Mouse maternal systemic inflammation at the zygote stage causes blunted cytokine responsiveness in lipopolysaccharide-challenged adult offspring

These results demonstrate for the first time that the preimplantation embryo in vivo is sensitive to maternal systemic inflammation, with effects on blastocyst cell lineage allocation and consequences for behaviour, adiposity and innate immune response in adult offspring. Critically, we identify a novel mechanism mediated through maternal-embryonic interactions that confers plasticity in the development of the innate immune system, which is potentially important in setting postnatal tolerance to environmental pathogens. Our study extends the concept of developmental programming of health and disease to include maternal health at the time of conceptio

Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus

<p>Abstract</p> <p>Background</p> <p><it>Mus spretus </it>diverged from <it>Mus musculus </it>over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing <it>M. musculus </it>and <it>M. spretus </it>for quantitative trait locus (QTL) mapping, relatively little genomic information on <it>M. spretus </it>exists, and most of the available sequence and polymorphic data is for one strain of <it>M. spretus</it>, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different <it>M. spretus </it>by <it>M. musculus </it>F1 backcrosses. One locus, <it>skin tumor susceptibility 5 </it>(<it>Skts5</it>) on chromosome 12, shows strong linkage in one cross.</p> <p>Results</p> <p>To identify potential candidate genes for <it>Skts5</it>, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred <it>spretus</it>, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional <it>M. spretus </it>strains and one additional <it>M. musculus </it>strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across <it>M. spretus</it>, we conducted phylogenetic analyses. The relatedness of the <it>M. spretus </it>strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.</p> <p>Conclusion</p> <p>Our analyses suggest that, if <it>Skts5 </it>on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other <it>M. spretus </it>strains.</p

Moving forward with actionable therapeutic targets and opportunities in endometrial cancer:NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials

The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials

A qualitative study of community pharmacists’ clinical decision-making skills.

In recent years, self-care has been in the forefront of UK health policy [1], with community pharmacies being promoted as a first point of contact for patients [2], when seeking advice for the treatment of a variety of conditions and minor ailments. As more medicines have become available without prescription this has led to community pharmacists dealing with a wider range of presenting problems and spending more time on making clinical decisions. Aims / objectives The area of how community pharmacists make a clinical diagnosis is under-researched. The aim of this exploratory study was to gain an initial insight on how community pharmacists make clinical decisions in order to reach a diagnosis. Method A qualitative methodology was employed where semi-structured, face-to-face interviews were conducted with community pharmacists that had been practicing for at least six months at the time of the interviews and did not hold, or were working towards, a prescribing qualification. Pharmacists were identified through snow balling sampling and consent sheets sent to their pharmacies’ registered address. Pharmacists who returned completed consent forms were recruited to the study. All interviews were audio recorded and transcribed ad verbatim. Interviews were analysed, with a team-based approach, using a clinical reasoning based framework analysis to identify themes and subthemes. Ethical approval was granted by the ethics committee at the University of Wolverhampton. Results Eight interviews were conducted across England, with five male and three female pharmacists, who had been practicing for periods ranging from one to forty years. The major theme that emerged from the analysis was the poor diagnostic knowledge and ability of the pharmacists and a non-evidence based approach to decision-making. Pharmacists constantly used and overly relied on mnemonic methods both for diagnostic purposes and product selection. Their motives within consultations appeared to be establishing an appropriate product to recommend, rather than the need to establish a diagnosis, and the inability to differentiate between the two processes. However, they did have a sense of the limitations of the methods they used and an awareness for the need to ‘delve deeper’ during consultations but could not articulate how or why this was the case. Themes and sub-themes are explained using confirmatory quotes from the data. Discussion or Conclusion The findings of this study suggest that even though community pharmacists are tasked with advising symptom-presenting patients, their poor clinical reasoning skills are preventing them from reaching appropriate diagnoses. In order for community pharmacists to better perform this role, greater emphasis should be given in teaching and practicing clinical reasoning skills during their studies and through continuous professional development. The study is limited by its small sample size. 1. Department of Health. The NHS Plan. A Plan for Investment, A Plan for Reform [Internet]. London: National Health Service; 2000 [cited 6 October 2012]. Available from: http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/publicationsandstatistics/publications/publicationspolicyandguidance/dh_4002960 2. Royal Pharmaceutical Society. Improving Urgent and Emergency care through better use of pharmacists [Internet]; 2014 [cited 5 October 2016]. Available from: http://www.rpharms.com/policy-pdfs/urgent-and-emergency-care.pd

