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Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the Oprm1 gene encoding µ opioid receptor 1 was selectively deleted from brain astrocytes in Oprm1 inducible conditional knockout (icKO) mice. These mice did not exhibit changes in locomotor activity, anxiety, or novel object recognition, or in their responses to the acute analgesic effects of morphine. Oprm1 icKO mice displayed increased locomotor activity in response to acute morphine administration but unaltered locomotor sensitization. Oprm1 icKO mice showed normal morphine-induced conditioned place preference but exhibited stronger conditioned place aversion associated with naloxone-precipitated morphine withdrawal. Notably, elevated conditioned place aversion lasted up to 6 weeks in Oprm1 icKO mice. Astrocytes isolated from the brains of Oprm1 icKO mice had unchanged levels of glycolysis but had elevated oxidative phosphorylation. The basal augmentation of oxidative phosphorylation in Oprm1 icKO mice was further exacerbated by naloxone-precipitated withdrawal from morphine and, similar to that for conditioned place aversion, was still present 6 weeks later. Our findings suggest that µ opioid receptors in astrocytes are linked to oxidative phosphorylation and they contribute to long-term changes associated with opioid withdrawal.

Choice behavior requires animals to evaluate both short- and long-term advantages and disadvantages of all potential alternatives. Impulsive choice is traditionally measured in laboratory tasks by utilizing delay discounting (DD), a paradigm that offers a choice between a smaller immediate reward, or a larger more delayed reward. This study tested a large sample of Heterogeneous Stock (HS) male (n = 896) and female (n = 898) rats, part of a larger genetic study, to investigate whether measures of reward maximization overlapped with traditional models of delay discounting via the patch depletion model using a Sequential Patch Depletion procedure. In this task, rats were offered a concurrent choice between two water “patches” and could elect to “stay” in the current patch or “leave” for an alternative patch. Staying in the current patch resulted in decreasing subsequent reward magnitudes, whereas the choice to leave a patch was followed by a delay and a resetting to the maximum reward magnitude. Based on the delay in a given session, different visit durations were necessary to obtain the maximum number of rewards. Visit duration may be analogous to an indifference point in traditional DD tasks. While differences in traditional DD measures (e.g., delay gradient) have been detected between males and females, these effects were small and inconsistent. However, when examining measures of reward maximization, females made fewer patch changes at all delays and spent more time in the patch before leaving for the alternative patch compared to males. This pattern of choice resulted in males having a higher rate of reinforcement than females. Consistent with this, there was some evidence that females deviated from the optimal more, leading to less reward. Measures of reward maximization were only weakly associated with traditional DD measures and may represent distinctive underlying processes. Taken together, females performance differed from males with regard to reward maximization that were not observed utilizing traditional measures of DD, suggesting that the patch depletion model was more sensitive to modest sex differences when compared to traditional DD measures in a large sample of HS rats.

Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor–mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. Cancer Prev Res; 5(1); 73–81. ©2011 AACR.

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Plasma sulforaphane concentrations by day, dose, and pre- or post-BSE-SFN administration

