Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although ...drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution.
There is a battle in the supermarket isle, a battle between what the consumer wants and what the retailer and others want her to see, and subsequently to buy. Product packages and displays contain a ...number of features and attributes tailored to catch consumers' attention. These are what we call external factors comprising the visual saliency, the number of facings, and the placement of each product. But a consumer also brings with her a number of goals and interests related to the products and their attributes. These are important internal factors, including brand preferences, price sensitivity, and dietary inclinations. We fit mobile eye trackers to consumers visiting real-life supermarkets in order to investigate to what extent external and internal factors affect consumers' visual attention and purchases. Both external and internal factors influenced what products consumers looked at, with a strong positive interaction between visual saliency and consumer preferences. Consumers appear to take advantage of visual saliency in their decision making, using their knowledge about products’ appearance to guide their visual attention towards those that fit their preferences. When it comes to actual purchases, however, visual attention was by far the most important predictor, even after controlling for all other internal and external factors. In other words, the very act of looking longer or repeatedly at a package, for any reason, makes it more likely that this product will be bought. Visual attention is thus crucial for understanding consumer behaviour, even in the cluttered supermarket environment, but it cannot be captured by measurements of visual saliency alone.
Homologous recombination of single-stranded oligonucleotides is a highly efficient process for introducing precise mutations into the genome of E. coli and other organisms when mismatch repair (MMR) ...is disabled. This can result in the rapid accumulation of off-target mutations that can mask desired phenotypes, especially when selections need to be employed following the generation of combinatorial libraries. While the use of inducible mutator phenotypes or other MMR evasion tactics have proven useful, reported methods either require non-mobile genetic modifications or costly oligonucleotides that also result in reduced efficiencies of replacement. Therefore a new system was developed, Transient Mutator Multiplex Automated Genome Engineering (TM-MAGE), that solves problems encountered in other methods for oligonucleotide-mediated recombination. TM-MAGE enables nearly equivalent efficiencies of allelic replacement to the use of strains with fully disabled MMR and with an approximately 12- to 33-fold lower off-target mutation rate. Furthermore, growth temperatures are not restricted and a version of the plasmid can be readily removed by sucrose counterselection. TM-MAGE was used to combinatorially reconstruct mutations found in evolved salt-tolerant strains, enabling the identification of causative mutations and isolation of strains with up to 75% increases in growth rate and greatly reduced lag times in 0.6 M NaCl.
Recombineering and multiplex automated genome engineering (MAGE) offer the possibility to rapidly modify multiple genomic or plasmid sites at high efficiencies. This enables efficient creation of ...genetic variants including both single mutants with specifically targeted modifications as well as combinatorial cell libraries. Manual design of oligonucleotides for these approaches can be tedious, time-consuming, and may not be practical for larger projects targeting many genomic sites. At present, the change from a desired phenotype (e.g. altered expression of a specific protein) to a designed MAGE oligo, which confers the corresponding genetic change, is performed manually. To address these challenges, we have developed the MAGE Oligo Design Tool (MODEST). This web-based tool allows designing of MAGE oligos for (i) tuning translation rates by modifying the ribosomal binding site, (ii) generating translational gene knockouts and (iii) introducing other coding or non-coding mutations, including amino acid substitutions, insertions, deletions and point mutations. The tool automatically designs oligos based on desired genotypic or phenotypic changes defined by the user, which can be used for high efficiency recombineering and MAGE. MODEST is available for free and is open to all users at http://modest.biosustain.dtu.dk.
Clinical expertise has since 1891 a Swedish counterpart in proven experience. This study aims to increase our understanding of clinicians' views of their professional expertise, both as a source or ...body of knowledge and as a skill or quality. We examine how Swedish healthcare personnel view their expertise as captured by the (legally and culturally relevant) Swedish concept of "proven experience," through a survey administered to a simple random sample of Swedish physicians and nurses (2018, n = 560). This study is the first empirical attempt to analyse the notion of proven experience as it is understood by Swedish physicians and nurses. Using statistical techniques for data dimensionality reduction (confirmatory factor analysis and multidimensional scaling), the study provides evidence that the proven experience concept is multidimensional and that a model consisting of three dimensions-for brevity referred to as "test/evidence", "practice", and "being an experienced/competent person"-describes the survey responses well. In addition, our results cannot corroborate the widely held assumption in evidence-based medicine that an important component of clinical expertise consists of experience of patients' preferences.