Framework for sustained climate assessment in the United States

Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society, 100(5), (2019): 897-908, doi:10.1175/BAMS-D-19-0130.1.As states, cities, tribes, and private interests cope with climate damages and seek to increase preparedness and resilience, they will need to navigate myriad choices and options available to them. Making these choices in ways that identify pathways for climate action that support their development objectives will require constructive public dialogue, community participation, and flexible and ongoing access to science- and experience-based knowledge. In 2016, a Federal Advisory Committee (FAC) was convened to recommend how to conduct a sustained National Climate Assessment (NCA) to increase the relevance and usability of assessments for informing action. The FAC was disbanded in 2017, but members and additional experts reconvened to complete the report that is presented here. A key recommendation is establishing a new nonfederal “climate assessment consortium” to increase the role of state/local/tribal government and civil society in assessments. The expanded process would 1) focus on applied problems faced by practitioners, 2) organize sustained partnerships for collaborative learning across similar projects and case studies to identify effective tested practices, and 3) assess and improve knowledge-based methods for project implementation. Specific recommendations include evaluating climate models and data using user-defined metrics; improving benefit–cost assessment and supporting decision-making under uncertainty; and accelerating application of tools and methods such as citizen science, artificial intelligence, indicators, and geospatial analysis. The recommendations are the result of broad consultation and present an ambitious agenda for federal agencies, state/local/tribal jurisdictions, universities and the research sector, professional associations, nongovernmental and community-based organizations, and private-sector firms.This report would not have been possible without the support and participation of numerous organizations and individuals. We thank New York State Governor Andrew M. Cuomo for announcing in his 2018 State of the State agenda that the IAC would be reconvened. The New York State Energy Research and Development Authority (Contract ID 123416), Columbia University’s Earth Institute, and the American Meteorological Society provided essential financial support and much more, including sage advice and moral support from John O’Leary, Shara Mohtadi, Steve Cohen, Alex Halliday, Peter deMenocal, Keith Seitter, Paul Higgins, and Bill Hooke. We thank the attendees of a workshop, generously funded by the Kresge Foundation in November of 2017, that laid a foundation for the idea to establish a civil-society-based assessment consortium. During the course of preparing the report, IAC members consulted with individuals too numerous to list here—state, local, and tribal officials; researchers; experts in nongovernmental and community-based organizations; and professionals in engineering, architecture, public health, adaptation, and other areas. We are so grateful for their time and expertise. We thank the members and staff of the National Academy of Sciences, Engineering, and Medicine’s Committee to Advise the U.S. Global Change Research Program for providing individual comments on preliminary recommendations during several discussions in open sessions of their meetings. The following individuals provided detailed comments on an earlier version of this report, which greatly sharpened our thinking and recommendations: John Balbus, Tom Dietz, Phil Duffy, Baruch Fischhoff, Brenda Hoppe, Melissa Kenney, Linda Mearns, Claudia Nierenberg, Kathleen Segerson, Soroosh Sorooshian, Chris Weaver, and Brian Zuckerman. Mary Black provided insightful copy editing of several versions of the report. We also thank four anonymous reviewers for their effort and care in critiquing and improving the report. It is the dedication, thoughtful feedback, expertise, care, and commitment of all these people and more that not only made this report possible, but allow us all to continue to support smart and insightful actions in a changing climate. We are grateful as authors and as global citizens. Author contributions: RM, SA, KB, MB, AC, JD, PF, KJ, AJ, KK, JK, ML, JM, RP, TR, LS, JS, JW, and DZ were members of the IAC and shared in researching, discussing, drafting, and approving the report. BA, JF, AG, LJ, SJ, PK, RK, AM, RM, JN, WS, JS, PT, GY, and RZ contributed to specific sections of the report

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr

Evaluating knowledge to support climate action: A framework for sustained assessment. report of an independent advisory committee on applied climate assessment.

Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Weather Climate and Society 11(3), (2019):465-487, doi: 10.1175/WCAS-D-18-0134.1.As states, cities, tribes, and private interests cope with climate damages and seek to increase preparedness and resilience, they will need to navigate myriad choices and options available to them. Making these choices in ways that identify pathways for climate action that support their development objectives will require constructive public dialogue, community participation, and flexible and ongoing access to science- and experience-based knowledge. In 2016, a Federal Advisory Committee (FAC) was convened to recommend how to conduct a sustained National Climate Assessment (NCA) to increase the relevance and usability of assessments for informing action. The FAC was disbanded in 2017, but members and additional experts reconvened to complete the report that is presented here. A key recommendation is establishing a new nonfederal “climate assessment consortium” to increase the role of state/local/tribal government and civil society in assessments. The expanded process would 1) focus on applied problems faced by practitioners, 2) organize sustained partnerships for collaborative learning across similar projects and case studies to identify effective tested practices, and 3) assess and improve knowledge-based methods for project implementation. Specific recommendations include evaluating climate models and data using user-defined metrics; improving benefit–cost assessment and supporting decision-making under uncertainty; and accelerating application of tools and methods such as citizen science, artificial intelligence, indicators, and geospatial analysis. The recommendations are the result of broad consultation and present an ambitious agenda for federal agencies, state/local/tribal jurisdictions, universities and the research sector, professional associations, nongovernmental and community-based organizations, and private-sector firms.This report would not have been possible without the support and participation of numerous organizations and individuals. We thank New York State Governor Andrew M. Cuomo for announcing in his 2018 State of the State agenda that the IAC would be reconvened. The New York State Energy Research and Development Authority (Contract ID 123416), Columbia University’s Earth Institute, and the American Meteorological Society provided essential financial support and much more, including sage advice and moral support from John O’Leary, Shara Mohtadi, Steve Cohen, Alex Halliday, Peter deMenocal, Keith Seitter, Paul Higgins, and Bill Hooke. We thank the attendees of a workshop, generously funded by the Kresge Foundation in November of 2017, that laid a foundation for the idea to establish a civil-society-based assessment consortium. During the course of preparing the report, IAC members consulted with individuals too numerous to list here—state, local, and tribal officials; researchers; experts in nongovernmental and community-based organizations; and professionals in engineering, architecture, public health, adaptation, and other areas. We are so grateful for their time and expertise. We thank the members and staff of the National Academy of Sciences, Engineering, and Medicine’s Committee to Advise the U.S. Global Change Research Program for providing individual comments on preliminary recommendations during several discussions in open sessions of their meetings. The following individuals provided detailed comments on an earlier version of this report, which greatly sharpened our thinking and recommendations: John Balbus, Tom Dietz, Phil Duffy, Baruch Fischhoff, Brenda Hoppe, Melissa Kenney, Linda Mearns, Claudia Nierenberg, Kathleen Segerson, Soroosh Sorooshian, Chris Weaver, and Brian Zuckerman. Mary Black provided insightful copy editing of several versions of the report. We also thank four anonymous reviewers for their effort and care in critiquing and improving the report. It is the dedication, thoughtful feedback, expertise, care, and commitment of all these people and more that not only made this report possible, but allow us all to continue to support smart and insightful actions in a changing climate. We are grateful as authors and as global citizens. Author contributions: RM, SA, KB, MB, AC, JD, PF, KJ, AJ, KK, JK, ML, JM, RP, TR, LS, JS, JW, and DZ were members of the IAC and shared in researching, discussing, drafting, and approving the report. BA, JF, AG, LJ, SJ, PK, RK, AM, RM, JN, WS, JS, PT, GY, and RZ contributed to specific sections of the report.2020-05-2

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas

A web-based Alcohol Clinical Training (ACT) curriculum: Is in-person faculty development necessary to affect teaching?

<p>Abstract</p> <p>Background</p> <p>Physicians receive little education about unhealthy alcohol use and as a result patients often do not receive efficacious interventions. The objective of this study is to evaluate whether a free web-based alcohol curriculum would be used by physician educators and whether in-person faculty development would increase its use, confidence in teaching and teaching itself.</p> <p>Methods</p> <p>Subjects were physician educators who applied to attend a workshop on the use of a web-based curriculum about alcohol screening and brief intervention and cross-cultural efficacy. All physicians were provided the curriculum web address. Intervention subjects attended a 3-hour workshop including demonstration of the website, modeling of teaching, and development of a plan for using the curriculum. All subjects completed a survey prior to and 3 months after the workshop.</p> <p>Results</p> <p>Of 20 intervention and 13 control subjects, 19 (95%) and 10 (77%), respectively, completed follow-up. Compared to controls, intervention subjects had greater increases in confidence in teaching alcohol screening, and in the frequency of two teaching practices – teaching about screening and eliciting patient health beliefs. Teaching confidence and teaching practices improved significantly in 9 of 10 comparisons for intervention, and in 0 comparisons for control subjects. At follow-up 79% of intervention but only 50% of control subjects reported using any part of the curriculum (p = 0.20).</p> <p>Conclusion</p> <p>In-person training for physician educators on the use of a web-based alcohol curriculum can increase teaching confidence and practices. Although the web is frequently used for disemination, in-person training may be preferable to effect widespread teaching of clinical skills like alcohol screening and brief intervention.</p

