Search

We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9-4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9-4.5 μm. PEARLS is designed to be of lasting benefit to the community.

Background: Cutaneous Leishmaniasis (CL) is a neglected tropical disease endemic in Brazil. Morbidity and disabilities caused by CL lesions require an analysis of a Global Burden of Disease (GBD), which would help discern the impact on the Brazilian population. Herein, we assess the burden of CL and its spatial and temporal patterns in Brazil between 2001 and 2021., Methodology/principal Findings: We estimated rates per 100,000 population for years lived with disabilities (YLD), years of life lost prematurely (YLL) and disability-adjusted life years (DALY) for each year of the study, sex assigned at birth, age group, and for each municipality in Brazil. In addition, the relative changes in these metrics over time for each region and sex were determined, as well as temporal trends using segmented joinpoint regression models. Using spatiotemporal analysis tools, we created choropleth maps representing DALY, YLD and YLL for three distinct periods (P1 = 2001 to 2007; P2 = 2008 to 2014; P3 = 2015 to 2021). These maps were constructed to visualize the inferences from Bayesian spatial statistics and Moran's autocorrelation using the Poisson model. The data were obtained from the DATASUS database. Although the global burden of CL has reduced over two decades, with the continual high impact among adults aged 20 to 39 years. In turn, YLL increased over time in 40-year-old populations, while among the elderly (>60 years old) this rate almost doubled from 2010 to 2021. Regarding the region of residence, we observed an average increase of 28% in YLL in Southeast, South and Central-West. Furthermore, the global burden of CL does not have a random spatial distribution, since there was a high-risk clustering of YLD in the north of the country. Interestingly, the YLL showed a vast geographic expansion through Brazilian territory., Conclusions: This study provides a comprehensive analysis of the burden of CL in Brazil, pointing out areas of highest disease burden, where control and surveillance efforts should be undertaken., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Reis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Study success depends on the engagement and inclusion of diverse populations of pregnant participants and their children across the United States, including those at high and low risk for prenatal substance use. The Communications, Engagement, and Dissemination (CED) Committee is responsible for the development and implementation of a strategy to promote awareness about the study, encourage participation, and engage HBCD families, community partners, and collaborators. Initial work involved developing versatile recruitment and awareness materials with a consistent and inclusive message that reduces stigma and negative bias towards marginalized populations, including people with substance use and other mental health conditions. These efforts were shaped by an integrated product development workflow and early engagement with HBCD partners to address challenges. Ongoing work includes the expansion of HBCD outreach through newsletters and social media platforms with an emphasis on protecting participant privacy. Future activities will focus on disseminating scientific information through generation of infographics and webinars that will inform participants, families, and the public of discoveries generated from HBCD Study data., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julie M. Croff reports financial support was provided by National Institutes of Health and the Bill & Melinda Gates Foundation. Julie M. Croff reports a relationship with Oklahoma State University Center for Health Sciences that includes: funding grants, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive Development SM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual's genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Julia L. Zehr reports a relationship with Jazz Pharmaceuticals Inc that includes: equity or stocks. Co-author’s spouse is employed by Jazz Pharmaceuticals, Inc - JLZ If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Ltd.)

Monoterpenoid indole alkaloid (MIA) biosynthesis in Catharanthus roseus is a paragon of the spatiotemporal complexity achievable by plant specialized metabolism. Spanning a range of tissues, four cell types, and five cellular organelles, MIA metabolism is intricately regulated and organized. This high degree of metabolic differentiation requires inter-cellular and organellar transport, which remains understudied. Here, we have characterized a vacuolar importer of secologanin belonging to the multidrug and toxic compound extrusion (MATE) family, named CrMATE1. Phylogenetic analyses of MATEs suggested a role in alkaloid transport for CrMATE1, and in planta silencing in two varieties of C. roseus resulted in a shift in the secoiridoid and MIA profiles. Subcellular localization of CrMATE1 confirmed tonoplast localization. Biochemical characterization was conducted using the Xenopus laevis oocyte expression system to determine substrate range, directionality, and rate. We can confirm that CrMATE1 is a vacuolar importer of secologanin, translocating 1 mM of substrate within 25 min. The transporter displayed strict directionality and specificity for secologanin and did not accept other secoiridoid substrates. The unique substrate-specific activity of CrMATE1 showcases the utility of transporters as gatekeepers of pathway flux, mediating the balance between a defense arsenal and cellular homeostasis., (© 2024. The Author(s).)

Competing Interests: Disclosures None.