IMPORTANCE: Mindfulness curricula can improve physician burnout, but implementation during residency presents challenges. OBJECTIVE: To examine whether a novel mindfulness curriculum implemented in the first 6 months of internship reduces burnout. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, multicenter, stratified cluster randomized clinical trial of a mindfulness curriculum randomized 340 pediatric interns to the intervention or control arm within program pairs generated based on program size and region. Fifteen US pediatric training programs participated from June 14, 2017, to February 28, 2019. INTERVENTIONS: The intervention included 7 hour-long sessions of a monthly mindfulness curriculum (Mindfulness Intervention for New Interns) and a monthly mindfulness refresher implemented during internship. The active control arm included monthly 1-hour social lunches. MAIN OUTCOMES AND MEASURES: The primary outcome was emotional exhaustion (EE) as measured by the Maslach Burnout Inventory 9-question EE subscale (range, 7-63; higher scores correspond to greater perceived burnout). Secondary outcomes were depersonalization, personal accomplishment, and burnout. The study assessed mindfulness with the Five Facet Mindfulness Questionnaire and empathy with the Interpersonal Reactivity Index subscales of perspective taking and empathetic concern. Surveys were implemented at baseline, month 6, and month 15. RESULTS: Of the 365 interns invited to participate, 340 (93.2%; 255 [75.0%] female; 51 [15.0%] 30 years or older) completed surveys at baseline; 273 (74.8%) also participated at month 6 and 195 (53.4%) at month 15. Participants included 194 (57.1%) in the Mindfulness Intervention for New Interns and 146 (42.9%) in the control arm. Analyses were adjusted for baseline outcome measures. Both arms’ EE scores were higher at 6 and 15 months than at baseline, but EE did not significantly differ by arm in multivariable analyses (6 months: 35.4 vs 32.4; adjusted difference, 3.03; 95% CI, −0.14 to 6.21; 15 months: 33.8 vs 32.9; adjusted difference, 1.42; 95% CI, −2.42 to 5.27). None of the 6 secondary outcomes significantly differed by arm at month 6 or month 15. CONCLUSIONS AND RELEVANCE: A novel mindfulness curriculum did not significantly affect EE, burnout, empathy, or mindfulness immediately or 9 months after curriculum implementation. These findings diverge from prior nonrandomized studies of mindfulness interventions, emphasizing the importance of rigorous study design and suggesting that additional study is needed to develop evidence-based methods to reduce trainee burnout. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03148626

Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain regions, particularly the VTA. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. Attenuation of H3Q5dop during abstinence induced persistent changes in gene expression programs associated with neuronal signaling and dopaminergic function in heroin abstinence and led to reduced heroin-seeking behavior. Interestingly, the observed changes in molecular pathways after heroin SA showed significant yet reversed overlap with the same genes altered in cocaine SA. These findings establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in heroin-induced functional plasticity in VTA.

Neutron-induced cross sections represent the main nuclear input to models of stellar and Big-Bang nucleosynthesis. While (n,γ) reactions are relevant for the formation of elements heavier than iron, (n,p) and (n,α) reactions can play an important role in specific cases. The time-of-flight method is routinely used at n_TOF to experimentally determine the cross section data. In addition, recent upgrades of the facility will allow the use of activation techniques as well, possibly opening the way to a systematic study of neutron interaction with radioactive isotopes. In the last 20 years n_TOF has provided a large amount of experimental data for Nuclear Astrophysics. Our plan is to carry on challenging measurements and produce nuclear data in the next decades as well.

A new isoflavonoid, xanthocerin J, along with previously described xanthocerin A, were isolated from a methanol extract of aerial parts of a traditional American Indian herb, Amorpha canescens Pursh (Asteraceae). The structures of these compounds were characterized using mass spectrometry and NMR based on an isolation protocol using magnetic microbead affinity selection screening (MagMASS) for ligands to the estrogen receptor alpha (ERα). These compounds bound to ERα from an active fraction that exhibited dose-dependent antiestrogenic activity in the in vitro Ishikawa assay. However, these compounds did not exhibit antiestrogenic activity in the cell-based Ishikawa assay. Xanthocerin A and J may exhibit synergistic or additive activity with other compounds found in A. canescens which needs further exploration. This work highlights the potential of A. canescens as a prospect for the future discovery of compounds for women’s health related to estrogen pathways.

With the aim of measuring the $^{235}$U(n,f) cross section at the n_TOF facility at CERNover a wide neutron energy range, a detection system consisting of two fission detectors and threedetectors for neutron flux determination was realized. The neutron flux detectors are RecoilProton Telescopes (RPTs), based on scintillators and solid state detectors, conceived to detectrecoil protons from the neutron-proton elastic scattering reaction. This system, along with afission chamber and an array of parallel plate avalanche counters for fission event detection, wasinstalled for the measurement at the n_TOF facility in 2018, at CERN.An overview of the performances of two RPTs — especially developed for this measurement — and of theparallel plate avalanche counters are described in this article. In particular, the characterizationin terms of detection efficiency by Monte Carlo simulations and response to neutron beam, the studyof the background, dead time correction and characterization of the samples, are reported. Theresults of the present investigation show that the performances of these detectors are suitable foraccurate measurements of fission reaction cross sections in the range from 10 to 450 MeV. With the aim of measuring the $^{235}$U(n,f) cross section at the n_TOF facility at CERN over a wide neutron energy range, a detection system consisting of two fission detectors and three detectors for neutron flux determination was realized. The neutron flux detectors are Recoil Proton Telescopes (RPT), based on scintillators and solid state detectors, conceived to detect recoil protons from the neutron-proton elastic scattering reaction. This system, along with a fission chamber and an array of parallel plate avalanche counters for fission event detection, was installed for the measurement at the n_TOF facility in 2018, at CERN. An overview of the performances of two RPTs - especially developed for this measurement - and of the parallel plate avalanche counters are described in this article. In particular, the characterization in terms of detection efficiency by Monte Carlo simulations and response to neutron beam, the study of the background, dead time correction and characterization of the samples, are reported. The results of the present investigation show that the performances of these detectors are suitable for accurate measurements of fission reaction cross sections in the range from 10 to 450~MeV.

