Racial disparities in the SOFA score among patients hospitalized with COVID-19

BACKGROUND: Sequential Organ Failure Assessment (SOFA) score predicts probability of in-hospital mortality. Many crisis standards of care suggest the use of SOFA scores to allocate medical resources during the COVID-19 pandemic. RESEARCH QUESTION: Are SOFA scores elevated among Non-Hispanic Black and Hispanic patients hospitalized with COVID-19, compared to Non-Hispanic White patients? STUDY DESIGN AND METHODS: Retrospective cohort study conducted in Yale New Haven Health System, including 5 hospitals with total of 2681 beds. Study population drawn from consecutive patients aged ≥18 admitted with COVID-19 from March 29th to August 1st, 2020. Patients excluded from the analysis if not their first admission with COVID-19, if they did not have SOFA score recorded within 24 hours of admission, if race and ethnicity data were not Non-Hispanic Black, Non-Hispanic White, or Hispanic, or if they had other missing data. The primary outcome was SOFA score, with peak score within 24 hours of admission dichotomized as \u3c6 or ≥6. RESULTS: Of 2982 patients admitted with COVID-19, 2320 met inclusion criteria and were analyzed, of whom 1058 (45.6%) were Non-Hispanic White, 645 (27.8%) were Hispanic, and 617 (26.6%) were Non-Hispanic Black. Median age was 65.0 and 1226 (52.8%) were female. In univariate logistic screen and in full multivariate model, Non-Hispanic Black patients but not Hispanic patients had greater odds of an elevated SOFA score ≥6 when compared to Non-Hispanic White patients (OR 1.49, 95%CI 1.11-1.99). INTERPRETATION: Given current unequal patterns in social determinants of health, US crisis standards of care utilizing the SOFA score to allocate medical resources would be more likely to deny these resources to Non-Hispanic Black patients

TLR4, but Neither Dectin-1 nor Dectin-2, Participates in the Mollusk Hemocyanin-Induced Proinflammatory Effects in Antigen-Presenting Cells From Mammals

Funding This study was supported by CONICYT-CHILE FONDECYT Regular Grant 1151337 to MB. FONDAP 15130011 to SL. CONICYT-CHILE National Ph.D. Fellowships were awarded to JJ (CONICYT-PCHA/Doctorado Nacional/2013-21130683) and to JO-Q (CONICYT-PFCHA/Doctorado Nacional/2017-21171588). FS holds a postdoctoral fellowship from the National Commission for Scientific and Technological Research (CONICYT), Chile. Funding was provided by the Wellcome Trust (102705, 097377), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1) to GB. Acknowledgments We thank Dr. María Rosa Bono, Dr. Sergio Vargas, and Dr. Juan Carlos Aguillón from Universidad de Chile and Dr. Mónica Imarai from Universidad de Santiago, Chile for helpful comments.Peer reviewedPublisher PD

Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways

The development of vaccine adjuvants is of interest for the management of chronic diseases, cancer, and future pandemics. Therefore, the role of Toll-like receptors (TLRs) in the effects of vaccine adjuvants has been investigated. TLR4 ligand-based adjuvants are the most frequently used adjuvants for human vaccines. Among TLR family members, TLR4 has unique dual signaling capabilities due to the recruitment of two adapter proteins, myeloid differentiation marker 88 (MyD88) and interferon-β adapter inducer containing the toll-interleukin-1 receptor (TIR) domain (TRIF). MyD88-mediated signaling triggers a proinflammatory innate immune response, while TRIF-mediated signaling leads to an adaptive immune response. Most studies have used lipopolysaccharide-based ligands as TLR4 ligand-based adjuvants; however, although protein-based ligands have been proven advantageous as adjuvants, their mechanisms of action, including their ability to undergo structural modifications to achieve optimal immunogenicity, have been explored less thoroughly. In this work, we characterized the effects of two protein-based adjuvants (PBAs) on TLR4 signaling via the recruitment of MyD88 and TRIF. As models of TLR4-PBAs, we used hemocyanin from Fissurella latimarginata (FLH) and a recombinant surface immunogenic protein (rSIP) from Streptococcus agalactiae. We determined that rSIP and FLH are partial TLR4 agonists, and depending on the protein agonist used, TLR4 has a unique bias toward the TRIF or MyD88 pathway. Furthermore, when characterizing gene products with MyD88 and TRIF pathway-dependent expression, differences in TLR4-associated signaling were observed. rSIP and FLH require MyD88 and TRIF to activate nuclear factor kappa beta (NF-κB) and interferon regulatory factor (IRF). However, rSIP and FLH have a specific pattern of interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10) secretion associated with MyD88 and TRIF recruitment. Functionally, rSIP and FLH promote antigen cross-presentation in a manner dependent on TLR4, MyD88 and TRIF signaling. However, FLH activates a specific TRIF-dependent signaling pathway associated with cytokine expression and a pathway dependent on MyD88 and TRIF recruitment for antigen cross-presentation. Finally, this work supports the use of these TLR4-PBAs as clinically useful vaccine adjuvants that selectively activate TRIF- and MyD88-dependent signaling to drive safe innate immune responses and vigorous Th1 adaptive immune responses