Background: Pre-exposure prophylaxis (PrEP) is a valuable tool in the response to the HIV epidemic, recommended for groups with a higher risk of HIV infection, such as men who have sex with men (MSM), particularly in the context of high-risk sexual behavior such as chemsex., Purpose: This study aimed to analyze the prevalence and factors associated with the intention to use PrEP among MSM who engage in chemsex in Brazil and Portugal., Methods: This was a cross-sectional study of a secondary dataset from a larger study conducted between January 2020 and May 2021 throughout Brazil and Portugal involving 1852 MSM who engage in chemsex. An initial descriptive analysis was performed to calculate the absolute and relative frequencies of independent variables related to the intention to use PrEP among MSM. A multivariate regression model was developed to identify factors independently associated with the intention to use PrEP., Results: Although a high level of PrEP knowledge (85.75%) was observed among MSM who engage in chemsex, the prevalence of intention to use PrEP was only 59.07%. Five variables were associated with a higher prevalence of intention to use PrEP [engaging in double penetration - adjusted prevalence ratio (aPR): 1.56, 95% CI: 1.44-1.69; being assigned female sex at birth - aPR: 1.34, 95% CI: 1.12-1.61; cruising - aPR: 1.21, 95% CI: 1.06-1.38; not using condoms - aPR: 1.20, 95% CI: 1.05-1.36; and being an immigrant - aPR: 1.16; 95% CI: 1.07-1.25], while having knowledge of postexposure prophylaxis (aPR: 0.91; 95% CI: 0.84-0.98), having a casual sexual partner (aPR: 0.86 and 0.85; 95% CI: 0.74-0.99 and 0.74-0.98), and engaging in group sex (aPR: 0.81; 95% CI: 0.73-0.90) were associated with a lower intention to use PrEP., Conclusion: The intention to use PrEP among MSM who engage in chemsex was high, and several factors were associated with this intention. Understanding the factors associated with the intention to use PrEP among MSM practicing chemsex is crucial for developing targeted interventions to increase PrEP uptake in this population. The results of this study suggest that tailored approaches are necessary to promote PrEP use in this population., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreER T2 ;Ai14 reporter mouse. We identified pericytes and "cartilage-like" fibroblasts as senescent and defined cell type-specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Cannabinoids modulate dopamine (DA) transmission and DA-related behavior, which has been thought to be mediated initially by activation of cannabinoid CB1 receptors (CB1Rs) on GABA neurons. However, there is no behavioral evidence supporting it. In contrast, here we report that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. RNAscope in situ hybridization (ISH) assays demonstrated CB1 mRNA in tyrosine hydroxylase (TH)-positive DA neurons in the ventral tegmental area (VTA) and glutamate decarboxylase 1 (GAD1)-positive GABA neurons. The CB1R-expressing DA neurons were located mainly in the middle portion of the VTA with the number of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2 (VgluT2, a glutamate neuronal marker) in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by optical intracranial self-stimulation. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) or ACEA (a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional knockout mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from DA neurons attenuated Δ 9 -THC-induced reduction in DA release in the NAc, locomotion, and anxiety. Together, these findings indicate that CB1Rs are expressed in a subset of DA neurons that corelease DA and glutamate, and functionally underlie cannabinoid modulation of DA release and DA-related behavior. SIGNIFICANCE STATEMENT Cannabinoids produce a series of psychoactive effects, such as aversion, anxiety, and locomotor inhibition in rodents. However, the cellular and receptor mechanisms underlying these actions are not fully understood. Here we report that CB1 receptors are expressed not only in GABA neurons but also in a subset of dopamine neurons, which are located mainly in the medial VTA close to the midline of the midbrain and corelease dopamine and glutamate. Optogenetic activation of these dopamine neurons is rewarding, which is dose-dependently inhibited by cannabinoids. Selective deletion of CB1 receptor from dopamine neurons blocked cannabinoid-induced aversion, hypoactivity, and anxiolytic effects. These findings demonstrate that dopaminergic CB1 receptors play an important role in mediating cannabinoid action., (Copyright © 2023 the authors.)

