Science progresses through debate and disagreement, and scientific controversies play a crucial role in the growth of scientific knowledge. However, not all controversies and disagreements are progressive in science. Sometimes, controversies can be pseudoscientific; in fact, bogus controversies, and what seem like genuine scientific disagreements, can be a distortion of science set up by non-scientific actors. Bogus controversies are detrimental to science because they can hinder scientific progress and eventually bias science-based decisions. The first goal of this paper is to (...) elucidate the distinction between bogus and genuine scientific controversies and provide a qualitative methodology, based on the literature on expertise, for distinguishing between the two. We will illustrate six epistemic criteria for distinguishing bogus from genuine scientific debates in science and medicine. This heuristic strategy applies directly to scientific reports, and it relies mostly on the social structure of science. We will then apply the above criteria to a case study: the controversy over statins, which are widely prescribed drugs for reducing the level of cholesterol and preventing cardiovascular disease. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 and few other proteins encoded by Herpesviridae, Nef, E1A, NS5A, PB2, HN, L83L, (...) MC155R, other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. Many human viruses, including HCV, HIV1, ASFV, and a number of Adeno-, Pox-, and herpesviruses, including CMV, encode the substrates for mammalian prenylation enzymes. Prenylation is advantageous for viral infection; its suppression by FT/GGT and FPPS inhibitors has antiviral effects. In bacteriophages, prenylation may aid in moderation of microbial infections. (shrink)

In 2001 the Italian Government defined Essential Assistance Levels (LEA), which can be considered as an important step forward in the health care system. The Italian health care system would provide payment of essential and uniform aid services in order to safeguard many values such as human dignity, personal health, equal assistance and good health practices. The Ministry of Health has worked to rationalize the National Formulary and to define evaluation methods for drugs in order to choose what to reimburse (...) without penalizing the rights of the individual and society.This paper describes how this job of rationalization was done and tries to illustrate the choices made in Italy by the use of two meaningful examples (statins and rivastigmine). (shrink)

In this chapter we explore the process of extrapolating causal claims from model organisms to humans in pharmacology. We describe and compare four strategies of extrapolation: enumerative induction, comparative process tracing, phylogenetic reasoning, and robustness reasoning. We argue that evidence of mechanisms plays a crucial role in several strategies for extrapolation and in the underlying logic of extrapolation: the more directly a strategy establishes mechanistic similarities between a model and humans, the more reliable the extrapolation. We present case studies from (...) the research on atherosclerosis and the development of statins, that illustrate these strategies and the role of mechanistic evidence in extrapolation. (shrink)

When new drugs are approved by the Food and Drug Administration, the default assumption is that they will be available by prescription only, safe for use exclusively under clinical supervision. The paternalism underlying this default must be interrogated in order to ensure appropriate respect for patient autonomy. Upon closer inspection, prescription requirements are justified when nonprescription status would risk harm to third parties and when a large segment of the population would struggle to exercise their autonomy in using a drug (...) safely and effectively on their own. Although these justifications can support prescription status for many drugs, we propose that reversing the FDA's current default to instead begin with a presumption in favor of over‐the‐counter status is the best way to avoid interference with valid claims of patient autonomy. Under this approach, a range of drug products could be considered for an OTC switch, including oral contraceptives, statins, and HIV‐prevention drugs. (shrink)

This paper discusses the problematic and sometimes implicit nature of some central notions and criteria used in debates about inclusion (or exclusion) of health care services in the health care benefit package. An analysis of discussions about four health care services—lungtransplantation, statins, (sildenafil (viagra) and rivastigmine—illustrates a case-by-case approach and inconsistent use of criteria, which present a challenge to develop a decision-making procedure in which important criteria or central notions can be discussed explicitly.

