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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.)

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.)

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).)

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.)

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.)

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.)

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.)

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.

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.)

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.

Cannabinoid CB 1 receptors are highly expressed in the brain and functionally modulate presynaptic neurotransmitter release, while cannabinoid CB 2 receptors (CB 2 Rs) were initially identified in the spleen and regarded as peripheral cannabinoid receptors. Recently, growing evidence indicates the presence of functional CB 2 Rs in the brain. However, this finding is disputed because of the specificity of CB 2 R antibody signals. We used two strains of currently available partial CB 2 -knockout (CB 2 -KO) mice as controls, four anti-rat or anti-mouse CB 2 R antibodies, and mRNA quantification to further address this issue. Western blot assays using the four antibodies detected a CB 2 R-like band at ~40 kD in both the brain and spleen. Notably, more bands were detected in the brain than in the spleen, and specific immune peptides blocked band detection. Immunohistochemical assays also detected CB 2 -like immunostaining in mouse midbrain dopamine neurons. CB 2 R deletion in CB 2 -KO mice may reduce or leave CB 2 R-like immunoreactivity unaltered depending on antibody epitope. Antibodies with epitopes at the receptor-deleted region detected a significant reduction in CB 2 R band density and immunostaining in N-terminal-deleted Deltagen and C-terminal-deleted Zimmer strain CB 2 -KO mice. Other antibodies with epitopes at the predicted receptor-undeleted regions detected similar band densities and immunostaining in wild-type and CB 2 -KO mice. Quantitative RT-PCR assays detected CB 2 mRNA expression using probes that targeted upstream or downstream gene sequences but not the probe that targeted the gene-deleted sequence in Deltagen or Zimmer CB 2 -KO mice. These findings suggest that none of the tested four polyclonal antibodies are highly mouse CB 2 R-specific. Non-specific binding may be related to the expression of mutant or truncated CB 2 R-like proteins in partial CB 2 -KO mice and the use of anti-rat CB 2 antibodies because the epitopes are different between rat and mouse CB 2 Rs.

Cannabinoid CB 1 receptors (CB 1 Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB 1 R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB 1 R antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB 1 R antagonists such as AM4113 deserve further research as a new class of CB 1 R-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

Opioid abuse is a rapidly growing public health crisis in the USA. Despite extensive research in the past decades, little is known about the etiology of opioid addiction or the neurobiological risk factors that increase vulnerability to opioid use and abuse. Recent studies suggest that the type 2 metabotropic glutamate receptor (mGluR2) is critically involved in substance abuse and addiction. In the present study, we evaluated whether low-mGluR2 expression may represent a risk factor for the development of opioid abuse and addiction using transgenic mGluR2-knockout (mGluR2-KO) rats. Compared to wild-type controls, mGluR2-KO rats exhibited higher nucleus accumbens (NAc) dopamine (DA) and locomotor responses to heroin, higher heroin self-administration and heroin intake, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms. In contrast, mGluR2-KO rats displayed lower motivation for heroin self-administration under high price progressive-ratio (PR) reinforcement conditions. Taken together, these findings suggest that mGluR2 may play an inhibitory role in opioid action, such that deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Low-mGluR2 expression in the brain may therefore be a risk factor for the initial development of opioid abuse and addiction.

Management of distal clavicle fractures remains controversial. Various treatment options have been described including open reduction and internal fixation with hook plate fixation, tension band wiring, screw fixation, and distal locking plates. Many of these techniques are associated with a high perioperative complication rate. We describe a surgical technique that allows indirect fixation of distal clavicle fractures and reconstruction of the CC ligaments without the use of prominent hardware.

Despite advances in ex vivo expansion of cord blood-derived hematopoietic stem/progenitor cells (CB-HSPC), challenges still remain regarding the ability to obtain, from a single unit, sufficient numbers of cells to treat an adolescent or adult patient. We and others have shown that CB-HSPC can be expanded ex vivo in two-dimensional (2D) cultures, but the absolute percentage of the more primitive stem cells decreases with time. During development, the fetal liver is the main site of HSPC expansion. Therefore, here we investigated, in vitro, the outcome of interactions of primitive HSPC with surrogate fetal liver environments. We compared bioengineered liver constructs made from a natural three-dimensional-liver-extracellular-matrix (3D-ECM) seeded with hepatoblasts, fetal liver-derived (LvSt), or bone marrow-derived stromal cells, to their respective 2D culture counterparts. We showed that the inclusion of cellular components within the 3D-ECM scaffolds was necessary for maintenance of HSPC viability in culture, and that irrespective of the microenvironment used, the 3D-ECM structures led to the maintenance of a more primitive subpopulation of HSPC, as determined by flow cytometry and colony forming assays. In addition, we showed that the timing and extent of expansion depends upon the biological component used, with LvSt providing the optimal balance between preservation of primitive CB HSPC and cellular differentiation. Stem Cells Translational Medicine 2018;7:271-282., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca ++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism.