Nuclear level densities (NLDs) and photon strength functions (PSFs), also called ¿ -ray or radiation strength functions, represent average properties of the nucleus in the regime of excitation where individual levels and transition probabilities by ¿ decay are not readily accessible by experimental or theoretical means. They are key ingredients for statistical calculations of the reaction cross sections involving ¿ rays via the Hauser-Feshbach approach [1], like inelastic scattering or neutron capture reactions. Peer Reviewed Aquest article té 124 autors/autores J. Moreno-Soto, S. Valenta, E. Berthoumieux, A. Chebboubi, M. Diakaki, W. Dridi, E. Dupont, F. Gunsing, M. Krticka, O. Litaize, O. Serot, O. Aberle, V. Alcayne, S. Amaducci, J. Andrzejewski, L. Audouin, V. Bécares, V. Babiano-Suarez, M. Bacak, M. Barbagallo, Th. Benedikt, S. Bennett, J. Billowes, D. Bosnar, A. Brown, M. Busso, M. Caamaño, L. Caballero-Ontanaya, F. Calviño, M. Calviani, D. Cano-Ott, A. Casanovas, F. Cerutti, E. Chiaveri, N. Colonna, G. Cortés, M. A. Cortés-Giraldo, L. Cosentino, Cristallo, L. A. Damone, P. J. Davies, M. Dietz, C. Domingo-Pardo, R. Dressler, Q. Ducasse, I. Durán, Z. Eleme, B. Fernández-Domínguez, A. Ferrari, P. Finocchiaro, V. Furman, K. Göbel, A. Gawlik-Rami, S. Gilardoni, I. F. Gonçalves, E. González-RomeroC. Guerrero, S. Heinitz, J. Heyse, D. G. Jenkins, A. Junghans, F. Käppeler, Y. Kadi, A. Kimura, I. Knapová, M. Kokkoris, Y. Kopatch, D. Kurtulgil, I. Ladarescu, C. Lampoudis, C. Lederer-Woods, S. J. Lonsdale, D. Macina, A. Manna, T. Martínez, A. Masi, C. Massimi, P. Mastinu, M. Mastromarco, E. A. Maugeri, A. Mazzone, E. Mendoza, A. Mengoni, V. Michalopoulou, P. M. Milazzo, F. MingroneA. Musumarra, A. Negret, R. Nolte, F. Ogállar, A. Oprea, N. Patronis, A. Pavlik, J. Perkowski, L. Piersanti, C. Petrone, E. Pirovano, I. Porras, J. Praena, J. M. Quesada, D. Ramos-Doval, T. Rauscher, R. Reifarth, D. Rochman, M. Sabaté-Gilarte, A. Saxena, P. Schillebeeckx, D. Schumann, A. Sekhar, A. G. Smith, N. V. Sosnin, P. Sprung, A. Stamatopoulos, G. Tagliente, J. L. Tain, A. Tarifeño-Saldivia, L. Tassan-Got, P. Torres-Sánchez, A. Tsinganis, J. Ulrich, S. Urlass, G. Vannini, V. Variale, P. Vaz, A. Ventura, D. Vescovi, V. Vlachoudis, R. Vlastou, A. Wallner, P. J. Woods, T. Wright, P. Žugec