Spontaneous coronary artery dissection (SCAD) is a relatively newly diagnosed area, and evidence-based medicine (EBM) standards are emerging and currently include an aspirin, β blocker, clopidogrel, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker for patients with hypertension, vascular abnormality imaging, and cardiac rehabilitation. Because SCAD is an uncommon condition, many providers are unfamiliar with EBM treatment standards which could affect the implementation of recommended treatment. This study documented the frequency of failure to meet EBM SCAD treatment standards and factors contributing to conformance failure. Patients who presented to a tertiary referral hospital from January 1, 2005, to July 6, 2020, were included. The electronic medical record was reviewed for EBM treatment. Patients who did not meet the criteria of EBM were contacted by phone for a phone interview. The study period included 118 patients with SCAD, 3 of whom (2.5%) died and were not eligible for this study. In the final cohort of 115 patients, the average age was 55 years, female gender (97%) and EBM standards were met in 30%. Of patients who participated in the phone interview, 38 (33%) reported frustration with SCAD misdiagnosis (39%), inadequate mental health resources (37%), and communication failure regarding the need for cardiologist follow-up (26%). Cardiac rehabilitation use was impacted by location, time of day, availability, and cost. The most common medication-limiting factor for β-blocker usage was fatigue (15%). Most (59%) patients did not undergo fibromuscular dysplasia imaging. In conclusion, in this 15-year SCAD study from a single tertiary care hospital SCAD registry, only 30% met the current EBM for SCAD. Unique solutions that are both patient-informed and evidence-driven are needed to achieve the best clinical outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ghrelin, an orexigenic hormone, has emerged as a critical biological substrate implicated in drug reward. However, the response of the ghrelin system to opioid-motivated behaviors and the role of ghrelin in oxycodone self-administration remain to be studied. Here, we investigated the reciprocal interactions between the endogenous ghrelin system and oxycodone self-administration behaviors in rats and the role of the ghrelin system in brain stimulation reward (BSR) driven by optogenetic stimulation of midbrain reward circuits in mice. Oxycodone self-administration significantly elevated plasma ghrelin, des-acyl ghrelin and growth hormone and showed no effect on plasma LEAP2, a newly identified endogenous ghrelin receptor (GHS-R1a) antagonist. Oxycodone self-administration produced significant decreases in plasma gastric inhibitory polypeptide and insulin. Acquisition of oxycodone self-administration significantly upregulated GHS-R1a mRNA levels in dopamine neurons in the ventral tegmental area (VTA), a brain region critical in drug reward. Pretreatment with JMV2959, a selective GHS-R1a antagonist, dose-dependently reduced oxycodone self-administration and decreased the breakpoint for oxycodone under a progressive ratio reinforcement in Long-Evans rats. The inhibitory effects of JMV2959 on oxycodone self-administration is selectively mediated by GHS-R1a as JMV2959 showed a similar effect in Wistar wildtype but not in GHS-R knockout rats. JMV2959 pretreatment significantly inhibited BSR driven by selective stimulation of VTA dopamine neurons, but not by stimulation of striatal GABA neurons projecting to the VTA in mice. These findings suggest that elevation of ghrelin signaling by oxycodone or oxycodone-associated stimuli is a causal process by which oxycodone motivates oxycodone drug-taking and targeting the ghrelin system may be a viable treatment approach for opioid use disorders., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Understanding risk factors for substance use disorders (SUD) can facilitate medication development for SUD treatment. While a rich literature exists discussing environmental factors that influence SUD, fewer articles have focused on genetic factors that convey vulnerability to drug use. Methods to identify SUD risk genes include Genome-Wide Association Studies (GWAS) and transgenic approaches. GWAS have identified hundreds of gene variants or single nucleotide polymorphisms (SNPs). However, few genes identified by GWAS have been verified by clinical or preclinical studies. In contrast, significant progress has been made in transgenic approaches to identify risk genes for SUD. In this article, we review recent progress in identifying candidate genes contributing to drug use and addiction using transgenic approaches. A central hypothesis is if a particular gene variant (e.g., resulting in reduction or deletion of a protein) is associated with increases in drug self-administration or relapse to drug seeking, this gene variant may be considered a risk factor for drug use and addiction. Accordingly, we identified several candidate genes such as those that encode dopamine D 2 and D 3 receptors, mGluR 2 , M 4 muscarinic acetylcholine receptors, and α 5 nicotinic acetylcholine receptors, which appear to meet the risk-gene criteria when their expression is decreased. Here, we describe the role of these receptors in drug reward and addiction, and then summarize major findings from the gene-knockout mice or rats in animal models of addiction. Lastly, we briefly discuss future research directions in identifying addiction-related risk genes and in risk gene-based medication development for the treatment of addiction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jordan and Xi.)

Light Sheet Fluorescence Microscopy (LSFM) has revolutionized how optical imaging of biological specimens can be performed as this technique allows to produce 3D fluorescence images of entire samples with a high spatiotemporal resolution. In this manuscript, we aim to provide readers with an overview of the field of LSFM on ex vivo samples. Recent advances in LSFM architectures have made the technique widely accessible and have improved its acquisition speed and resolution, among other features. These developments are strongly supported by quantitative analysis of the huge image volumes produced thanks to the boost in computational capacities, the advent of Deep Learning techniques, and by the combination of LSFM with other imaging modalities. Namely, LSFM allows for the characterization of biological structures, disease manifestations and drug effectivity studies. This information can ultimately serve to develop novel diagnostic procedures, treatments and even to model the organs physiology in healthy and pathological conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Addictive drugs are habit-forming. Addiction is a learned behavior; repeated exposure to addictive drugs can stamp in learning. Dopamine-depleted or dopamine-deleted animals have only unlearned reflexes; they lack learned seeking and learned avoidance. Burst-firing of dopamine neurons enables learning-long-term potentiation (LTP)-of search and avoidance responses. It sets the stage for learning that occurs between glutamatergic sensory inputs and GABAergic motor-related outputs of the striatum; this learning establishes the ability to search and avoid. Independent of burst-firing, the rate of single-spiking-or "pacemaker firing"-of dopaminergic neurons mediates motivational arousal. Motivational arousal increases during need states and its level determines the responsiveness of the animal to established predictive stimuli. Addictive drugs, while usually not serving as an external stimulus, have varying abilities to activate the dopamine system; the comparative abilities of different addictive drugs to facilitate LTP is something that might be studied in the future., (© 2021. The Author(s).)

