Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry

A growing number of imaging studies suggest that alcohol cues, mainly visual, elicit activation in mesocorticolimbic structures. Such findings are consistent with the growing recognition that these structures play an important role in the attribution of incentive salience and the pathophysiology of addiction. The present study investigated whether the presentation of alcohol taste cues can activate brain regions putatively involved in the acquisition and expression of incentive salience. Using functional magnetic resonance imaging, we recorded BOLD activity while delivering alcoholic tastes to 37 heavy drinking but otherwise healthy volunteers. The results yielded a pattern of BOLD activity in mesocorticolimbic structures (ie prefrontal cortex, striatum, ventral tegmental area/substantia nigra) relative to an appetitive control. Further analyses suggested strong connectivity between these structures during cue-elicited urge and demonstrated significant positive correlations with a measure of alcohol use problems (ie the Alcohol Use Disorders Identification Test). Thus, repeated exposure to the taste alcohol in the scanner elicits activation in mesocorticolimbic structures, and this activation is related to measures of urge and severity of alcohol problems

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities

Racial differences in influenza vaccination among older americans 1996–2000: longitudinal analysis of the Health and Retirement Study (HRS) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey

BACKGROUND: Influenza is a common and serious public health problem among the elderly. The influenza vaccine is safe and effective. METHODS: The purpose of the study was to determine whether frequencies of receipt vary by race, age group, gender, and time (progress from 1995/1996 to 2000), and whether any racial differences remain in age groups covered by Medicare. Subjects were selected from the Health and Retirement Study (HRS) (12,652 Americans 50–61 years of age (1992–2000)) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey (8,124 community-dwelling seniors aged 70+ years (1993–2000)). Using multivariate logistic regression, adjusting for potential confounders, we estimated the relationship between race, age group, gender, time and the main outcome measure, receipt of influenza vaccination in the last 2 years. RESULTS: There has been a clear increase in the unadjusted rates of receipt of influenza vaccination for all groups from 1995/1996 to 2000. However, the proportions immunized are 10–20% higher among White than among Black elderly, with no obvious narrowing of the racial gap from 1995/1996 to 2000. There is an increase in rates from age 50 to age 65. After age 70, the rate appears to plateau. In multivariate analyses, the racial difference remains after adjusting for a series of socioeconomic, health, and health care related variables. (HRS: OR = 0.63 (0.55–0.72), AHEAD: OR = 0.55 (0.44–0.66)) CONCLUSIONS: There is much work left if the Healthy People 2010 goal of 90% of the elderly immunized against influenza annually is to be achieved. Close coordination between public health programs and clinical prevention efforts in primary care is necessary, but to be truly effective, these services must be culturally appropriate

Spectroscopic verification of very luminous galaxy candidates in the early universe

During the first 500 million years of cosmic history, the first stars and galaxies formed and seeded the cosmos with heavy elements. These early galaxies illuminated the transition from the cosmic "dark ages" to the reionization of the intergalactic medium. This transitional period has been largely inaccessible to direct observation until the recent commissioning of JWST, which has extended our observational reach into that epoch. Excitingly, the first JWST science observations uncovered a surprisingly high abundance of early star-forming galaxies. However, the distances (redshifts) of these galaxies were, by necessity, estimated from multi-band photometry. Photometric redshifts, while generally robust, can suffer from uncertainties and/or degeneracies. Spectroscopic measurements of the precise redshifts are required to validate these sources and to reliably quantify their space densities, stellar masses, and star formation rates, which provide powerful constraints on galaxy formation models and cosmology. Here we present the results of JWST follow-up spectroscopy of a small sample of galaxies suspected to be amongst the most distant yet observed. We confirm redshifts z > 10 for two galaxies, including one of the first bright JWST-discovered candidates with z = 11.4, and show that another galaxy with suggested z ~ 16 instead has z = 4.9, with strong emission lines that mimic the expected colors of more distant objects. These results reinforce the evidence for the rapid production of luminous galaxies in the very young Universe, while also highlighting the necessity of spectroscopic verification for remarkable candidates.Comment: Submitted to Natur

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Comprehensive Fragment Screening of the SARS-CoV-2 Proteome Explores Novel Chemical Space for Drug Development

12 pags., 4 figs., 3 tabs.SARS-CoV-2 (SCoV2) and its variants of concern pose serious challenges to the public health. The variants increased challenges to vaccines, thus necessitating for development of new intervention strategies including anti-virals. Within the international Covid19-NMR consortium, we have identified binders targeting the RNA genome of SCoV2. We established protocols for the production and NMR characterization of more than 80 % of all SCoV2 proteins. Here, we performed an NMR screening using a fragment library for binding to 25 SCoV2 proteins and identified hits also against previously unexplored SCoV2 proteins. Computational mapping was used to predict binding sites and identify functional moieties (chemotypes) of the ligands occupying these pockets. Striking consensus was observed between NMR-detected binding sites of the main protease and the computational procedure. Our investigation provides novel structural and chemical space for structure-based drug design against the SCoV2 proteome.Work at BMRZ is supported by the state of Hesse. Work in Covid19-NMR was supported by the Goethe Corona Funds, by the IWBEFRE-program 20007375 of state of Hesse, the DFG through CRC902: “Molecular Principles of RNA-based regulation.” and through infrastructure funds (project numbers: 277478796, 277479031, 392682309, 452632086, 70653611) and by European Union’s Horizon 2020 research and innovation program iNEXT-discovery under grant agreement No 871037. BY-COVID receives funding from the European Union’s Horizon Europe Research and Innovation Programme under grant agreement number 101046203. “INSPIRED” (MIS 5002550) project, implemented under the Action “Reinforcement of the Research and Innovation Infrastructure,” funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the EU (European Regional Development Fund) and the FP7 REGPOT CT-2011-285950—“SEE-DRUG” project (purchase of UPAT’s 700 MHz NMR equipment). The support of the CERM/CIRMMP center of Instruct-ERIC is gratefully acknowledged. This work has been funded in part by a grant of the Italian Ministry of University and Research (FISR2020IP_02112, ID-COVID) and by Fondazione CR Firenze. A.S. is supported by the Deutsche Forschungsgemeinschaft [SFB902/B16, SCHL2062/2-1] and the Johanna Quandt Young Academy at Goethe [2019/AS01]. M.H. and C.F. thank SFB902 and the Stiftung Polytechnische Gesellschaft for the Scholarship. L.L. work was supported by the French National Research Agency (ANR, NMR-SCoV2-ORF8), the Fondation de la Recherche Médicale (FRM, NMR-SCoV2-ORF8), FINOVI and the IR-RMN-THC Fr3050 CNRS. Work at UConn Health was supported by grants from the US National Institutes of Health (R01 GM135592 to B.H., P41 GM111135 and R01 GM123249 to J.C.H.) and the US National Science Foundation (DBI 2030601 to J.C.H.). Latvian Council of Science Grant No. VPP-COVID-2020/1-0014. National Science Foundation EAGER MCB-2031269. This work was supported by the grant Krebsliga KFS-4903-08-2019 and SNF-311030_192646 to J.O. P.G. (ITMP) The EOSC Future project is co-funded by the European Union Horizon Programme call INFRAEOSC-03-2020—Grant Agreement Number 101017536. Open Access funding enabled and organized by Projekt DEALPeer reviewe

Developing learning outcomes for medical students and foundation doctors in palliative care: a national consensus-seeking initiative in Scotland

&lt;b&gt;Background&lt;/b&gt; Undergraduate education in palliative care is essential if doctors are to be competent to care for dying patients and their families in a range of specialties and healthcare settings. However, creating space for this within existing undergraduate and foundation year curricula poses significant challenges. We aimed to develop consensus learning outcomes for palliative care teaching in the university medical schools in Scotland.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; The General Medical Council (GMC) outlines a number of learning outcomes with clear relevance to palliative care. Leaders from the five Scottish medical schools identified and agreed a small number of outcomes, which we judged most relevant to teaching palliative care and collated teaching resources to support these.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; Consensus learning outcomes for undergraduate palliative care were agreed by our mixed group of clinician educators over a number of months. There were many secondary gains from this process, including the pooling of educational resources and best practice, and the provision of peer support for those struggling to establish curriculum time for palliative care.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; The process and outcomes were presented to the Scottish Teaching Deans, with a view to their inclusion in undergraduate and foundation year curricula. It is through a strong commitment to achieving these learning outcomes that we will prepare all doctors for providing palliative care to the increasing numbers of patients and families that require it