INTRODUCTIONChest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs).METHODSWe performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens.RESULTSWe found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, pCONCLUSIONReproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

Persons identified in early childhood as having autism spectrum disorder (autism) often have co-occurring health problems that extend into adolescence (1-3). Although only limited data exist on their health and use of health care services as they transition to adolescence, emerging data suggest that a minority of these persons receive recommended guidance* from their primary care providers (PCPs) starting at age 12 years to ensure a planned transition from pediatric to adult health care (4,5). To address this gap in data, researchers analyzed preliminary data from a follow-up survey of parents and guardians of adolescents aged 12-16 years who previously participated in the Study to Explore Early Development (https://www.cdc.gov/ncbddd/autism/seed.html). The adolescents were originally studied at ages 2-5 years and identified at that age as having autism (autism group) or as general population controls (control group). Adjusted prevalence ratios (aPRs) that accounted for differences in demographic characteristics were used to compare outcomes between groups. Adolescents in the autism group were more likely than were those in the control group to have physical difficulties (21.2% versus 1.6%; aPR = 11.6; 95% confidence interval [CI] = 4.2-31.9), and to have additional mental health or other conditions† (one or more condition: 63.0% versus 28.9%; aPR = 1.9; 95% CI = 1.5-2.5). Adolescents in the autism group were more likely to receive mental health services (41.8% versus 22.1%; aPR = 1.8, 95% CI = 1.3-2.6) but were also more likely to have an unmet medical or mental health service need§ (11.0% versus 3.2%; aPR = 3.1; 95% CI = 1.1-8.8). In both groups, a small percentage of adolescents (autism, 7.5%; control, 14.1%) received recommended health care transition (transition) guidance. These findings are consistent with previous research (4,5) indicating that few adolescents receive the recommended transition guidance and suggest that adolescents identified with autism in early childhood are more likely than adolescents in the general population to have unmet health care service needs. Improved provider training on the heath care needs of adolescents with autism and coordination of comprehensive programs¶ to meet their needs can improve delivery of services and adherence to recommended guidance for transitioning from pediatric to adult health care.

The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts population-based surveillance of autism spectrum disorder (ASD) among 8-year-old children in multiple US communities. From 2000 to 2016, investigators at ADDM Network sites classified ASD from collected text descriptions of behaviors from medical and educational evaluations which were reviewed and coded by ADDM Network clinicians. It took at least 4 years to publish data from a given surveillance year. In 2018, we developed an alternative case definition utilizing ASD diagnoses or classifications made by community professionals. Using data from surveillance years 2014 and 2016, we compared the new and previous ASD case definitions. Compared with the prevalence based on the previous case definition, the prevalence based on the new case definition was similar for 2014 and slightly lower for 2016. Sex and race/ethnicity prevalence ratios were nearly unchanged. Compared with the previous case definition, the new case definition’s sensitivity was 86% and its positive predictive value was 89%. The new case definition does not require clinical review and collects about half as much data, yielding more timely reporting. It also more directly measures community identification of ASD, thus allowing for more valid comparisons among communities, and reduces resource requirements while retaining measurement properties similar to those of the previous definition.

Der Ubergabe als Ubertragung der Verantwortlichkeit und Zustandigkeit fur die weitere Versorgung des Patienten kommt eine besondere Bedeutung im Behandlungsprozess und fur die Patientensicherheit zu. Dies gilt umso mehr fur die Ubergabe des Rettungsdiensts an die zentrale Notaufnahme in ihrem komplexen und stressbehafteten Umfeld. Dieser Prozess ist auf eine in allen Aspekten funktionierende Kommunikation angewiesen, um unerwunschte Ereignisse fur den Patienten zu vermeiden und eine optimale Weiterversorgung zu gewahrleisten. Bisher existieren in Deutschland nur in einzelnen Bereichen uberhaupt Vorgaben und Konzepte fur eine strukturierte Ubergabe. Im vorliegenden Konsensuspapier werden funfzehn Empfehlungen fur einen standardisierten Ubergabeprozess des Notfallpatienten vorgestellt, die durch die Fachgesellschaften der an der Ubergabe beteiligten Berufsgruppen (Notfallmediziner, Notfallpflege, Rettungsdienstorganisationen) sowie das Bundnis fur Patientensicherheit als Vertreter der Patienten erarbeitet wurden.