Early adolescent substance use dramatically increases the risk of lifelong substance use disorder (SUD). An adolescent sensitive period evolved to allow the development of risk-taking traits that aid in survival; today these may manifest as a vulnerability to drugs of abuse. Early substance use interferes with ongoing neurodevelopment to induce neurobiological changes that further augment SUD risk. Although many individuals use drugs recreationally, only a small percentage transition to SUD. Current theories on the etiology of addiction can lend insights into the risk factors that increase vulnerability from early recreational use to addiction. Building on the work of others, we suggest individual risk for SUD emerges from an immature PFC combined with hyper-reactivity of reward salience, habit, and stress systems. Early identification of risk factors is critical to reducing the occurrence of SUD. We suggest preventative interventions for SUD that can be either tailored to individual risk profiles and/or implemented broadly, prior to the sensitive adolescent period, to maximize resilience to developing substance dependence. Recommendations for future research include a focus on the juvenile and adolescent periods as well as on sex differences to better understand early risk and identify the most efficacious preventions for SUD., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: As many as one-third of all pregnancies in Bangladesh are unplanned, with nearly one-half of these pregnancies ending in either menstrual regulation (MR) or illegal clandestine abortion. Although MR is provided free of charge, or at a nominal cost, through the public sector and various non-profits organizations, many women face barriers in accessing safe, affordable MR and post-MR care. Mobile health (mHealth) services present a promising platform for increasing access to MR among low-income women at risk for clandestine abortion. We sought to investigate the knowledge, attitudes and practices regarding mHealth of both MR clients and formal and informal sexual and reproductive healthcare providers in urban and rural low-income settlements in Bangladesh., Methods: A total of 58 interviews were conducted with MR clients, formal MR providers, and informal MR providers in four low-income settlements in the Dhaka and Sylhet districts of Bangladesh. Interview data was coded and qualitatively analysed for themes using standard qualitative research practices., Results: Our findings suggest that low-income MR clients in Bangladesh have an inadequate understanding of how to use their mobile phones to obtain health service information or counselling related to MR, and correspondingly low levels of formal or informal mHealth service utilization. Few were aware of any formal mHealth services in place in their communities, despite the fact that providers stated that hotlines were available. Overall, MR clients expressed positive opinions of mHealth services as a means of improving women's access to affordable and timely MR. Formal and informal MR providers believed that mobile phones had benefits with respect to information dissemination and making appointments, but emphasized the necessity of in-person consultations for effective sexual and reproductive healthcare., Conclusions: We report low utilization yet high acceptability of mHealth services among low-income MR clients in Bangladesh. Expanding formal and informal mHealth services targeted towards MR - and increasing publicity of these services in low-income communities - may help increase timely access to accurate MR information and formal providers among women at risk for clandestine abortion. While expanding formal and informal mHealth services for SRHR in Bangladesh may be useful in disseminating information about MR and connecting women with formal providers, in-person visits remain necessary for adequate treatment.

Cocaine abuse and attention deficit/hyperactivity disorder (ADHD) are often comorbid. Preclinical research indicates that medial prefrontal (mPFC) and orbitofrontal (OFC) cortices are important neural substrates for both disorders. Using the spontaneously hypertensive rat (SHR) model of ADHD, we reported that adolescent treatment with the stimulant methylphenidate, a dopamine (DAT) and norepinephrine (NET) transporter inhibitor, enhanced cocaine self-administration during adulthood, and was associated with increased DAT function in mPFC. This study investigates the effects of atomoxetine ((R)-N-methyl-γ-(2-methylphenoxy)-benzenepropanamine hydrochloride) treatment, a selective NET inhibitor, during adolescence on cocaine self-administration and on DAT function and cell-surface expression in mPFC and OFC during adulthood. SHR acquired cocaine self-administration faster than Wistar-Kyoto and Wistar. Across cocaine doses, SHR earned more cocaine infusions and had higher progressive-ratio breakpoints than Wistar-Kyoto and Wistar, demonstrating that the SHR phenotype models comorbid ADHD and cocaine abuse. Prior atomoxetine treatment did not augment cocaine self-administration in SHR, but acquisition was enhanced in Wistar-Kyoto. No strain differences were found for DAT kinetic parameters or cellular localization in the vehicle controls. Atomoxetine did not alter DAT kinetic parameters or localization in SHR mPFC. Rather, atomoxetine decreased V(max) and DAT cell surface expression in SHR OFC, indicating that inhibition of NET by atomoxetine treatment during adolescence indirectly reduced DAT function and trafficking to the cell surface in OFC, specifically in the ADHD model. Thus, atomoxetine, unlike methylphenidate, does not enhance vulnerability to cocaine abuse in SHR and may represent an important alternative for teens with ADHD when drug addiction is a concern.

Introduction: The advent of universal health care coverage in the United States and the use of electronic health records can make the medical record a disease surveillance tool. The objective of our study was to identify criteria that accurately categorize acute coronary and heart failure events by using electronic health record data exclusively so that the medical record can be used for surveillance without manual record review., Methods: We serially compared 3 computer algorithms to manual record review. The first 2 algorithms relied on ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes, troponin levels, electrocardiogram (ECG) data, and echocardiograph data. The third algorithm relied on a detailed coding system, Intelligent Medical Objects, Inc., (IMO) interface terminology, troponin levels, and echocardiograph data., Results: Cohen's κ for the initial algorithm was 0.47 (95% confidence interval [CI], 0.41-0.54). Cohen's κ was 0.61 (95% CI, 0.55-0.68) for the second algorithm. Cohen's κ for the third algorithm was 0.99 (95% CI, 0.98-1.00)., Conclusion: Electronic medical record data are sufficient to categorize coronary heart disease and heart failure events without manual record review. However, only moderate agreement with medical record review can be achieved when the classification is based on 4-digit ICD-9-CM codes because ICD-9-CM 410.9 includes myocardial infarction with elevation of the ST segment on ECG (STEMI) and myocardial infarction without elevation of the ST segment on ECG (nSTEMI). Nearly perfect agreement can be achieved using IMO interface terminology, a more detailed coding system that tracks to ICD9, ICD10 (International Classification of Diseases, Tenth Revision, Clinical Modification), and SnoMED-CT (Systematized Nomenclature of Medicine - Clinical Terms).

Introduction: We developed a decision support tool that can guide the development of heart disease prevention programs to focus on the interventions that have the most potential to benefit populations. To use it, however, users need to know the prevalence of heart disease in the population that they wish to help. We sought to determine the accuracy with which the prevalence of heart disease can be estimated from health care claims data., Methods: We compared estimates of disease prevalence based on insurance claims to estimates derived from manual health records in a stratified random sample of 480 patients aged 30 years or older who were enrolled at any time from August 1, 2007, through July 31, 2008 (N = 474,089) in HealthPartners insurance and had a HealthPartners Medical Group electronic record. We compared randomly selected development and validation samples to a subsample that was also enrolled on August 1, 2005 (n = 272,348). We also compared the records of patients who had a gap in enrollment of more than 31 days with those who did not, and compared patients who had no visits, only 1 visit, or 2 or more visits more than 31 days apart for heart disease., Results: Agreement between claims data and manual review was best in both the development and the validation samples (Cohen's κ, 0.92, 95% confidence interval [CI], 0.87-0.97; and Cohen's κ, 0.94, 95% CI, 0.89-0.98, respectively) when patients with only 1 visit were considered to have heart disease., Conclusion: In this population, prevalence of heart disease can be estimated from claims data with acceptable accuracy.

Context: A decision-support tool was created to identify opportunities to improve outcomes for patients with coronary artery disease and heart failure by delivering all efficacious interventions; that is, "optimizing" care. When national data were applied, nearly 75% of the deaths that could be prevented or postponed by optimizing care for patients with heart disease would occur among ambulatory patients., Objective: The purpose of this analysis is two-fold: 1) to determine whether medical group data are adequate to use in the decision-support tool, and 2) to determine whether the conclusions generated from the medical group data are similar to the conclusions generated from US data. DESIGN/MAIN OUTCOME MEASURE: The potential impact of optimizing care for patients age 40 to 75 years treated for coronary artery disease and heart failure by a multispecialty group between August 2007 and July 2008 was calculated using deaths that might be prevented or postponed if optimal care was achieved., Results: The greatest opportunity to prevent or postpone deaths-70% of the total opportunity-lies with optimizing care for ambulatory patients. Optimizing care for patients hospitalized for acute myocardial infarction with or without ST-segment elevation on electrocardiography would prevent or postpone only 2% of deaths., Conclusions: This study demonstrates that 1) it is feasible to use the decision-support tool to analyze opportunities for improvement in a medical group, and 2) as concluded from national data analysis, optimizing ambulatory care presents the greatest opportunity to improve outcomes for patients with heart disease.

Data from national telephone surveys conducted in 1988 and 1993 were used to describe consumer perceptions of foodborne illness. The 1993 data were also used to assess the relationship between the perception that a foodborne illness had recently been experienced and awareness, concern, knowledge, and behavior related to food safety. Respondents described foodborne disease primarily as a minor illness without fever that occurs within a day of eating a contaminated food prepared in a restaurant. However, several common pathogens have a latency period longer than a day, and experts on foodborne disease estimate that most cases of foodborne illness originate from foods prepared at home. In both surveys, people 18 to 39 years of age were more likely than those in other age groups to believe they had experienced a foodborne illness. In 1993, people with at least some college education were more likely to believe they had experienced foodborne illness than were people with less education. People who believed they had experienced foodborne illness had greater awareness of foodborne microbes and concern about food safety issues, were more likely to eat raw protein foods from animals, and were less likely to practice safe food handling than were those who did not perceive that they had experienced such an illness.