FDA's Menu Labeling Final Rule requires covered establishments provide calorie information on menus or menu boards, among other requirements. This study describes correlates of noticing and using menu calorie information in a nationally representative sample of U.S. adults before implementation of the Final Rule in May 2018. Data from the 2018 National Cancer Institute Health Information National Trends Survey was used to assess noticing menu calorie information, using menu calorie information to change menu ordering behavior, and knowledge of daily calorie needs. Regression analysis of weighted data tested associations between individual characteristics and noticing and using menu calorie information. Nearly half of adults (44%) reported noticing menu calorie information. Women, younger individuals, those who seek health information, individuals with a BMI ≥ 30, and those with higher education or higher income were more likely to report noticing menu calorie information. Among adults who reported noticing menu calorie information, three-quarters responded by ordering less (e.g., fewer calories), which equates to about one-third of the population. About 36% of women and 42% of men lacked calorie knowledge. Men with, versus without, calorie knowledge were twice as likely to report noticing menu calorie information (adjusted OR 2.23 95% CI 1.51, 3.29). Findings suggest behavioral response to menu calorie information varies and most individuals who notice the information respond by ordering less in ways that could reduce caloric intake. Future analyses could compare noticing and using menu calorie information before and after menu labeling implementation to assess the effect of policy on population behaviors., (Published by Elsevier Inc.)

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn 2+ ) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn 2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn 2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn 2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn 2+ were dependent on the Zn 2+ transporter 3 (ZnT3), a neuronal Zn 2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn 2+ . ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn 2+ deficiency in mice resulted in decreased striatal Zn 2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn 2+ release and turnover/metabolism in the striatum, and that synaptically released Zn 2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine's pharmacological mechanism of action and suggest that Zn 2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Discussions about non-pharmacologic interventions for Neonatal Abstinence Syndrome and Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) have been minor compared with wider attention to pharmacologic treatments. Although historically under-recognized, non-pharmacologic interventions are of paramount importance for all substance-exposed infants and remain as a first line therapy for the care of infants affected by NAS. Here we examine the role of non-pharmacologic interventions for NAS/NOWS by incorporating theoretical perspectives from different disciplines that inform the importance of individualized assessment of the mother-caregiver/infant dyad and interventions that involve both individuals. NAS/NOWS is a complex, highly individualized constellation of signs/symptoms that vary widely in onset, duration, severity, expression, responses to treatment and influence on long-term outcomes. NAS/NOWS often occurs in infants with multiple prenatal/postnatal factors that can compromise neurobiological self-regulatory functioning. We propose to rethink some of the long-held assumptions, beliefs, and paradigms about non-pharmacologic care of the infant with NAS/NOWS, which is provided as non-specific or as "bundled" in current approaches. This paper is Part I of a two-part series on re-conceptualizing non-pharmacologic care for NAS/NOWS as individualized treatment of the dyad. Here, we set the foundation for a new treatment approach grounded in developmental theory and evidence-based observations of infant neurobiology and neurodevelopment. In Part II, we provide actionable, individually tailored evaluations and approaches to non-pharmacologic NAS/NOWS treatment based on measurable domains of infant neurobehavioral functioning., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity < 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) × 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of -0.312 mL/min/100 g (95% confidence interval: -0.4729 to -0.1510; P = .0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ 9 -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB 1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB 2 Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB 1 R and/or CB 2 R in different populations of neurons in the brain may underlie the observed actions., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Neonatal abstinence syndrome (NAS) results from discontinuation of in utero exposures to opioids/substances. The rising incidence of NAS has prompted an increased need for accurate research and public health data. To examine how NAS has been defined in clinical studies of opioid-exposed mothers and infants, a review process was developed based on the RAND/UCLA Appropriateness Method, yielding 888 abstracts. Per inclusion criteria, 57 abstracts underwent full-text review. To define NAS, studies cited using modified versions of the Finnegan NAS scoring tool (n = 21; 37%), ICD-9/10 coding (n = 17; 30%), original Finnegan tool (n = 16; 28%), Eat Sleep Console (n = 3; 5%), and Lipsitz (n = 3; 5%) tools, (3 cited 2+ tools). Most studies utilized subjective NAS scoring/assessment algorithms and neonatal coding as key elements defining NAS. While most cited opioid exposure as integral to their inclusion criteria, 26% did not. These approaches highlight the need for a more refined and standardized definition of NAS.

Abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that frequently has cutaneous manifestations. The diagnosis can be a challenge because of its heterogenous clinical presentation, ranging from a brown or violaceous solitary nodule or patch to mixed, disseminated lesions. Furthermore, BPDCN tumor cells express immunohistochemical markers in common with acute myeloid leukemia, which can lead to misdiagnosis. Timely diagnosis requires awareness of its cutaneous manifestations and unique histopathology and immunophenotype. We present a case series of patients diagnosed with BPDCN and review the cutaneous and histopathologic characteristics of this uncommon entity., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli -induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment., Sources of Information: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors., Methods: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies., Key Findings: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli -induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA., Limitations: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The membership of the group of authors was identified following a series of meetings and conferences related to thrombotic microangiopathy (TMA). The final membership was struck following an industry-sponsored TMA meeting; however, the sponsor was not involved in the genesis or content of the project or the selection of physician members. There was no support either financial or otherwise provided to this group from any industry or other sponsors. P.A.M and J.G. received honoraria from Alexion and Sanofi Genzyme. M.B., A.-L.L., K.G., and D.B. from Alexion. C.B. from Alexion, Sanofi, Argenx, and Appelis. L.-P.G. from Alexion and Genzyme and clinical trials from Chemocentryx and Alexion. C.J.P. from Alexion, Octapharma, Apellis, Biocryst, and Sanofi; received research support from Alexion, Octapharma, and Sanofi; and clinical trial participation—Site PI—Alexion, Ra Pharma, Apellis, and Sanofi. K.P. from Alexion, Sanofi, and Takeda and clinical trials from Sanofi and Takeda. C.L. received honoraria and unrestricted grants from Alexion, Apellis, Aurin, and Novartis., (© The Author(s) 2021.)

Competing Interests: Competing interests: None declared.

Background: Evidence is scarce regarding the analgesic effect of music for the relief of acute pain during the care of surgical tibial fracture wounds., Objective: To evaluate the analgesic effect of music on acute procedural pain during the care of surgical tibial fracture wounds., Method: This was a randomized, controlled, blinded clinical trial with 70 patients in the immediate postoperative period for diaphyseal tibial fracture surgery. Participants were randomly allocated to two groups: a control group (CG), in which patients received only the institution's standard analgesia, and an intervention group (IG) composed of patients receiving a 30-min session of music of their own choice, as a complementary method to the institution's standard analgesia. Pain was evaluated during the first postoperative dressing change, using the Numerical Rating Scale (NRS)., Results: The sample was homogeneously composed of men (91.4%), young adults (61.4%), without previous diseases (88.6%) and whose traumas were related to a motorcycle crash (84.3%). The main musical genres chosen by participants were the most popular in their region (61.4%). Those who listened to music presented lower pain scores when compared with those in the CG (IG:2.4 ± 2.4 versus CG:5.8 ± 2.7; p < 0.001; η 2  = 0.171; p < 0.001)., Conclusion: Listening to music is effective for relieving acute procedural pain during the first post-operative tibial fracture dressing change. Music should be incorporated into the multimodal analgesia protocols for management of orthopedic postoperative wound care-related pain., Significance: Patients with diaphyseal tibial fractures that listened to music before and during the wound dressing change showed less pain when compared to those who received the standardized pharmacologic analgesia alone., (© 2020 European Pain Federation - EFIC®.)

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D 3 receptors are described as two promising targets for future drug development.