High-quality healthcare decisions need to balance input from science and clinical practice. When two sources of evidence — such as scientific and practice-derived evidence — are compared, integrated, ...or need to stand-in for one another, they need to be comparable on similar dimensions. Since 1891, Swedish physicians have been operating under a legal requirement to base their healthcare decisions on science and “proven experience” (approximately clinical expertise), and today all healthcare personnel in Sweden fall under this legal requirement.
We investigated the dynamics between these two kinds of evidence with respect to importance, systematicity, and certainty by studying Swedish healthcare professionals.
Survey to professionals; document studies of political discourse.
In this study, a survey was sent to simple random samples of Swedish professionals in medicine, nursing, occupational therapy, dentistry, and dental hygiene, asking about the roles of science and proven experience in medical decision making. Outcome measures were how important, certain, and systematic science and proven experience are for successful medical decision making.
The sampling frame was each profession's most recent occupational registry accessed by the Swedish federal statistical agency. 3500 surveys were distributed. 1626 surveys were returned. 26 participants were removed prior to analysis (exclusion criteria: more than one profession indicated, missing certificate, and mistake in stratum). The final sample consisted of 295 physicians, 300 nurses, 365 occupational therapists, 339 dentists, and 301 hygienists. 162 responses in questions used as variables in the analyses were either uninterpretable or empty; those were replaced with the modal response for a given participant's profession on a given question.
In the study, proven experience's perceived importance for clinical decision making is positively correlated with its certainty and systematicity, and an increased certainty and systematicity is positively correlated with a diminished difference in importance between science and proven experience for almost all professions surveyed in this study.
Proven experience has an evidentiary role in clinical decision making, and this role depends in part on its certainty and systematicity. Notably, this makes the EBM-based perspective that practice-derived knowledge is primarily of implementation value less plausible.
The visual behaviour of consumers buying (or searching for) products in a supermarket was measured and used to analyse the stages of their decision process. Traditionally metrics used to trace ...decision-making processes are difficult to use in natural environments that often contain many options and unstructured information. Unlike previous attempts in this direction (i.e. Russo & Leclerc, 1994), our methodology reveals differences between a decision-making task and a search task. In particular the second (evaluation) stage of a decision task contains more re-dwells than the second stage of a comparable search task. This study addresses the growing concern of taking eye movement research from the laboratory into the ‘real-world’, so findings can be better generalised to natural situations.
Reinforcement learning systems usually assume that a value function is defined over all states (or state-action pairs) that can immediately give the value of a particular state or action. These ...values are used by a selection mechanism to decide which action to take. In contrast, when humans and animals make decisions, they collect evidence for different alternatives over time and take action only when sufficient evidence has been accumulated. We have previously developed a model of memory processing that includes semantic, episodic and working memory in a comprehensive architecture. Here, we describe how this memory mechanism can support decision making when the alternatives cannot be evaluated based on immediate sensory information alone. Instead we first imagine, and then evaluate a possible future that will result from choosing one of the alternatives. Here we present an extended model that can be used as a model for decision making that depends on accumulating evidence over time, whether that information comes from the sequential attention to different sensory properties or from internal simulation of the consequences of making a particular choice. We show how the new model explains both simple immediate choices, choices that depend on multiple sensory factors and complicated selections between alternatives that require forward looking simulations based on episodic and semantic memory structures. In this framework, vicarious trial and error is explained as an internal simulation that accumulates evidence for a particular choice. We argue that a system like this forms the "missing link" between more traditional ideas of semantic and episodic memory, and the associative nature of reinforcement learning.
Conclusions The strength of having both the patient's hospital file and her/his own health journal at the same screen being able to discuss all relevant finding at the visit will hopefully result in ...improved care, lead to better health related quality of life, and increased survival of the patients.
PDF