Breast cancer risk continues to rise post menopause. Endocrine therapies are employed to prevent postmenopausal breast cancer in high-risk women. However, their adverse effects have reduced acceptability and overall success in cancer preventionatural products such as hops (Humulus lupulus) and pharmacopoeial licorice (Glycyrrhiza) species, which are used for managing menopausal symptoms, have demonstrated estrogenic and chemopreventive properties. Their beneficial effects on aromatase activity and expression as important factors in postmenopausal breast carcinogenesis are understudied. The presented data show that Gycyrrhiza inflata (GI) has the highest aromatase inhibition potency among these plants. Moreover, phytoestrogens such as 8-prenylnaringenin from hops as well as liquiritigenin and 8-prenylapigenin from licorice are shown to be potent bioactives, in line with computational docking studies. 8-Prenylnaringenin, GI extract, liquiritigenin, and licochalcone A all suppress aromatase expression in postmenopausal women’s breast tissue. Collectively, these data suggest that these natural products may have breast cancer prevention potential for high-risk postmenopausal women.

Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-β (TGF-β) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

Botanical dietary supplements (BDS) containing hops are sold as women's health supplements due to the potent hop phytoestrogen, 8-prenylnaringenin (8-PN), and the cytoprotective chalcone, xanthohumol. Previous studies have shown a standardized hop extract to beneficially influence chemical estrogen carcinogenesis in vitro by fostering detoxified 2-hydroxylation over genotoxic 4-hydroxylation estrogen metabolism. In this study, hop extract and its bioactive compounds were investigated for its mechanism of action within the chemical estrogen carcinogenesis pathway, which is mainly mediated through the 4-hydroxylation pathway catalyzed by CYP1B1 that can form gentoxic quinones. Aryl hydrocarbon receptor (AhR) agonists induce CYP1A1 and CYP1B1, while estrogen receptor alpha (ERα) inhibits transcription of CYP1A1, the enzyme responsible for 2-hydroxylated estrogens and the estrogen detoxification pathway. An In-Cell Western MCF-7 cell assay revealed hop extract and 6-prenylnaringenin (6-PN) degraded ERα via an AhR-dependent mechanism. Reverse transcription PCR and xenobiotic response element luciferase assays showed hop extract and 6-PN-mediated activation of AhR and induction of CYP1A1. A reduction in estrogen-mediated DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation of CYP1A1 accompanied this activity in a chromatin immunoprecipitation assay. Ultimately, hop extract and 6-PN induced preferential metabolism of estrogens to their detoxified form in vitro. These results suggest that the standardized hop extract and 6-PN activate AhR to attenuate epigenetic inhibition of CYP1A1 through degradation of ERα, ultimately increasing 2-hydroxylated estrogens. A new mechanism of action rationalizes the positive influence of hop BDS and 6-PN on oxidative estrogen metabolism in vitro and, thus, potentially on chemical estrogen carcinogenesis. The findings underscore the importance of elucidating various biological mechanisms of action and standardizing BDS to multiple phytoconstituents for optimal resilience promoting properties.

Previous studies investigating the association between dysmorphology and cognitive, behavioral, and developmental outcomes among individuals with autism spectrum disorder (ASD) have been limited by the binary classification of dysmorphology and lack of comparison groups. We assessed the association using a continuous measure of dysmorphology severity (DS) in preschool children aged 2-5 years (322 with ASD and intellectual disability [ID], 188 with ASD without ID, and 371 without ASD from the general population [POP]). In bivariate analyses, an inverse association between DS and expressive language, receptive language, fine motor, and visual reception skills was observed in children with ASD and ID. An inverse association of DS with fine motor and visual reception skills, but not expressive language and receptive language, was found in children with ASD without ID. No associations were observed in POP children. These results persisted after exclusion of children with known genetic syndromes or major morphologic anomalies. Quantile regression models showed that the inverse relationships remained significant after adjustment for sex, race/ethnicity, maternal education, family income, study site, and preterm birth. DS was not associated with autistic traits or autism symptom severity, behaviors, or regression among children with ASD with or without ID. Thus, DS was associated with a global impairment of cognitive functioning in children with ASD and ID, but only with fine motor and visual reception deficits in children with ASD without ID. A better understanding is needed for mechanisms that explain the association between DS and cognitive impairment in children with different disorders. Autism Res 2020, 13: 1227-1238. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined whether having more dysmorphic features (DFs) was related to developmental problems among children with autism spectrum disorder (ASD) with or without intellectual disability (ID), and children without ASD from the general population (POP). Children with ASD and ID had more language, movement, and learning issues as the number of DFs increased. Children with ASD without ID had more movement and learning issues as the number of DFs increased. These relationships were not observed in the POP group. Implications are discussed.

