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Concept: Unknown unknown

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Suicide risk assessment aims to reduce uncertainty in order to focus treatment and supervision on those who are judged to be more likely to die by suicide. In this article we consider recent meta-analytic research that highlights the difference between uncertainty about suicide due to chance factors (aleatory uncertainty) and uncertainty that results from lack of knowledge (epistemic uncertainty). We conclude that much of the uncertainty about suicide is aleatory rather than epistemic, and discuss the implications for clinicians.

Concepts: Risk management, Donald Rumsfeld, Risk, Knowledge, Unknown unknown, Decision theory, Epistemology

2

In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening.

Concepts: Drug discovery hit to lead, Drug discovery, Learning, Detection theory, Screening, Unknown unknown, Type I and type II errors, Typography

0

Although the phenomenon of transposition has been known for over 60 years, its overarching importance in modifying and streamlining genomes took some time to recognize. In spite of a robust understanding of transposition of some TE, there remain a number of important TE groups with potential high genome impact and unknown transposition mechanisms and yet others, only recently identified by bioinformatics, yet to be formally confirmed as mobile. Here, we point to some areas of limited understanding concerning well established important TE groups with DDE Tpases, to address central gaps in our knowledge of characterised Tn with other types of Tpases and finally, to highlight new potentially mobile DNA species. It is not exhaustive. Examples have been chosen to provide encouragement in the continued exploration of the considerable prokaryotic mobilome especially in light of the current threat to public health posed by the spread of multiple Ab®.

Concepts: Donald Rumsfeld, Organism, Knowledge, RNA, Plasmid, DNA, Unknown unknown, Epistemology

0

The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system. Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals' data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies. The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases. Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways. Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective. We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.

Concepts: Data, Blood vessel, Blood, Unknown unknown, Epistemology, Circulatory system, Heart, Inflammation

0

The poor record of basic-to-clinical translation in recent decades has led to speculation that preclinical research is “irreproducible”, and this irreproducibility in turn has largely been attributed to deficiencies in reporting and statistical practices. There are, however, a number of other reasonable explanations of both poor translation and difficulties in one laboratory replicating the results of another. This article examines these explanations as they pertain to preclinical pain research. I submit that many instances of apparent irreproducibility are actually attributable to interactions between the phenomena and interventions under study and “latent” environmental factors affecting the rodent subjects. These environmental variables-often causing stress, and related to both animal husbandry and the specific testing context-differ greatly between labs, and continue to be identified, suggesting that our knowledge of their existence is far from complete. In pain research in particular, laboratory stressors can produce great variability of unpredictable direction, as stress is known to produce increases (stress-induced hyperalgesia) or decreases (stress-induced analgesia) in pain depending on its parameters. Much greater attention needs to be paid to the study of the laboratory environment if replication and translation are to be improved.

Concepts: Sociology, Unknown unknown, Logic, Metaphysics, Environment, Philosophy of science, Epistemology, Scientific method

0

Recently, the concept of black swans has gained increased attention in the fields of risk assessment and risk management. Different types of black swans have been suggested, distinguishing between unknown unknowns (nothing in the past can convincingly point to its occurrence), unknown knowns (known to some, but not to relevant analysts), or known knowns where the probability of occurrence is judged as negligible. Traditional risk assessments have been questioned, as their standard probabilistic methods may not be capable of predicting or even identifying these rare and extreme events, thus creating a source of possible black swans. In this article, we show how a simulation model can be used to identify previously unknown potentially extreme events that if not identified and treated could occur as black swans. We show that by manipulating a verified and validated model used to predict the impacts of hazards on a system of interest, we can identify hazard conditions not previously experienced that could lead to impacts much larger than any previous level of impact. This makes these potential black swan events known and allows risk managers to more fully consider them. We demonstrate this method using a model developed to evaluate the effect of hurricanes on energy systems in the United States; we identify hurricanes with potentially extreme impacts, storms well beyond what the historic record suggests is possible in terms of impacts.