Therapeutic options for mucinous ovarian carcinoma

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition

iAnn: an event sharing platform for the life sciences

Summary: We present iAnn, an open source community-driven platform for dissemination of life science events, such as courses, conferences and workshops. iAnn allows automatic visualisation and integration of customised event reports. A central repository lies at the core of the platform: curators add submitted events, and these are subsequently accessed via web services. Thus, once an iAnn widget is incorporated into a website, it permanently shows timely relevant information as if it were native to the remote site. At the same time, announcements submitted to the repository are automatically disseminated to all portals that query the system. To facilitate the visualization of announcements, iAnn provides powerful filtering options and views, integrated in Google Maps and Google Calendar. All iAnn widgets are freely available. Availability: http://iann.pro/iannviewer Contact: [email protected]

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.KLG is supported by the Victorian Cancer Agency (MCRF15013) and the Australian National Health and Medical Research Council (APP1045783 and #628434). This study was supported by the Peter MacCallum Cancer Foundation. CS is supported by a University of Melbourne Postgraduate Scholarship. DDB is supported by National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044 and by the US National Cancer Institute U54 programme (U54CA209978-04). ELG and SHK are supported through P50 CA136393-10. The following cohorts that contributed to the GAMuT study were supported as follows: CASCADE: Supported by the Peter MacCallum Cancer Foundation AOCS: The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID400413 and ID400281). The Australian Ovarian Cancer Study gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. The AOCS also acknowledges the cooperation of the participating institutions in Australia and acknowledges the contribution of the study nurses, research assistants and all clinical and scientific collaborators to the study. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in these research programs. OVCARE receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation. The Gynaecological Oncology Biobank at Westmead is a member of the Australasian Biospecimen Network-Oncology group, which was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. COEUR: This study uses resources provided by the Canadian Ovarian Cancer Research Consortium’s - COEUR biobank funded by the Terry Fox Research Institute and managed and supervised by the Centre hospitalier de l’Université de Montréal (CRCHUM). The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see http://www.tfri.ca/en/research/translational-research/coeur/coeur_biobanks.aspx). The following cohorts that contributed to OTTA were supported as follows: AOV: Canadian Institutes of Health Research (MOP-86727), Cancer Research Society (19319). BAV: ELAN Funds of the University of Erlangen-Nuremberg; DOV: NCI/NIH R01CA168758. Huntsman Cancer Foundation and the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014. HAW: U.S. National 19 Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; SEA: SEARCH team: Mitul Shah, Jennifer Alsopp, Mercedes Jiminez-Linan SEARCH funding: Cancer Research UK (C490/A16561), the Cancer Research UK Cambridge Cancer Centre and the National Institute for Health Research Cambridge Biomedical Research Centres. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. JBD: Cancer Research UK Institute Group Award UK A22905 and A15601; STA: NIH grants U01 CA71966 and U01 CA69417; SWE: Swedish Cancer foundation, WeCanCureCancer and årKampMotCancer foundation; TVA: Canadian Institutes of Health Research grant (MOP-86727) and NIH/NCI 1 R01CA160669- 01A1; VAN: M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. The Vancouver study cohort (TVAN) is supported by BC’s Ovarian Cancer Research team (OVCARE), the BC Cancer Foundation and The VGH+UBC Hospital Foundation. WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 & ID 628903. Cancer Institute NSW Grants 12/RIG/1-17 & 15/RIG/1-16