Background We previously showed that the transcription factor Egr3 (early growth response 3) is oppositely regulated in nucleus accumbens (NAc) cell subtypes 24 hours following cocaine exposure and bidirectionally mediates cocaine-related behaviors in male rodents. Overexpressing Egr3 in D2 receptor–containing medium spiny neurons (D2-MSNs) before drug exposure reduces the rewarding and psychomotor sensitization effects of cocaine. However, it is unknown if Egr3 plays a role in long-term neuroadaptations in the NAc and relapse to cocaine seeking. Methods We measured EGR3 protein levels in the NAc following 20 days of forced abstinence from intravenous cocaine self-administration in 10-week-old Sprague Dawley rats and C57BL/6 mice. In 8- to 10-week-old A2A-Cre mice, we used virally mediated Egr3 overexpression in NAc D2-MSNs to test the role of Egr3 on operant responding during seeking, extinction, and drug-induced reinstatement of cocaine self-administration. To evaluate if Egr3 contributed to sex differences to cocaine relapse, we conducted these procedures in both male and female rodents. Results We found that EGR3 expression was reduced only in female rodents after 20 days of forced abstinence. Additionally, we showed that our self-administration paradigm in mice recapitulated the sex differences in cocaine intake and relapse demonstrated in humans and rats. Finally, whereas Egr3 overexpression in D2-MSNs during forced abstinence facilitated extinction and blunted drug-induced reinstatement in female mice, it had the opposite effect in male mice. Conclusions We showed that the immediate early gene Egr3 has long-term effects on drug-related behaviors. Our work suggests that changes in Egr3 expression in D2-MSNs contributes to sex differences in cocaine relapse.

More than a normal neurotransmitter The molecular mechanisms underlying the persistence of addiction remain largely unclear. Lepack et al. found that, with cocaine exposure, there is an intracellular accumulation of dopamine in neurons of a brain region called the ventral tegmental area (see the Perspective by Girault). Dopamine associates with chromatin to initiate a previously unknown form of epigenetic regulation called dopaminylation. This modification has an impact on ventral tegmental area function and, consequently, on dopaminergic action potentials. The result is aberrant dopamine signaling in the ventral striatum during periods of drug seeking. Science , this issue p. 197 ; see also p. 134

