186 research outputs found

    Saturn’s northern auroras as observed using the Hubble Space Telescope

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    We discuss the features of Saturn’s northern FUV auroras as observed during a program of Hubble Space Telescope observations which executed over 2011-2013 and culminated, along with Cassini observations, in a comprehensive multi-spectral observing campaign. Our 2011-2013 observations of the northern aurora are also compared with those from our 2007-2008 observation of the southern aurora. We show that the variety of morphologies of the northern auroras is broadly consistent with the southern, and determine the statistical equatorward and poleward boundary locations. We find that our boundaries are overall consistent with previous observations, although a modest poleward displacement of the poleward boundaries is due to the increased prevalence of poleward auroral patches in the noon and afternoon sectors during this program, likely due to the solar wind interaction. We also show that the northern auroral oval oscillates with the northern planetary period oscillation (PPO) phase in an elongated ellipse with semi-major axis ∼1.6°1.6° oriented along the post-dawn/post-dusk direction. We further show that the northern auroras exhibit dawn-side brightenings at zero northern magnetic PPO phase, although there is mixed evidence of auroral emissions fixed in the rotating frame of the northern PPO current system, such that overall the dependence of the auroras on northern magnetic phase is somewhat weak

    Global aridity during the Early Miocene? A Terrestrial Paleoclimate Record from the Ebro Basin, Spain

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    Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148622/1/Hamer_et_al_2007_J_Geology-Miocene_climate.pd

    Prominent Role Of Platelets In The Formation Of Circulating Neutrophil-red Cell Heterocellular Aggregates In Sickle Cell Anemia

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    [No abstract available]9911e214e217Hidalgo, A., Chang, J., Jang, J.E., Peired, A.J., Chiang, E.Y., Frenette, P.S., Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury (2009) Nat Med, 15 (4), pp. 384-391Turhan, A., Jenab, P., Bruhns, P., Ravetch, J.V., Coller, B.S., Frenette, P.S., Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes (2004) Blood, 103 (6), pp. 2397-2400Turhan, A., Weiss, L.A., Mohandas, N., Coller, B.S., Frenette, P.S., Primary role for adherent leukocytes in sickle cell vascular occlusion: A new paradigm (2002) Proc Natl Acad Sci USA, 99 (5), pp. 3047-3051May, A.E., Langer, H., Seizer, P., Bigalke, B., Lindemann, S., Gawaz, M., Platelet-leukocyte interactions in inflammation and atherothrombosis (2007) Semin Thromb Hemost, 33 (2), pp. 123-127Gawaz, M., Fateh-Moghadam, S., Pilz, G., Gurland, H.J., Werdan, K., Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure (1995) Eur J Clin Invest, 25 (11), pp. 843-851Polanowska-Grabowska, R., Wallace, K., Field, J.J., Chen, L., Marshall, M.A., Figler, R., P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease (2010) Art Thromb Vascular Biol, 30 (12), pp. 2392-2399Brittain, J.E., Knoll, C.M., Ataga, K.I., Orringer, E.P., Parise, L.V., Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1 (2008) Br J Haematol, 141 (6), pp. 872-881Chaar, V., Picot, J., Renaud, O., Bartolucci, P., Nzouakou, R., Bachir, D., Aggregation of mononuclear and red blood cells through an {alpha}4{beta}1-Lu/basal cell adhesion molecule interaction in sickle cell disease (2010) Haematologica, 95 (11), pp. 1841-1848Finnegan, E.M., Turhan, A., Golan, D.E., Barabino, G.A., Adherent leukocytes capture sickle erythrocytes in an in vitro flow model of vasoocclusion (2007) Am J Hematol, 82 (4), pp. 266-275Wun, T., Paglieroni, T., Tablin, F., Welborn, J., Nelson, K., Cheung, A., Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia (1997) J Lab Clin Med, 129 (5), pp. 507-516Hynes, R.O., Integrins: Versatility, modulation, and signaling in cell adhesion (1992) Cell, 69 (1), pp. 11-25Novelli, E.M., Kato, G.J., Ragni, M.V., Zhang, Y., Hildesheim, M.E., Nouraie, M., Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates (2012) Am J Hematol, 87 (3), pp. 326-330Proenca-Ferreira, R., Brugnerotto, A.F., Garrido, V.T., Dominical, V.M., Vital, D.M., Ribeiro Mde, F., Endothelial activation by platelets from sickle cell anemia patients (2014) PloS one, 9 (2)Kutlar, A., Ataga, K.I., McMahon, L., Howard, J., Galacteros, F., Hagar, W., A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease (2012) Am J Hematol, 87 (5), pp. 536-539Telen, M.J., Wun, T., McCavit, T.L., De Castro, L.M., Krishnamurti, L., Lanzkron, S., GMI 1070: Reduction In Time To Resolution Of Vaso-Occlusive Crisis and Decreased Opioid Use In a Prospective, Randomized, Multi-Center Double Blind, Adaptive Phase 2 Study In Sickle Cell Disease (2013) Blood, 122 (21), p. 7. , Abstrac

    Health outcomes and cost-effectiveness of monoclonal SARS-CoV-2 antibodies as pre-exposure prophylaxis