Concepts: Hazard, Management, Decision theory, Swan, Unknown unknown, Risk assessment, Risk, Risk management

0

Environmental, or ‘choice-architecture’, interventions aim to change behaviour by changing properties/contents of the environment and are commonly used in the workplace to promote healthy behaviours in employees. The present review aimed to evaluate and synthesize the evidence surrounding the effectiveness of environmental interventions targeting eating behaviour in the workplace. A systematic search identified 8157 articles, of which 22 were included in the current review. All included studies were coded according to risk of bias and reporting quality and were classified according to the emergent typology of choice-architecture interventions. More than half of included studies (13/22) reported significant changes in primary measures of eating behaviour (increased fruit/veg consumption, increased sales of healthy options and reduction in calories purchased). However, only one study produced a small significant improvement in weight/body mass index. Many studies had a high or unknown risk of bias; reporting of interventions was suboptimal; and the only trial to measure compensatory behaviours found that intervention participants who ate less during the intervention ate more out with the workplace later in the day. Hence, we conclude that more rigorous, well-reported studies that account for compensatory behaviours are needed to fully understand the impact of environmental interventions on diet and importantly on weight/body mass index outcomes.

Concepts: Unknown unknown, Employment, Intervention, Behavior, Nutrition, Natural environment, Environment, Change

0

Cardiothoracic surgery residents often enter their training with fairly limited prior exposure to the field. Obviously, they need to master the essential knowledge and skills of the discipline during their training. In addition to following a didactic curriculum of one sort or another, much of the necessary knowledge and understanding will accrue from their experiences caring for and operating on the patients who will be under their auspices, not only during their formal training but also after they finish their training.  Some of these cases and situations, such as elective cases, allow for careful preparation, while some more urgent or emergent cases require generic, advance preparation in order to be ready to perform optimally in these cases when they arise. And then there will always be cases for which one will not be able to prepare in any meaningful way, and these types of cases will require creativity and innovation “on the fly."  I will describe three cases, which are examples of each of these situations, with suggestions on how to handle each type of situation optimally. I will describe the preparation, such as it was for each, in some detail to help the reader understand how it felt to deal with each of these cases. The technical details of each of these cases resulted in a publication, which will be cited in the references, should the reader want to learn more about them.

Concepts: Decision theory, Donald Rumsfeld, Want, Learning, Unknown unknown, Understanding, Knowledge, Epistemology

0

The aim of this study is to explore the risk factors for ectopic pregnancy (EP) in the Taiwanese population and to identify any unknown risk factors for EP that could assist awareness and diagnosis.

Concepts: Miscarriage, Scientific method, Pregnancy test, Pregnancy, Unknown unknown, Retrospective, Ectopic pregnancy, Observational study

0

In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss of efficacy with repeated drug exposure, is rarely addressed as a potential source of clinical failures. In this review, we argue that preclinical methods of tolerance development may have predictive validity and, therefore, inclusion of studies using repeated drug exposure early during the drug discovery and development process should serve to mitigate a proportion of clinical failures. Our analysis indicates that many published preclinical efficacy studies in the neuropsychiatry arena are conducted with acute drug administration only. Furthermore, specifically in the field of schizophrenia, there are several examples where tolerance development may be suspected as a factor contributing to translational failures. These and other examples highlight the need for built-for-purpose tolerance studies to be conducted, regardless of the target interaction mode of the drugs (i.e., agonist or antagonist, allosteric or orthosteric). We suggest that, for compounds that have failed in clinical studies, preclinical efficacy data sets need to be revisited to estimate the potential impact of tolerance development, one of the most significant known unknowns in the preclinical-to-clinical translation.

Concepts: Psychiatry, Unknown unknown, Drug development, Pre-clinical development, Drug discovery, Pharmaceutical industry, Clinical trial, Pharmacology