PROBLEM/CONDITION Autism spectrum disorder (ASD). PERIOD COVERED 2016. DESCRIPTION OF SYSTEM The Early Autism and Developmental Disabilities Monitoring (Early ADDM) Network, a subset of the overall ADDM Network, is an active surveillance program that estimates ASD prevalence and monitors early identification of ASD among children aged 4 years. Children included in surveillance year 2016 were born in 2012 and had a parent or guardian who lived in the surveillance area in Arizona, Colorado, Missouri, New Jersey, North Carolina, or Wisconsin, at any time during 2016. Children were identified from records of community sources including general pediatric health clinics, special education programs, and early intervention programs. Data from comprehensive evaluations performed by community professionals were abstracted and reviewed by trained clinicians using a standardized ASD surveillance case definition with criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). RESULTS In 2016, the overall ASD prevalence was 15.6 per 1,000 (one in 64) children aged 4 years for Early ADDM Network sites. Prevalence varied from 8.8 per 1,000 in Missouri to 25.3 per 1,000 in New Jersey. At every site, prevalence was higher among boys than among girls, with an overall male-to-female prevalence ratio of 3.5 (95% confidence interval [CI] = 3.1-4.1). Prevalence of ASD between non-Hispanic white (white) and non-Hispanic black (black) children was similar at each site (overall prevalence ratio: 0.9; 95% CI = 0.8-1.1). The prevalence of ASD using DSM-5 criteria was lower than the prevalence using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria at one of four sites that used criteria from both editions. Among sites where ≥60% of children aged 4 years had information about intellectual disability (intelligence quotient ≤70 or examiner's statement of intellectual disability documented in an evaluation), 53% of children with ASD had co-occurring intellectual disability. Of all children aged 4 years with ASD, 84% had a first evaluation at age ≤36 months and 71% of children who met the surveillance case definition had a previous ASD diagnosis from a community provider. Median age at first evaluation and diagnosis for this age group was 26 months and 33 months, respectively. Cumulative incidence of autism diagnoses received by age 48 months was higher for children aged 4 years than for those aged 8 years identified in Early ADDM Network surveillance areas in 2016. INTERPRETATION In 2016, the overall prevalence of ASD in the Early ADDM Network using DSM-5 criteria (15.6 per 1,000 children aged 4 years) was higher than the 2014 estimate using DSM-5 criteria (14.1 per 1,000). Children born in 2012 had a higher cumulative incidence of ASD diagnoses by age 48 months compared with children born in 2008, which indicates more early identification of ASD in the younger group. The disparity in ASD prevalence has decreased between white and black children. Prevalence of co-occurring intellectual disability was higher than in 2014, suggesting children with intellectual disability continue to be identified at younger ages. More children received evaluations by age 36 months in 2016 than in 2014, which is consistent with Healthy People 2020 goals. Median age at earliest ASD diagnosis has not changed considerably since 2014. PUBLIC HEALTH ACTION More children aged 4 years with ASD are being evaluated by age 36 months and diagnosed by age 48 months, but there is still room for improvement in early identification. Timely evaluation of children by community providers as soon as developmental concerns have been identified might result in earlier ASD diagnoses, earlier receipt of evidence-based interventions, and improved developmental outcomes.

Importance: The novel coronavirus 2019 (SARS-CoV-2) has been well described in adults. Further, the impact on older children and during the perinatal time is becoming better studied. As community spread increases, it is important to recognize that neonates are vulnerable to community spread as well. The impact that community-acquired SARS-CoV-2 has in the neonatal time period is unclear, as this population has unique immunity considerations. Objective: To report on a case series of SARS-CoV-2 in neonates through community acquisition in the USA. Design: This is an early retrospective study of patients admitted to the Neonatal Intensive Care Unit (NICU) identified as having SAR-CoV-2 through positive real-time polymerase chain reaction assay of nasopharyngeal swabs. Findings: Three patients who required admission to the NICU between the ages of 17 and 33 days old were identified. All 3 had ill contacts in the home or had been to the pediatrician and presented with mild to moderate symptoms including fever, rhinorrhea, and hypoxia, requiring supplemental oxygen during their hospital stay. One patient was admitted with neutropenia, and the other 2 patients became neutropenic during hospitalization. None of the patients had meningitis or multiorgan failure. Conclusions and Relevance: Infants with community-acquired SARS-CoV-2 may require hospitalization due to rule-out sepsis guidelines if found to have fever and/or hypoxia. Caregivers of neonates should exercise recommended guidelines before contact with neonates to limit community spread of SARS-CoV-2 to this potentially vulnerable population, including isolation, particularly as asymptomatic cases become prevalent.

Botanical dietary supplements contain multiple bioactive compounds that target numerous biological pathways. The lack of uniform standardization requirements is one reason that inconsistent clinical effects are reported frequently. The multifaceted biological interactions of active principles can be disentangled by a coupled pharmacological/phytochemical approach using specialized ("knock-out") extracts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent separation, Humulus lupulus extracts were designed for pre- and postmenopausal women by containing various amounts of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Analysis of their estrogenic (alkaline phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concentrations provided evidence for the interdependence of the biological effects. A designed postmenopausal hop extract was prepared to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An extract designed for premenopausal women contains reduced 8-PN levels and high XH concentrations to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concentrations of bioactive compounds in botanical extracts for potentially improved efficacy and safety.