Opioid reward has traditionally been thought to be mediated by GABA-induced disinhibition of dopamine (DA) neurons in the VTA. However, direct behavioral evidence supporting this hypothesis is still lacking. In this study, we found that the μ opioid receptor (MOR) gene, Oprm1 , is highly expressed in GABA neurons, with ∼50% of GABA neurons in the substantia nigra pars reticulata (SNr), ∼30% in the VTA, and ∼70% in the tail of the VTA (also called the rostromedial tegmental nucleus) in male rats. No Oprm1 mRNA was detected in midbrain DA neurons. We then found that optogenetic inhibition of VTA DA neurons reduced intravenous heroin self-administration, whereas activation of these neurons produced robust optical intracranial self-stimulation in DAT-Cre mice, supporting an important role of DA neurons in opioid reward. Unexpectedly, pharmacological blockade of MORs in the SNr was more effective than in the VTA in reducing heroin reward. Optogenetic activation of VTA GABA neurons caused place aversion and inhibited cocaine, but not heroin, self-administration, whereas optogenetic activation of SNr GABA neurons caused a robust increase in heroin self-administration with an extinction pattern, suggesting a compensatory response in drug intake due to reduced heroin reward. In addition, activation of SNr GABA neurons attenuated heroin-primed, but not cue-induced, reinstatement of drug-seeking behavior, whereas inhibition of SNr GABA neurons produced optical intracranial self-stimulation and place preference. Together, these findings suggest that MORs on GABA neurons in the SNr play more important roles in opioid reward and relapse than MORs on VTA GABA neurons. SIGNIFICANCE STATEMENT Opioid reward has long been believed to be mediated by inhibition of GABA interneurons in the VTA that subsequently leads to disinhibition of DA neurons. In this study, we found that more μ opioid receptors (MORs) are expressed in GABA neurons in the neighboring SNr than in the VTA, and that pharmacological blockade of MORs in the SNr is more effective in reducing heroin reward than blockade of MORs in the VTA. Furthermore, optogenetic activation of VTA GABA neurons inhibited cocaine, but not heroin, self-administration, whereas activation of SNr GABA neurons inhibited heroin reward and relapse. These findings suggest that opioid reward is more likely mediated by stimulation of MORs in GABA afferents from other brain regions than in VTA GABA neurons., (Copyright © 2020 the authors.)

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB 1 receptor (CB 1 R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB 2 R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB 2 R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose: Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with up-regulated dopamine D 3 receptor expression in the brain. Therefore, most D 3 -based medication development has focused on D 3 antagonists. However, D 3 antagonists do not attenuate cocaine intake under "easy" self-administration conditions, when response requirements are low. We evaluated a novel, highly selective and metabolically stable D 3 partial agonist, (±)VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking., Experimental Approach: The impact of (±)VK4-40 on cocaine intake and relapse was evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of (±)VK4-40 and cocaine in the mesolimbic dopamine system in mice. Sucrose self-administration in rats and a conditioned place preference paradigm in mice were used to evaluate the abuse potential of (±)VK4-40 alone and other unwanted effects., Key Results: (±)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. (±)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. (±)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D 3 partial agonist also failed to alter oral sucrose self-administration., Conclusion and Implications: The novel D 3 partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D 3 partial agonists as putative treatments for cocaine use disorder., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as "smart drugs" by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.

When treating invasive basal cell carcinoma (BCC) with Mohs micrographic surgery (MMS), including infiltrative and nodular subtypes, the goal is complete surgical removal of the tumor. In some cases, after several stages of MMS, residual foci of superficial BCC are noted with no dermal invasive components apparent. Some patients and surgeons have opted for halting surgery and treating residual superficial BCC with adjuvant topical fluorouracil. In this retrospective study, this treatment method is shown to be effective with a recurrence rate of BCC of 3.7% over a mean follow up of 28 months. This treatment method reduces the number of stages of MMS as the surgery is stopped was invasive BCC is removed. This can be beneficial when considering the morbidity of prolonged surgical procedures in frail, elderly patients experiencing surgical fatigue, the cost of additional stages, and the cost of advanced repairs due to enlarging defect size. J Drugs Dermatol. 2020;19(5): doi:10.36849/JDD.2020.4811.

The HEALthy Brain and Child Development (HBCD) study will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis and follow them and their children for at least 10 years. Findings from this cohort will help researchers understand normative childhood brain development as well as the long-term impact of prenatal and postnatal opioid and other drug and environmental exposures. The study will collect data on pregnancy and fetal development; infant and early childhood structural and functional brain imaging; anthropometrics; medical history; family history; biospecimens; and social, emotional, and cognitive development. Knowledge gained from this research will be critical to help predict and prevent some of the known effects of prenatal and postnatal exposure to certain drugs or environmental exposures, including risk for future substance use, mental disorders, and other behavioral and developmental problems. In this special issue, a subset of investigators that received funding for planning grants for the HBCD study provide careful guidelines and frameworks for study design, recruitment and retention of vulnerable populations, culturally sensitive practices, and biospecimen and neurodevelopmental assessment recommendations gathered in feasibility studies that will help inform the full HBCD study planned to begin recruitment in 2022., (© The Author(s) 2020.)

