Although synergy is a pillar of modern pharmacology, toxicology, and medicine, there is no consensus on its definition despite its nearly one hundred-year history. Moreover, methods for statistical ...determination of synergy that account for variation of response to treatment are underdeveloped and if exist are reduced to the traditional t-test, but do not comply with the normal distribution assumption. We offer statistical models for estimation of synergy using an established definition of Bliss drugs' independence. Although Bliss definition is well-known, it remains a theoretical concept and has never been applied for statistical determination of synergy with various forms of treatment outcome. We rigorously and consistently extend the Bliss definition to detect statistically significant synergy under various designs: (1) in vitro, when the outcome of a cell culture experiment with replicates is the proportion of surviving cells for a single dose or multiple doses, (2) dose-response methodology, (3) in vivo studies in organisms, when the outcome is a longitudinal measurement such as tumor volume, and (4) clinical studies, when the outcome of treatment is measured by survival. For each design, we developed a specific statistical model and demonstrated how to test for independence, synergy, and antagonism, and compute the associated p-value.
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Fact and Method Miller, Richard W
2021, 1988, 2021-04-13
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In this bold work, of broad scope and rich erudition, Richard Miller sets out to reorient the philosophy of science. By questioning both positivism and its leading critics, he develops new solutions ...to the most urgent problems about justification, explanation, and truth. Using a wealth of examples from both the natural and the social sciences, Fact and Method applies the new account of scientific reason to specific questions of method in virtually every field of inquiry, including biology, physics, history, sociology, anthropology, economics, psychology, and literary theory. Explicit and up-to-date analysis of leading alternative views and a wealth of examples make it an ideal introduction to the philosophy of science, as well as a powerful attempt to change the field. Like the works of Hempel, Reichenbach, and Nagel in an earlier generation, it will challenge, instruct, and help anyone with an interest in science and its limits. For the past quarter-century, the philosophy of science has been in a crisis brought on by the failure of the positivist project of resolving all basic methodological questions by applying absolutely general rules, valid for all fields at all times. Professor Miller presents a new view in which what counts as an explanation, a cause, a confirming test, or a compelling case for the existence of an unobservable is determined by frameworks of specific substantive principles, rationally adopted in the light of the actual history of inquiry. While the history of science has usually been the material for relativism, Professor Miller uses arguments of Darwin, Newton, Einstein, Galileo, and others both to undermine positivist conceptions of rationality and to support the positivists' optimism that important theoretical findings are often justifiable from all reasonable perspectives.
Analyzing Marx Miller, Richard W
2020, 1984, 2020-10-06
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In this book Marx is revealed as a powerful contributor to the debates that now dominate philosophy and political theory. Using the techniques of analytic philosophy to unite Marx's general ...statements with his practice as historian and activist, Richard W. Miller derives important arguments about the rational basis of morality, the nature of power, and the logic of testing and explanation. The book also makes Marx's theory of change useful for current social science, by replacing economic determinist readings with a new interpretation in which systems of power relations are the basis of change. Part One discusses Marx's criticisms of the moral point of view as a basis for social choice. The outlook that emerges is humane but antimoral. Part Two argues that Marx's concept of the ruling class is a means, of measuring political power that is ignored yet urgently needed by present-day social science. Part Three bases Marx's theory of history on the dynamics of power, challenging both the standard, economic determinist readings of the theory and standard conceptions of science.
The goal of metrological traceability is to have equivalent results for a measurand in clinical samples (CSs) irrespective of the
diagnostic medical device (IVD-MD) used for measurements. The ...International Standards Organization standard 17511 defines requirements for establishing metrological traceability of values assigned to calibrators, trueness control materials and human samples used with IVD-MDs. Each step in metrological traceability has an uncertainty associated with the value assigned to a material. The uncertainty at each step adds to the uncertainty from preceding steps such that the combined uncertainty gets larger at each step. The combined uncertainty for a CS result must fulfil an analytical performance specification (APS) for the maximum allowable uncertainty (
). The
can be partitioned among the steps in a metrological traceability calibration hierarachy to derive the APS for maximum allowable uncertainty at each step. Similarly, the criterion for maximum acceptable noncommutability bias can be derived from the
. One of the challenges in determining if
is fulfilled is determining the repeatability uncertainty (
) from operating an IVD-MD within a clinical laboratory. Most of the current recommendations for estimating
from internal quality control data do not use a sufficiently representative time interval to capture all relevant sources of variability in measurement results. Consequently, underestimation of
is common and may compromise assessment of how well current IVD-MDs and their supporting calibration hierarchies meet the needs of clinical care providers.
Post-traumatic stress disorder (PTSD) is associated with elevated risk for a variety of age-related diseases and neurodegeneration. In this paper, we review evidence relevant to the hypothesis that ...chronic PTSD constitutes a form of persistent life stress that potentiates oxidative stress (OXS) and accelerates cellular aging. We provide an overview of empirical studies that have examined the effects of psychological stress on OXS, discuss the stress-perpetuating characteristics of PTSD, and then identify mechanisms by which PTSD might promote OXS and accelerated aging. We review studies on OXS-related genes and the role that they may have in moderating the effects of PTSD on neural integrity and conclude with a discussion of directions for future research on antioxidant treatments and biomarkers of accelerated aging in PTSD.
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Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors ...can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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Compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought significant improvements for patients in terms of survival and quality ...of life. Immunotherapy has now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types. In this review article, we highlight how the history of cancer immunotherapy paved the way for discoveries that are now part of the standard of care. We also highlight the current pitfalls and limitations of cancer checkpoint immunotherapy and how novel research in the fields of personalized cancer vaccines, autoimmunity, the microbiome, the tumour microenvironment, and metabolomics is aiming to solve those challenges.
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Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. ...To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
The prevalence of many chronic diseases has increased over the last decades. It has been postulated that dysbiosis driven by environmental factors such as antibiotic use is shifting the microbiome in ...ways that increase inflammation and the onset of chronic disease. Dysbiosis can be defined through the loss or gain of bacteria that either promote health or disease, respectively. Here we use multiple independent datasets to determine the nature of dysbiosis for a cluster of chronic diseases that includes urinary stone disease (USD), obesity, diabetes, cardiovascular disease, and kidney disease, which often exist as co-morbidities. For all disease states, individuals exhibited a statistically significant association with antibiotics in the last year compared to healthy counterparts. There was also a statistically significant association between antibiotic use and gut microbiota composition. Furthermore, each disease state was associated with a loss of microbial diversity in the gut. Three genera, Bacteroides, Prevotella, and Ruminococcus, were the most common dysbiotic taxa in terms of being enriched or depleted in disease populations and was driven in part by the diversity of operational taxonomic units (OTUs) within these genera. Results of the cross-sectional analysis suggest that antibiotic-driven loss of microbial diversity may increase the risk for chronic disease. However, longitudinal studies are needed to confirm the causative effect of diversity loss for chronic disease risk.
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