Turn off that night light! Light-at-night as a stressor for adolescents.

Light-at-night is known to produce a wide variety of behavioral outcomes including promoting anxiety, depression, hyperactivity, abnormal sociability, and learning and memory deficits. Unfortunately, we all live in a 24-h society where people are exposed to light-at-night or light pollution through night-shift work - the need for all-hours emergency services - as well as building and street-lights, making light-at-night exposure practically unavoidable. Additionally, the increase in screentime (tvs and smart devices) during the night also contributes to poorer sleep and behavioral impairments. Compounding these factors is the fact that adolescents tend to be "night owls" and prefer an evening chronotype compared to younger children and adults, so these teenagers will have a higher likelihood of being exposed to light-at-night. Making matters worse is the prevalence of high-school start times of 8 am or earlier - a combination of too early school start times, light exposure during the night, and preference for evening chronotypes is a recipe for reduced and poorer sleep, which can contribute to increased susceptibility for behavioral issues for this population. As such, this mini-review will show, using both human and rodent model studies, how light-at-night affects behavioral outcomes and stress responses, connecting photic signaling and the circadian timing system to the hypothalamic-pituitary adrenal axis. Additionally, this review will also demonstrate that adolescents are more likely to exhibit abnormal behavior in response to light-at-night due to changes in development and hormone regulation during this time period, as well as discuss potential interventions that can help mitigate these negative effects.

Would plain packaging and health warning labels reduce smoking in the presence of informal markets? A choice experiment in Colombia.

BACKGROUND: Despite progress made by many countries on the adoption of plain tobacco packaging laws over the last years, low- and middle-income countries, with a large supply of loose cigarettes via informal vendors, remain far behind. AIM: To study the potential effectiveness of plain tobacco packaging and dissuasive cigarette sticks, via willingness-to-pay estimates, when illicit cigarette options are available. METHODS: We conducted a discrete choice experiment (DCE) in which respondents chose licit and illicit products with three attributes: packaging (standard vs. plain packaging), stick design (branded stick vs. stick with warning), and price level. The sample, collected on 12/2021, consisted of 1761 respondents from an internet panel involving smokers and nonsmokers. Conditional logit and latent class models were used to estimate the willingness-to-pay (WTP) to avoid restrictive packaging elements. RESULTS: Nonsmokers are willing to pay USD $5.63 for a pack of cigarettes to avoid plain packaging, which is higher than the actual commercial price of illicit cigarettes (USD $2.40). The WTP increases to USD $12.14 in the presence of illicit alternatives. Smokers are also willing to pay to avoid illicit options, which they also deem riskier, and the presence of such options increases the WTP to avoid plain packaging. However, nonsmokers do not perceive the illicit option as riskier. The dissuasive stick (stick with warning) does not affect perceptions of risk and plays a small role in terms of choice for both smokers and nonsmokers. CONCLUSIONS: Even in the presence of illicit tobacco alternatives, plain packaging seems to be as effective in reducing the attractiveness of tobacco products in Colombia as in other countries that have already adopted it. Given conflicting results on the case for dissuasive sticks, there is a need for more research.

The Canadian Fire Spread Dataset.

Satellite data are effective for mapping wildfires, particularly in remote locations where monitoring is rare. Geolocated fire detections can be used for enhanced fire management and fire modelling through daily fire progression mapping. Here we present the Canadian Fire Spread Dataset (CFSDS), encompassing interpolated progressions for fires >1,000 ha in Canada from 2002-2021, representing the day-of-burning and 50 environmental covariates for every pixel. Day-of-burning was calculated by ordinary kriging of active fire detections from the Moderate Resolution Imaging Spectroradiometer and the Visible Infrared Imaging Radiometer Suite, enabling a substantial improvement in coverage and resolution over existing datasets. Day of burning at each pixel was used to identify environmental conditions of burning such as daily weather, derived weather metrics, topography, and forest fuels characteristics. This dataset can be used in a broad range of research and management applications, such as retrospective analysis of fire spread, as a benchmark dataset for validating statistical or machine-learning models, and for forecasting the effects of climate change on fire activity.

The effect of probiotic supplementation on sleep, depression-like behaviour, and central glucose and lactate metabolism in male and female pubertal mice exposed to chronic sleep disruption.