Statistical evidence is pervasive in medicine. In this chapter we will focus on the reliability of randomized clinical trials (RCTs) conducted to test the safety and efficacy of medical treatments. RCTs are scientific experiments and, as such, we expect them to be replicable: if we repeat the same experiment time and again, we should obtain the same outcome (Norton 2015). The statistical design of the test should guarantee that the observed outcome is not a random event, but rather a real (...) effect of the treatments administered. However, for more than a decade now, we have been discussing a replicability crisis across different experimental disciplines including medicine: the outcomes of trials published in very prestigious journals often disappear when the experiment is repeated (see, e.g., Lehrer 2010, Begley and Ellis 2012, Horton 2015). -/- There are different accounts of the reason for this replicability crisis, ranging from scientific fraud to lack of institutional incentives to double-check someone else’s results. In this chapter we will use the replicability crisis as a thread to introduce some central issues in the design of scientific experiments in medicine. First, in section 1, we will see how replicability and statistical significance are connected: we can only make sense of the p-value of a trial outcome within a series of replications of the test. But in order to conduct these replications properly, we need to agree on the proper design of the experiment we are going to repeat. In particular, we need to prevent the preferences of the experimenters from biasing the outcome of the experiment. If there is such a bias, when the experiment is replicated by a third party, the observed outcome will vanish. In section 2, we will argue that trialists need to agree on the debiasing procedures and the statistical quality controls that feature in the trial protocol, if they want the outcome to be replicable. In section 3, we will make two complementary points. On the one hand, replicability per se is not everything: we need trial outcomes that are not only statistically significant but also clinically relevant. On the other hand, trials are not everything: the experts analyzing the evidence can improve the reliability of statistical evidence, although they sometimes fail; we need to further study how they make their decisions. In section 4, we will use a controversy about the overprescription of statins to show how non-replicable effects are obtained in trials and how experts may fail at detecting such flaws, if the commercial interests are big enough. (shrink)

In 2003 and 2018 researchers discussed the perils of blind reliance on randomized controlled trials that have been substituted for medical experience and clinical acumen. Although these past articles do well to shed light on this issue, they neglect to discuss the topic of all-cause mortality in controlled trials. The current essay seeks to fill this void and expand the thought put into the appropriateness of all-cause mortality, especially when trials extend excessively far into the future. To do this effectively (...) the current essay leans on trial data from statin research and evidence from cancer screening—where researchers have explicitly called for all-cause mortality to be used in lieu of cancer or cardiovascular specific mortality. The issue with such an endpoint is that it obfuscates the issue at hand, namely that a specific intervention is intended to have a specific effect, not that a specific intervention is supposed to have any kind of effect. The effect(s) of medical interventions ought to be relevant to their intended mechanism of action and not simply any positive effect that can be pulled from trial data. (shrink)

The text is taken from the edition of D. E. Hill, Mnemosyne Supplement 79 . The following works are referred to by author's surname only: H. W. Garrod, P. Papini Stati Thebais et Achilleis ; L. Håkanson, Statins Thebaid ; A. Klotz, P. Papini Stati Thebais ; R. Kühner, C. Stegmann, and A. Thierfelder, Ausführliche Grammatik der lateinischen Sprache ; R. Lesueur, Stace Thébaïde ; J. H. Mozley, Statius ; E. C. Woodcock, A New Latin Syntax.

The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on ‘what regulates cell size’, the question ‘why cell size needs to be maintained’ has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative cell surface area impose biophysical limitations on cells, which (...) can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity. Cell size is intimately connected to metabolism and growth rate, which are influenced by mitochondrial activity and biophysical constraints. We discuss that cellular fitness is often cell-size dependent. While the current evidence relies largely on proliferating cells, this connection from cell size to fitness may also help explain metabolic diseases. (shrink)

This article explores some implications of the increasing reliance on clinical trials in contemporary health care, particularly health care payers’ efforts to use them in the so-called fourth hurdle decisions. How do these agencies manage medical uncertainty given the desire to produce clear guidelines for clinicians? Their solutions take account of trials in at least two ways, reflecting broader debates about the meaning of these medical experiments. Trials can be read as either ‘‘proofs of protocol’’—straightforward guides to action with individual (...) drugs in specific populations—or ‘‘proofs of principle’’— where extrapolation is made possible through an appeal to underlying biological mechanisms. These contrasting readings of trials are illustrated with reference to guidelines on heart disease prevention/cholesterol reduction using statins among the elderly in North America and the United Kingdom. Uncertainty in these cases does not lead to inertia but solutions use different fixed points to aid navigation, including both physiological principles and moral values. (shrink)