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    IMPORTANCE Pre-exposure prophylaxis with neutralizing SARS-CoV-2 monoclonal antibodies (mAbs PrEP) prevents infection and reduces hospitalizations and the duration thereof for COVID-19 and death among high-risk individuals. However, reduced effectiveness due to a changing SARS-CoV-2 viral landscape and high drug prices remain substantial implementation barriers.OBJECTIVE To assess the cost-effectiveness of mAbs PrEP as COVID-19 PrEP.DESIGN, SETTING, AND PARTICIPANTS For this economic evaluation, a decision analytic model was developed and parameterized with health care outcome and utilization data from individuals with high risk for COVID-19. The SARS-CoV-2 infection probability, mAbs PrEP effectiveness, and drug pricing were varied. All costs were collected from a third-party payer perspective. Data were analyzed from September 2021 to December 2022.MAIN OUTCOMES AND MEASURES Health care outcomes including new SARS-CoV-2 infections, hospitalization, and deaths. The cost per death averted and cost-effectiveness ratios using a threshold for prevention interventions of 22000orlessperqualityadjustedlifeyear(QALY)gained.RESULTSTheclinicalcohortconsistedof636individualswithCOVID19(mean[SD]age63[18]years;341[5422000 or less per quality-adjusted life year (QALY) gained.RESULTS The clinical cohort consisted of 636 individuals with COVID-19 (mean [SD] age 63 [18] years; 341 [54%] male). Most individuals were at high risk for severe COVID-19, including 137 (21%) with a body mass index of 30 or higher, 60 (9.4%) with hematological malignant neoplasm, 108 (17%) post-transplantation, and 152 (23.9%) who used immunosuppressive medication before COVID-19. Within the context of a high (18%) SARS-CoV-2 infection probability and low (25%) effectiveness the model calculated a short-term reduction of 42% ward admissions, 31% intensive care unit (ICU) admissions, and 34% deaths. Cost-saving scenarios were obtained with drug prices of 275 and 75% or higher effectiveness. With a 100% effectiveness mAbs PrEP can reduce ward admissions by 70%, ICU admissions by 97%, and deaths by 92%. Drug prices, however, need to reduce to 550forcosteffectivenessratioslessthan550 for cost-effectiveness ratios less than 22000 per QALY gained per death averted and to 2200forratiosbetween2200 for ratios between 22000 and 88000.CONCLUSIONSANDRELEVANCEInthisstudy,useofmAbsPrEPforpreventingSARSCoV2infectionswascostsavingatthebeginningofanepidemicwave(highinfectionprobability)with7588000.CONCLUSIONS AND RELEVANCE In this study, use of mAbs PrEP for preventing SARS-CoV-2 infections was cost-saving at the beginning of an epidemic wave (high infection probability) with 75% or higher effectiveness and drug price of 275. These results are timely and relevant for decision-makers involved in mAbs PrEP implementation. When newer mAbs PrEP combinations become available, guidance on implementation should be formulated ensuring a fast rollout. Nevertheless, advocacy for mAbs PrEP use and critical discussion on drug prices are necessary to ensuring cost-effectiveness for different epidemic settings.Clinical epidemiolog

    Inhibitors of COP-mediated Transport and Cholera Toxin Action Inhibit Simian Virus 40 Infection

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    Simian virus 40 (SV40) is a nonenveloped virus that has been shown to pass from surface caveolae to the endoplasmic reticulum in an apparently novel infectious entry pathway. We now show that the initial entry step is blocked by brefeldin A and by incubation at 20degreesC. Subsequent to the entry step, the virus reaches a domain of the rough endoplasmic reticulum by an unknown pathway. This intracellular trafficking pathway is also brefeldin A sensitive. Infection is strongly inhibited by expression of GTP-restricted ADP-ribosylation factor 1 (Arf1) and Sar1 mutants and by microinjection of antibodies to betaCOP. In addition, we demonstrate a potent inhibition of SV40 infection by the dipeptide N-benzoyl-oxycarbonyl-Gly-Phe-amide, which also inhibits late events in cholera toxin action. Our results identify novel inhibitors of SV40 infection and show that SV40 requires COPI- and COPII-dependent transport steps for successful infection

    Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019

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    Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2•72 (95% uncertainty interval [UI] 2•66–2•79) in 2000 to 2•31 (2•17–2•46) in 2019. Global annual livebirths increased from 134•5 million (131•5–137•8) in 2000 to a peak of 139•6 million (133•0–146•9) in 2016. Global livebirths then declined to 135•3 million (127•2–144•1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2•1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27•1% (95% UI 26•4–27•8) of global livebirths. Global life expectancy at birth increased from 67•2 years (95% UI 66•8–67•6) in 2000 to 73•5 years (72•8–74•3) in 2019. The total number of deaths increased from 50•7 million (49•5–51•9) in 2000 to 56•5 million (53•7–59•2) in 2019. Under-5 deaths declined from 9•6 million (9•1–10•3) in 2000 to 5•0 million (4•3–6•0) in 2019. Global population increased by 25•7%, from 6•2 billion (6•0–6•3) in 2000 to 7•7 billion (7•5–8•0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58•6 years (56•1–60•8) in 2000 to 63•5 years (60•8–66•1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

    Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

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    Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

    ATLAS detector and physics performance: Technical Design Report, 1

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