The prevalence of depression significantly increases during puberty and adolescence. Puberty is the period during which sexual maturity is attained, while adolescence persists beyond puberty and includes physiological, social, emotional, and cognitive maturation. A stressor that has been shown previously to induce depression is chronic sleep disruption. Probiotics can prevent stress-induced depression. However, it was unclear whether probiotics could prevent depression following chronic sleep disruption and what mechanism may be involved. Therefore, we investigated whether pubertal probiotic treatment could prevent depression-like behavior in mice following chronic sleep disruption. We also examined whether probiotic treatment could improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in chronically sleep-disrupted mice. We hypothesized that probiotic treatment would prevent depression-like behavior, improve sleep quality, and increase serotonin, tryptophan, glucose, and L-lactate concentrations in sleep-disrupted mice. Male and female mice (N=120) received cannula and electroencephalogram (EEG) electrode implants at postnatal day (PND) 26. Mice received Lacidofil® or Cerebiome® probiotics (PND 33-51) and were sleep-disrupted for the first 4 hours of the light phase (sleep period) (PND 40-51). Hippocampal L-lactate and glucose concentrations and sleep were measured over a 24-h period (PND 48-49). Depression-like behaviour was evaluated using tail suspension (PND 49) and forced swim tests (PND 50). Chronic sleep disruption increased depression-like behaviour and NREM duration in the dark phase, and reduced all metabolites and neuromodulating biomolecules measured within the brain. However, mice treated with probiotics did not display depression-like behaviour or decreased hippocampal L-lactate following chronic sleep disruption. Cerebiome prevented decreases to prefrontal serotonin and hippocampal glucose concentrations, while Lacidofil increased NREM duration in the latter half of the light phase. The current study not only replicates previous findings linking chronic sleep disruption to depression, but also demonstrates that pubertal probiotic treatment can mitigate the effects of chronic sleep disruption on depression-like behaviour and on the neural mechanisms underlying depression in a strain-dependent manner.

Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Modeling the velocity of evolving lineages and predicting dispersal patterns.

Accurate estimation of the dispersal velocity or speed of evolving organisms is no mean feat. In fact, existing probabilistic models in phylogeography or spatial population genetics generally do not provide an adequate framework to define velocity in a relevant manner. For instance, the very concept of instantaneous speed simply does not exist under one of the most popular approaches that models the evolution of spatial coordinates as Brownian trajectories running along a phylogeny [30]. Here, we introduce a new family of models - the so-called "Phylogenetic Integrated Velocity" (PIV) models - that use Gaussian processes to explicitly model the velocity of evolving lineages instead of focusing on the fluctuation of spatial coordinates over time. We describe the properties of these models and show an increased accuracy of velocity estimates compared to previous approaches. Analyses of West Nile virus data in the U.S.A. indicate that PIV models provide sensible predictions of the dispersal of evolving pathogens at a one-year time horizon. These results demonstrate the feasibility and relevance of predictive phylogeography in monitoring epidemics in time and space.

On the connections between the spatial Lambda-Fleming-Viot model and other processes for analysing geo-referenced genetic data.

The introduction of the spatial Lambda-Fleming-Viot model (ΛV) in population genetics was mainly driven by the pioneering work of Alison Etheridge, in collaboration with Nick Barton and Amandine Véber about ten years ago (Barton et al., 2010; Barton et al., 2013). The ΛV model provides a sound mathematical framework for describing the evolution of a population of related individuals along a spatial continuum. It alleviates the "pain in the torus" issue with Wright and Malécot's isolation by distance model and is sampling consistent, making it a tool of choice for statistical inference. Yet, little is known about the potential connections between the ΛV and other stochastic processes generating trees and the spatial coordinates along the corresponding lineages. This work focuses on a version of the ΛV whereby lineages move rapidly over small distances. Using simulations, we show that the induced ΛV tree-generating process is well approximated by a birth-death model. Our results also indicate that Brownian motions modelling the movements of lines of descent along birth-death trees do not generally provide a good approximation of the ΛV due to habitat boundaries effects that play an increasingly important role in the long run. Accounting for habitat boundaries through reflected Brownian motions considerably increases the similarity to the ΛV model however. Finally, we describe efficient algorithms for fast simulation of the backward and forward in time versions of the ΛV model.

A modest increase in fire weather overcomes resistance to fire spread in recently burned boreal forests.