Long term impact of systemic bacterial infection on the cerebral vasculature and microglia

Background: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against over-activity of the immune system. In this study we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Methods: Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry.mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral, intracerebral injection of LPS. Results: Repeated systemic LPS challenges resulted in increased brain IL-1?, TNF? and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1? and IL-12 levels in Salmonella typhimurium infected mice increased over three weeks, with high interferon-? levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS 4 weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. Conclusions: These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have aprofound effect on the onset and/ or progression of pre-existing neurodegenerative disease.Humans and animals are regularly exposed to bacterial and viral pathogens that can have a considerable impact on our day-to-day living [1]. Upon infection, a set of immune, physiological, metabolic, and behavioural responses is initiated, representing a highly organized strategy of the organism to fight infection. Pro-inflammatory mediators generated in peripheral tissue communicate with the brain to modify behaviour [2], which aids our ability to fight and eliminate the pathogen. The communication pathways from the site of inflammation to the brain have been investigated in animal models and systemic challenge with lipopolysaccharide (LPS) or double stranded RNA (poly I:C) have been widely used to mimic aspects of bacterial and viral infection respectively [3, 4]. These studies have provided evidence that systemically generated inflammatory mediators signal to the brain via both neural and humoral routes, the latter signalling via the circumventricular organs or across the blood-brain barrier (BBB). Signalling into the brain via these routes evokes a response in the perivascular macrophages (PVMs) and microglia, which in turn synthesise diverse inflammatory mediators including cytokines, prostaglandins and nitric oxide [2, 5, 6]. Immune-to-brain communication also occurs in humans who show changes in mood and cognition following systemic inflammation or infection, which are associated with changes in activity in particular regions of the CNS [7-9]. While these changes are part of our normal homeostasis, it is increasingly evident that systemic inflammation has a detrimental effect in animals and also humans, that suffer from chronic neurodegeneration [10, 11]. We, and others, have shown that microglia become primed by on-going neuropathology in the brain, which increases their response towards subsequent inflammatory stimuli, including systemic inflammation [12, 13] Similar findings have been made in aged rodents [14, 15], where it has been shown that there is an exaggerated behavioural and innate immune response in the brainto systemic bacterial and viral infections, but the molecular mechanisms underlying the microglial priming under these conditions is far from understood.Humans and animals are rarely exposed to a single acute systemic inflammatory event: they rather encounter infectious pathogens that replicate in vivo or are exposed to low concentrations of LPS over a prolonged period of time. There is limited information on the impact of non-neurotrophic bacterial infections on the CNS and whether prolonged systemic inflammation will give rise to either a hyper-(priming) or hypo-(tolerance) innate immune response in the brain in response to a subsequent inflammatory stimulus.In this study we measured the levels of cytokines in the serum, spleen and brain as well as assessing sickness behaviour following a systemic bacterial infection using attenuated Salmonella typhimurium SL3261: we compared the effect to that of repeated LPS injections. We show that Salmonella typhimurium caused acute, transient behavioural changes and a robust peripheral immune response that peaks at day 7. Systemic inflammation resulted in a delayed increase in cytokine production in the brain and priming of microglia, which persisted up to four weeks post infection. These effects were not mimicked by repeated LPS challenges. It is well recognised that systemic bacterial and viral infections are significant contributors to morbidity in the elderly [16], and it has been suggested that primed microglia play a role in the increased clinical symptoms seen in patients with Alzheimer’s disease who have systemic inflammation or infections [11, 17]. We show here that systemic infection leads to prolonged cytokine synthesis in the brain and also priming of brain innate immune cells to a subsequent focal inflammatory challenge in the brain parenchyma