.6, p < 0.01). After adjusting for minimum tertile of MAP and other confounders, higher SD remained significantly associated (p < 0.05) with higher odds of in-hospital death for patients with acute ischemic strokes (AISs, odds ratio [OR] 2.7, 95% CI 1.5-4.8), intracerebral hemorrhage (ICH, OR 2.6, 95% CI 1.6-4.3), subarachnoid hemorrhage (SAH, OR 3.4, 95% CI 1.2-9.3), and pneumonia (OR 1.9, 95% CI 1.1-3.3) and lower odds of favorable discharge destination in patients with ischemic stroke (OR 0.3, 95% CI 0.2-0.6) and ICH (OR 0.4, 95% CI 0.3-0.6). No interaction was found between minimum MAP tertile with SD (p > 0.05). Higher ARV was not significantly associated with increased risk of death in any condition when adjusting for illness severity but portended worse discharge destination in those with AIS (OR favorable discharge 0.4, 95% CI 0.3-0.7), ICH (OR favorable discharge 0.5, 95% CI 0.3-0.7), sepsis (OR favorable discharge 0.8, 95% CI 0.6-1.0), and pneumonia (OR favorable discharge 0.5, 95% CI 0.4-0.8). DISCUSSION: BPV is higher and generally associated with worse outcomes among patients with stroke compared with nonstroke patients. BPV in patients with AIS and patients with ICH may be a marker of central autonomic network injury, although clinician-driven blood pressure goals likely contribute to the association between BPV and outcomes.

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.

Differences in airborne stability of SARS-CoV-2 variants of concern is impacted by alkalinity of surrogates of respiratory aerosol.

The mechanistic factors hypothesized to be key drivers for the loss of infectivity of viruses in the aerosol phase often remain speculative. Using a next-generation bioaerosol technology, we report measurements of the aero-stability of several SARS-CoV-2 variants of concern in aerosol droplets of well-defined size and composition at high (90%) and low (40%) relative humidity (RH) upwards of 40 min. When compared with the ancestral virus, the infectivity of the Delta variant displayed different decay profiles. At low RH, a loss of viral infectivity of approximately 55% was observed over the initial 5 s for both variants. Regardless of RH and variant, greater than 95% of the viral infectivity was lost after 40 min of being aerosolized. Aero-stability of the variants correlate with their sensitivities to alkaline pH. Removal of all acidic vapours dramatically increased the rate of infectivity decay, with 90% loss after 2 min, while the addition of nitric acid vapour improved aero-stability. Similar aero-stability in droplets of artificial saliva and growth medium was observed. A model to predict loss of viral infectivity is proposed: at high RH, the high pH of exhaled aerosol drives viral infectivity loss; at low RH, high salt content limits the loss of viral infectivity.

Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study.

Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson's disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.

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.