Recently burned boreal forests have lower aboveground fuel loads, generating a negative feedback to subsequent wildfires. Despite this feedback, short-interval reburns (≤20 years between fires) are possible under extreme weather conditions. Reburns have consequences for ecosystem recovery, leading to enduring vegetation change. In this study, we characterize the strength of the fire-fuel feedback in recently burned Canadian boreal forests and the weather conditions that overwhelm resistance to fire spread in recently burned areas. We used a dataset of daily fire spread for thousands of large boreal fires, interpolated from remotely sensed thermal anomalies to which we associated local weather from ERA5-Land for each day of a fire's duration. We classified days with >3 ha of fire growth as spread days and defined burned pixels overlapping a fire perimeter ≤20 years old as short-interval reburns. Results of a logistic regression showed that the odds of fire spread in recently burned areas were ~50% lower than in long-interval fires; however, all Canadian boreal ecozones experienced short-interval reburning (1981-2021), with over 100,000 ha reburning annually. As fire weather conditions intensify, the resistance to fire spread declines, allowing fire to spread in recently burned areas. The weather associated with short-interval fire spread days was more extreme than the conditions during long-interval spread, but overall differences were modest (e.g. relative humidity 2.6% lower). The frequency of fire weather conducive to short-interval fire spread has significantly increased in the western boreal forest due to climate warming and drying (1981-2021). Our results suggest an ongoing degradation of fire-fuel feedbacks, which is likely to continue with climatic warming and drying.

How fast are viruses spreading in the wild?

Genomic data collected from viral outbreaks can be exploited to reconstruct the dispersal history of viral lineages in a two-dimensional space using continuous phylogeographic inference. These spatially explicit reconstructions can subsequently be used to estimate dispersal metrics allowing to unveil the dispersal dynamics and evaluate the capacity to spread among hosts. Heterogeneous sampling intensity of genomic sequences can however impact the accuracy of dispersal insights gained through phylogeographic inference. In our study, we implement a simulation framework to evaluate the robustness of three dispersal metrics - a lineage dispersal velocity, a diffusion coefficient, and an isolation-by-distance signal metric - to the sampling effort. Our results reveal that both the diffusion coefficient and isolation-by-distance signal metrics appear to be robust to the number of samples considered for the phylogeographic reconstruction. We then use these two dispersal metrics to compare the dispersal pattern and capacity of various viruses spreading in animal populations. Our comparative analysis reveals a broad range of isolation-by-distance patterns and diffusion coefficients mostly reflecting the dispersal capacity of the main infected host species but also, in some cases, the likely signature of rapid and/or long-distance dispersal events driven by human-mediated movements through animal trade. Overall, our study provides key recommendations for the lineage dispersal metrics to consider in future studies and illustrates their application to compare the spread of viruses in various settings.

Synthesis of 4'-Thionucleoside Analogues Bearing a C2' Stereogenic All-Carbon Quaternary Center.

The design of novel 4'-thionucleoside analogues bearing a C2' stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2' center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1',2'-anti thioaminal furnished the desired ß-D-4'-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1',4'-trans isomers, causing a significant decrease in their reaction rate relative to 1',4'-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4'-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.

Association between children's caregivers time preferences and childhood overweight and obesity in Mexico.

BACKGROUND: Parents or children's primary caregivers are a key influence on child weight as both decision makers and role models for eating patterns, physical activity, and other social behaviors. It is unknown whether caregivers' time preferences are associated with overweight or obesity in children. The primary objective was to estimate the association between parents' or caregivers' time preferences and children having overweight or obesity in Mexico. METHODS: A cross-sectional study was conducted using a representative survey of the Mexican population. A multinomial logistic model was used to examine the association between parents' or caregivers' time preferences (patience and time consistency) and child overweight or obesity, adjusting for potential confounders. RESULTS: The study included 9,102 children (mean age 10, 43% female) and 5,842 caregivers (mean age 37; 95% female). Intertemporal preference was strongly associated with increased odds of overweight or obesity in children. A medium patient caregiver had higher odds of having overweight (adjusted OR: 1.73; 95% CI: 1.19, 2.52). Similarly, having a caregiver with a present (OR: 2.52; 95% CI: 1.72, 3.70) or future bias (OR: 1.48; 95% CI: 1.11, 1.98) was associated with higher odds of obesity. CONCLUSION: Caregivers' time preferences were associated with having overweight and obesity in children and should be considered when developing policies to reduce children's obesity status.

EvoLaps 2: Advanced phylogeographic visualization.

