180 research outputs found

    First-Class and Coach-Class Knowledge

    Get PDF

    Reflective Naturalism

    Get PDF
    Here I will develop a naturalistic account of epistemic reflection and its significance for epistemology. I will first argue that thought, as opposed to mere information processing, requires a capacity for cognitive self-regulation. After discussing the basic capacities necessary for cognitive self-regulation of any kind, I will consider qualitatively different kinds of thought that can emerge when the basic capacities enable the creature to interiorize a form of social cooperation. First, I will discuss second-personal cooperation and the kind of thought that emerges from its interiorization. Then, I will discuss third-personal cooperation and the kind of thought that emerges from its interiorization. We will see that epistemic reflection is the interiorized version of interpersonal argumentation, which is the epistemic component of third-personal cooperation. In developing this account, I will draw heavily on the work of Michael Tomasello and other cognitive scientists advocating the ‚Äúsocial intentionality hypothesis‚ÄĚ. However, I will show how work done in the defeasible reasoning tradition can provide us with a deeper explanation of some claims made by advocates of the social intentionality hypothesis. Additionally, we will see that work done on social intentionality can help us better understand the significance of knowledge and justification as understood by the defeasible reasoning tradition. We will see that the social intentionality hypothesis and the defeasible reasoning tradition are mutually illuminating. By drawing equally on both, I will provide a novel account of the foundations of knowledge

    The very idea of rational irrationality

    Get PDF

    Luck and Reasons

    Get PDF

    A Rare Presentation of In Situ

    Get PDF
    A 65-year-old gentleman presented with left groin swelling over the course of two months. Physical exam revealed nontender left inguinal adenopathy, and computed tomography scans detected multiple lymph nodes in the mesenteric, aortocaval, and right common iliac regions. An excisional lymph node biopsy was performed. Pathologic evaluation demonstrated follicular center site which stained positive for PAX5, CD20, CD10, Bcl-2, Bcl-6, and mantle zone cells. These findings demonstrated CCND1 and CD5 positivity, suggesting composite lymphoma comprising follicular lymphoma (FL) with in situ mantle cell lymphoma (MCLIS). FL is known as indolent non-Hodgkin lymphoma; however, the clinical significance of a coexisting MCLIS continues to be elusive, and optimal management of these patients remains largely unknown. This case illustrates the diagnostic and therapeutic challenges of composite lymphomas. This paper also discusses advances in molecular pathogenesis and lymphoma genomics which offer novel insights into these rare diseases

    Fractional deuteration applied to biomolecular solid-state NMR spectroscopy

    Get PDF
    Solid-state Nuclear Magnetic Resonance can provide detailed insight into structural and dynamical aspects of complex biomolecules. With increasing molecular size, advanced approaches for spectral simplification and the detection of medium to long-range contacts become of critical relevance. We have analyzed the protonation pattern of a membrane-embedded ion channel that was obtained from bacterial expression using protonated precursors and D2O medium. We find an overall reduction of 50% in protein protonation. High levels of deuteration at HőĪ and Hő≤ positions reduce spectral congestion in (1H,13C,15N) correlation experiments and generate a transfer profile in longitudinal mixing schemes that can be tuned to specific resonance frequencies. At the same time, residual protons are predominantly found at amino-acid side-chain positions enhancing the prospects for obtaining side-chain resonance assignments and for detecting medium to long-range contacts. Fractional deuteration thus provides a powerful means to aid the structural analysis of complex biomolecules by solid-state NMR

    Global burden of 369 diseases and injuries in 204 countries and territories, 1990‚Äď2019: a systematic analysis for the Global Burden of Disease Study 2019

    Get PDF
    Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990‚Äď2010 time period, with the greatest annualised rate of decline occurring in the 0‚Äď9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10‚Äď24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10‚Äď24 years were also in the top ten in the 25‚Äď49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50‚Äď74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. 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 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

    Get PDF
    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‚Äď14 and 50‚Äď54 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‚Äď2¬∑79) in 2000 to 2¬∑31 (2¬∑17‚Äď2¬∑46) in 2019. Global annual livebirths increased from 134¬∑5 million (131¬∑5‚Äď137¬∑8) in 2000 to a peak of 139¬∑6 million (133¬∑0‚Äď146¬∑9) in 2016. Global livebirths then declined to 135¬∑3 million (127¬∑2‚Äď144¬∑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‚Äď27¬∑8) of global livebirths. Global life expectancy at birth increased from 67¬∑2 years (95% UI 66¬∑8‚Äď67¬∑6) in 2000 to 73¬∑5 years (72¬∑8‚Äď74¬∑3) in 2019. The total number of deaths increased from 50¬∑7 million (49¬∑5‚Äď51¬∑9) in 2000 to 56¬∑5 million (53¬∑7‚Äď59¬∑2) in 2019. Under-5 deaths declined from 9¬∑6 million (9¬∑1‚Äď10¬∑3) in 2000 to 5¬∑0 million (4¬∑3‚Äď6¬∑0) in 2019. Global population increased by 25¬∑7%, from 6¬∑2 billion (6¬∑0‚Äď6¬∑3) in 2000 to 7¬∑7 billion (7¬∑5‚Äď8¬∑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‚Äď60¬∑8) in 2000 to 63¬∑5 years (60¬∑8‚Äď66¬∑1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

    Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017 : a systematic analysis for the Global Burden of Disease Study 2017