Opioid and cocaine abuse are major public health burdens. Existing medications for opioid use disorder are limited by abuse liability and side effects, whereas no treatments are currently approved in the United States for cocaine use disorder. Dopamine D 3 receptor (D 3 R) antagonists have shown promise in attenuating opioid and cocaine reward and mitigating relapse in preclinical models. However, translation of D 3 R antagonists to the clinic has been hampered by reports that the D 3 R antagonists GSK598,809 (5-(5-((3-((1 S ,5 R )-1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)propyl)thio)-4-methyl-4 H -1,2,4-triazol-3-yl)-4-methyloxazole) and SB-277,011A (2-(2-((1 r ,4 r )-4-(2-oxo-2-(quinolin-4-yl)ethyl)cyclohexyl)ethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile) have adverse cardiovascular effects in the presence of cocaine. Recently, we developed two structurally novel D 3 R antagonists, R -VK4-40 and R -VK4-116, which are highly selective for D 3 R and display translational potential for treatment of opioid use disorder. Here, we tested whether R -VK4-40 (( R )- N -(4-(4-(2-Chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1 H -indole-2-carboxamide) and R -VK4-116 (( R )- N -(4-(4-(3-Chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1 H -indole-2-carboxamide) have unwanted cardiovascular effects in the presence of oxycodone, a prescription opioid, or cocaine in freely moving rats fitted with surgically implanted telemetry transmitters. We also examined cardiovascular effects of the D 3 R antagonist, SB-277,011A, and L-741,626 (1-((1 H -indol-3-yl)methyl)-4-(4-chlorophenyl)piperidin-4-ol), a dopamine D 2 receptor-selective antagonist, for comparison. Consistent with prior reports, SB-277,011A increased blood pressure, heart rate, and locomotor activity alone and in the presence of cocaine. L-741,626 increased blood pressure and heart rate. In contrast, R -VK4-40 alone dose-dependently reduced blood pressure and heart rate and attenuated oxycodone-induced increases in blood pressure and oxycodone or cocaine-induced increases in heart rate. Similarly, R -VK4-116 alone dose-dependently reduced cocaine-induced increases in blood pressure and heart rate. These results highlight the safety of new D 3 R antagonists and support the continued development of R -VK4-40 and R -VK4-116 for the treatment of opioid and cocaine use disorders. SIGNIFICANCE STATEMENT: Opioid and cocaine abuse are major public health challenges and new treatments that do not adversely impact the cardiovascular system are needed. Here, we show that two structurally novel dopamine D 3 receptor antagonists, R -VK4-40 and R -VK4-116, do not potentiate, and may even protect against, oxycodone- or cocaine-induced changes in blood pressure and heart rate, supporting their further development for the treatment of opioid and/or cocaine use disorders., (U.S. Government work not protected by U.S. copyright.)

Substance use disorders (SUD) are serious public health problems worldwide. Although significant progress has been made in understanding the neurobiology of drug reward and the transition to addiction, effective pharmacotherapies for SUD remain limited and a majority of drug users relapse even after a period of treatment. The United States Food and Drug Administration (FDA) has approved several medications for opioid, nicotine, and alcohol use disorders, whereas none are approved for the treatment of cocaine or other psychostimulant use disorders. The medications approved by the FDA for the treatment of SUD can be divided into two major classes - agonist replacement therapies, such as methadone and buprenorphine for opioid use disorders (OUD), nicotine replacement therapy (NRT) and varenicline for nicotine use disorders (NUD), and antagonist therapies, such as naloxone for opioid overdose and naltrexone for promoting abstinence. In the present review, we primarily focus on the pharmacological rationale of agonist replacement strategies in treatment of opioid dependence, and the potential translation of this rationale to new therapies for cocaine use disorders. We begin by describing the neural mechanisms underlying opioid reward, followed by preclinical and clinical findings supporting the utility of agonist therapies in the treatment of OUD. We then discuss recent progress of agonist therapies for cocaine use disorders based on lessons learned from methadone and buprenorphine. We contend that future studies should identify agonist pharmacotherapies that can facilitate abstinence in patients who are motivated to quit their illicit drug use. Focusing on those that are able to achieve abstinence from cocaine will provide a platform to broaden the effectiveness of medication and psychosocial treatment strategies for this underserved population. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of R-VK4-40, a highly selective dopamine (DA) D 3 receptor (D 3 R) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of R-VK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with R-VK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D 3 antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with R-VK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, R-VK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with R-VK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and R-VK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest R-VK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of R-VK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: When treated conservatively, unstable distal clavicle fractures demonstrate a high symptomatic nonunion rate. While a variety of surgical techniques have been described, many of these techniques are associated with high failure rates and hardware-related complications. The surgical technique used in this study has shown promising biomechanical results; however, long-term clinical results have not yet been described., Purpose: To assess the clinical and radiological outcomes of a surgical technique for fixing displaced distal clavicle fractures using a combination of cortical button fixation and coracoclavicular (CC) ligament reconstruction., Study Design: Case series; Level of evidence, 4., Methods: We conducted a retrospective review of 22 consecutive patients with displaced, unstable Neer type II or V distal clavicle fractures who underwent this surgical technique from 2012 to 2019. Primary outcome variables were radiographic union, patient satisfaction, and postoperative shoulder function. Preoperative and postoperative University of California, Los Angeles (UCLA), and American Shoulder and Elbow Surgeons (ASES) scores were compared. Secondary outcome variables included intraoperative complications, postoperative complications, time to radiographic union, and preoperative and postoperative CC distance. Quality of life was assessed using preoperative and postoperative 36-Item Short Form Health Survey (SF-36) scores., Results: Nearly all (21/22) patients were available for a final review; 1 patient was lost to follow-up at 2 weeks. All 21 patients achieved radiographic union by 4 months (mean, 60.38 days; range, 41-84 days; 95% CI, 53.80-66.96 days). All patients were satisfied with the surgical procedure and their functional outcome. The mean UCLA score improved from 5.36 (95% CI, 4.14-6.60) preoperatively to 32.52 (95% CI, 30.56-34.48) postoperatively (mean difference, 27.14; P < .001). The mean ASES score improved from 16.23 (95% CI, 9.79-22.67) preoperatively to 88.11 (95% CI, 81.82-94.40) postoperatively (mean difference, 71.91; P < .001). Statistically significant improvements in SF-36 scores were seen in the physical functioning, role limitations due to physical health, pain, social functioning, and emotional well-being categories. There were 3 postoperative complications, including 1 patient with a minor complication secondary to hardware irritation, 1 patient with adhesive capsulitis, and 1 patient with wound dehiscence requiring wound closure., Conclusion: We describe a surgical technique for fixing displaced distal clavicle fractures using a combination of cortical button fixation and CC ligament reconstruction that resulted in a 100% union rate and excellent clinical outcomes with acceptable complications., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: G.P.Y. has received educational support, consulting fees, and nonconsulting fees from Arthrex. C.J.J. has received consulting fees from Advanced Orthopaedic Solutions. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2019.)

Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.

Background: Unstable distal clavicular fractures treated surgically are associated with high failure rates and hardware-related complications. Newer techniques have shown promising early clinical results with fewer hardware complications; however, their biomechanical performance has not been assessed. This study biomechanically compared a distal-third locking plate with 3 newer techniques that incorporate coracoid fixation into the construct., Methods: The study randomized 36 adult fresh frozen cadaveric shoulders to 4 groups: (1) distal-third locking plate (P); (2) distal-third locking plate with a coracoid button augmentation (P + CB); (3) coracoclavicular button (CB); and (4) coracoclavicular button with coracoclavicular ligament reconstruction using semitendinosus allograft (CB + CC). After fixation, each specimen was stressed in the coronal plane. Cyclic displacement, load at 10-mm displacement, and ultimate load to failure were measured., Results: All 3 experimental groups biomechanically outperformed the locking plate. Mean load to failure was significantly higher in the CB (343 ± 76 N) and CB + CC (349 ± 94 N) groups compared with the P group (193 ± 52 N). There was also significantly less cyclic displacement in the CB (4.3 ± 1.9 mm) and CB + CC (4.4 ± 1.9 mm) groups compared with the P group (8.2 ± 2.9 mm). With respect to load at 10 mm of displacement, which essentially measures a clinical failure, the P + CB (235 ± 112 N), CB (253 ± 111 N), and CB+CC (238 ± 76 N) experimental groups significantly outperformed the P group (96 ± 29 N)., Conclusions: CB and CB + CC techniques demonstrated more than 75% greater strength than the traditional locking plate alone. Coupled with greater overall construct strength and lower-profile hardware, these newer techniques may result in improved clinical outcome and fewer hardware-related complications., (Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

There are limited radiographic-guided injection techniques of the insertion of the distal interphalangeal joint (DIPJ) collateral ligaments. The objective of this study was to develop and evaluate a palmar/plantar radiographic-guided injection of the collateral ligament insertion in cadavers. Fifty limbs were used to develop the technique and 24 additional limbs were used to evaluate accuracy. An 18 G, 9 cm spinal needle was placed in the depression between the palmar digital neurovascular bundle and arch of the ungular cartilage with dorsodistal advancement towards the distal phalanx collateral fossa. Radiographs verified ideal needle location on the proximal border of the distal phalanx at the collateral fossa. Dye was injected. Hoof walls were partially removed and collateral ligaments were dissected with needles in place to determine needle and dye location. Accuracy of needle placement into the insertion of the DIPJ collateral ligament was 41/48 (85 per cent), with lower accuracy of dye within the ligament (34/48; 71 per cent). Dye entered the DIPJ in 2/48 injections, but dye entered periligamentous structures in 22/48 (46 per cent) injections. A palmar/plantar radiographic-guided injection of the insertion of the DIPJ collateral ligament had high accuracy rate with low injection rate of the DIPJ in cadavers., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2019. No commercial re-use. See rights and permissions. Published by BMJ.)