EvoLaps is a user-friendly web application designed to visualize the spatial and temporal spread of pathogens. It takes an annotated tree as entry, such as a maximum clade credibility tree obtained through continuous phylogeographic inference. By following a 'Top-Down' reading of a tree recursively, transitions (latitude/longitude changes from a node to its children) are represented on a cartographic background using graphical paths. The complete set of paths forms the phylogeographic scenario. EvoLaps offers several features to analyze complex scenarios: (1) enhanced path display using multiple graphical variables with time-dependent gradients, (2) cross-highlighting and selection capabilities between the phylogeographic scenario and the phylogenetic tree, (3) production of specific spatio-temporal scales and synthetic views through dynamic and iterative clustering of localities into spatial clusters, (4) animation of the phylogeographic scenario using tree brushing, which can be done manually or automatically, gradually over time or at specific time intervals, and for the entire tree or a specific clade, and (5) an evolving library of additional tools. EvoLaps is freely available for use at evolaps.org.

Sialyl LewisX glycomimetics bearing an extended anionic chain targeting E- and P- selectin binding sites.

Neutrophil binding to vascular P- and E-selectin is the rate-limiting step in the recruitment of immune cells to sites of inflammation. Many diseases, including sickle cell anemia, post-myocardial infarction reperfusion injury, and acute respiratory distress syndrome are characterized by dysregulated inflammation. We have recently reported sialyl Lewisx analogues as potent antagonists of P- and E-selectin and demonstrated their in vivo immunosuppressive activity. A key component of these molecules is a tartrate diester that serves as an acyclic tether to orient the fucoside and the galactoside moiety in the required gauche conformation for optimal binding. The next stage of our study involved attaching an extended carbon chain onto one of the esters. This chain could be utilized to tether other pharmacophores, lipids, and contrast agents in the context of enhancing pharmacological applications through the sialyl Lewisx / receptor-mediated mechanism. Herein, we report our preliminary studies to generate a small library of tartrate based sialyl Lewisx analogues bearing extended carbon chains. Anionic charged chemical entities are attached to take advantage of proximal charged amino acids in the carbohydrate recognition domain of the selectin receptors. Starting with a common azido intermediate, synthesized using copper-catalyzed Huisgen 1,3-dipolar cycloadditions, these molecules demonstrate E- and P-selectin binding properties.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Cigarette packaging, warnings, prices, and contraband: A discrete choice experiment among smokers in Ontario, Canada.

In Canada, despite substantial decline, tobacco use remains the leading risk factor responsible for mortality and morbidity. There is overwhelming evidence that higher tobacco taxes reduce tobacco use, even if high taxes create an incentive to avoid or evade tobacco taxes. Recently, in addition to taxes, plain and standardized packaging and printing a warning on each cigarette have been lauded to reduce tobacco use. In November 2019, Canada became the country with the most comprehensive cigarette packaging regulations; and in June 2022, Canada proposed to print health warnings on individual cigarettes, the first jurisdiction to ever do so. The regulations came into force on August 1, 2023, and are being implemented through a stepwise approach. Our objective was to examine the effects of plain and standardized packaging, warning on cigarettes, price, and the availability of illicit cigarettes on intention to purchase and risk perceptions. We conducted a discrete choice experiment, and examined heterogeneity in preferences using latent class models among smokers in Ontario, Canada. We found that using latent class analyses was essential in quantifying preferences for attributes of cigarettes and cigarette packs. First, nearly half of smokers stated a preference for cheaper illicit cigarettes in a branded pack without any health warnings, regardless of the licit cigarette alternatives. For about 20% of respondents, plain packaging and especially warning on cigarette sticks decreased the probability of stating a purchasing preference for these alternatives. Third, about a third of respondents chose competing alternatives with mostly one attribute in mind, price. Lastly, none of the products and attributes seem to have significantly influenced risk perception. Our findings attest to the importance of prices and taxes, to the potential of warnings on cigarette sticks to control tobacco use, and indicate that efforts to restrict the availability of illicit cigarettes may yield substantial benefits.

Pain and aging: A unique challenge in neuroinflammation and behavior.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding $600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact. This review article examines and summarizes pre-clinical research and clinical data on chronic pain among older adults to identify knowledge gaps and provide the base for future research and clinical practice. We provide evidence to suggest that neurodegenerative conditions engender a loss of neural plasticity involved in pain response, whereas low-grade inflammation in aging increases CNS sensitization but decreases PNS sensitivity. Insights from preclinical studies are needed to answer mechanistic questions. However, the selection of appropriate aging models presents a challenge that has resulted in conflicting data regarding pain processing and behavioral outcomes that are difficult to translate to humans.

Socioeconomic differences in the impact of prices and taxes on tobacco use in low- and middle-income countries-A systematic review.

There is indisputable evidence that increases in taxes that raise tobacco prices reduce tobacco use. Consumption taxes on manufactured tobacco products, however, can be regressive in socioeconomic status (e.g., when the ratio of tax paid to income is lower for higher-income groups than for lower-income groups). Nevertheless, if the poor or less educated are more price responsive, a change in tobacco tax may be progressive in socioeconomic status. Existing reviews clearly indicate that populations with lower income or education are more responsive to tobacco tax and price changes than higher-income and more educated populations in high-income countries. Research pertaining to low- and middle-income countries was, however, limited and inconclusive. We conducted a review of quantitative studies that examined if socioeconomic status modified the association between prices and taxes and tobacco use in low- and middle-income countries. We searched two electronic databases, two search engines, and two working paper repositories. At least two reviewers independently screened articles for inclusion, extracted detailed characteristics, and assessed the risk of bias of each included study. Thirty-two studies met our inclusion criteria. Overall, we found that the evidence in low- and middle-income countries was too limited and methodologically weak to make any conclusive statements. Our review highlights a number of data and methodological limitations in existing studies. The most important limitation was the lack of formal assessment of socioeconomic differences in price responsiveness. Only seven of 32 studies assessed statistically whether own-price effects were modified by socioeconomic status. Many modelling studies have examined the distributional effect of a tax increase on tobacco use, while assuming a strong own-price elasticity gradient in income. The poor were generally assumed to be more responsive to price by a factor of two to five, relative to the wealthy. Although there are theoretical reasons to expect poorer individuals to be more responsive to monetary prices than wealthy ones in low- and middle-income countries, our review provides little empirical support.

Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury.

Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.

Readmission Reduction for Hyperbilirubinemia in Infants ≥ 35 Weeks Estimated Gestational Age Using a Standardized Protocol.

BACKGROUND: Most newborns experience hyperbilirubinemia. Monitoring and treatment must be balanced with the risk of unintended harm, including readmission to the birth hospital. From January 2019 to April 2021, the average rate of inborn readmission for all causes was 2.09% at the study hospital; hyperbilirubinemia accounted for 91% of these readmissions. The aim of this project was to decrease readmission rate for hyperbilirubinemia by 60% within eight months of protocol implementation. METHODS: The Lean system of quality improvement was used to assess root causes and implement countermeasures. A hyperbilirubinemia protocol was developed, and phototherapy equipment was upgraded. Monthly readmission rates were the main outcome measure. Process measures included hour of life for initial transcutaneous bilirubin measurement. Balance measures included number of serum bilirubin labs obtained per 100 infants, percentage treated with phototherapy, mean length of phototherapy treatment, and length of hospital stay. Statistical process control charts were used to measure changes in quality over time. RESULTS: Baseline data showed a monthly readmission rate for hyperbilirubinemia of 1.9%. Following countermeasure implementation, there was a clinically significant downward shift in the monthly readmission rate to 0.64%, representing a 66% decrease from baseline. CONCLUSION: Implementation of the project protocol was associated with a clinically significant decrease in readmissions for hyperbilirubinemia with no concurrent clinically significant changes in the number of labs drawn, number of infants started on phototherapy, or average length of hospital stay. For military treatment facilities or institutions with similar staffing models, this protocol may offer a model for improvement.

Synthesis of Sialyl LewisX Mimetics with E- and P-Selectin Binding Properties and Immunosuppressive Activity.

E- and P-selectins are adhesion proteins implicated in immune cell recruitment at sites of infection, making them important drug targets for diseases involving excessive and uncontrolled inflammation. In this study, we developed an efficient strategy to synthesize bicyclic galactopyranosides through a key stereoselective equatorial C4-propiolate addition and TMSCN axial C-glycosidation. The nitrile group can then be converted to the carboxyl and different bioisosteres at a late stage in the synthesis, allowing for various derivatizations to potentially enhance biological activity. The sialyl LewisX glycomimetic featuring this rigidified bicyclic galactopyranoside moiety prevents neutrophil adhesion to endothelial cells in vitro by binding to both E- and P-selectins. We show here that the axial carboxyl analogue blocks immune cell recruitment in vivo, demonstrating its potential as an immunomodulator.