RNA-seq analyses of blood-induced changes in gene expression in the mosquito vector species, Aedes aegypti

<p>Abstract</p> <p>Background</p> <p>Hematophagy is a common trait of insect vectors of disease. Extensive genome-wide transcriptional changes occur in mosquitoes after blood meals, and these are related to digestive and reproductive processes, among others. Studies of these changes are expected to reveal molecular targets for novel vector control and pathogen transmission-blocking strategies. The mosquito <it>Aedes aegypti </it>(Diptera, Culicidae), a vector of Dengue viruses, Yellow Fever Virus (YFV) and Chikungunya virus (CV), is the subject of this study to look at genome-wide changes in gene expression following a blood meal.</p> <p>Results</p> <p>Transcriptional changes that follow a blood meal in <it>Ae. aegypti </it>females were explored using RNA-seq technology. Over 30% of more than 18,000 investigated transcripts accumulate differentially in mosquitoes at five hours after a blood meal when compared to those fed only on sugar. Forty transcripts accumulate only in blood-fed mosquitoes. The list of regulated transcripts correlates with an enhancement of digestive activity and a suppression of environmental stimuli perception and innate immunity. The alignment of more than 65 million high-quality short reads to the <it>Ae. aegypti </it>reference genome permitted the refinement of the current annotation of transcript boundaries, as well as the discovery of novel transcripts, exons and splicing variants. <it>Cis</it>-regulatory elements (CRE) and <it>cis</it>-regulatory modules (CRM) enriched significantly at the 5'end flanking sequences of blood meal-regulated genes were identified.</p> <p>Conclusions</p> <p>This study provides the first global view of the changes in transcript accumulation elicited by a blood meal in <it>Ae. aegypti </it>females. This information permitted the identification of classes of potentially co-regulated genes and a description of biochemical and physiological events that occur immediately after blood feeding. The data presented here serve as a basis for novel vector control and pathogen transmission-blocking strategies including those in which the vectors are modified genetically to express anti-pathogen effector molecules.</p

Introduction: Toward an Engaged Feminist Heritage Praxis

We advocate a feminist approach to archaeological heritage work in order to transform heritage practice and the production of archaeological knowledge. We use an engaged feminist standpoint and situate intersubjectivity and intersectionality as critical components of this practice. An engaged feminist approach to heritage work allows the discipline to consider women’s, men’s, and gender non-conforming persons’ positions in the field, to reveal their contributions, to develop critical pedagogical approaches, and to rethink forms of representation. Throughout, we emphasize the intellectual labor of women of color, queer and gender non-conforming persons, and early white feminists in archaeology

Expert range maps of global mammal distributions harmonised to three taxonomic authorities

AimComprehensive, global information on species' occurrences is an essential biodiversity variable and central to a range of applications in ecology, evolution, biogeography and conservation. Expert range maps often represent a species' only available distributional information and play an increasing role in conservation assessments and macroecology. We provide global range maps for the native ranges of all extant mammal species harmonised to the taxonomy of the Mammal Diversity Database (MDD) mobilised from two sources, the Handbook of the Mammals of the World (HMW) and the Illustrated Checklist of the Mammals of the World (CMW).LocationGlobal.TaxonAll extant mammal species.MethodsRange maps were digitally interpreted, georeferenced, error-checked and subsequently taxonomically aligned between the HMW (6253 species), the CMW (6431 species) and the MDD taxonomies (6362 species).ResultsRange maps can be evaluated and visualised in an online map browser at Map of Life (mol.org) and accessed for individual or batch download for non-commercial use.Main conclusionExpert maps of species' global distributions are limited in their spatial detail and temporal specificity, but form a useful basis for broad-scale characterizations and model-based integration with other data. We provide georeferenced range maps for the native ranges of all extant mammal species as shapefiles, with species-level metadata and source information packaged together in geodatabase format. Across the three taxonomic sources our maps entail, there are 1784 taxonomic name differences compared to the maps currently available on the IUCN Red List website. The expert maps provided here are harmonised to the MDD taxonomic authority and linked to a community of online tools that will enable transparent future updates and version control

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder