Do Monkeys and Young Children Understand Exclusive “Or” Relations? A Commentary on Ferrigno et al. (2021)

Ferrigno et al. (2021) claim to provide evidence that monkeys can reason through the disjunctive syllogism (given A or B, not A, therefore B) and conclude that monkeys therefore understand logical “or” relations. Yet their data fail to provide evidence that the baboons they tested understood the exclusive “or” relations in the experimental task. For two mutually exclusive possibilities—A or B—the monkeys appeared to infer that B was true when A was shown to be false, but they failed to infer that B was false when A was shown to be true. In our own research, we recently found an identical response pattern in 2.5- to 4-year-old children, whereas 5-year-olds demonstrated that they could make both inferences. The monkeys’ and younger children’s responses are instead consistent with an incorrect understanding of A and B as having an inclusive “or” relation. Only the older children provided compelling evidence of representing the exclusive “or” relation between A and B.

Unscheduled DNA replication in G1 causes genome instability through head-to-tail replication fork collisions

DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineered genetic systems in budding yeast to induce unscheduled replication in the G1-phase of the cell cycle. Unscheduled G1 replication initiated at canonical S-phase origins across the genome. We quantified differences in replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se did not trigger cellular checkpoints. Subsequent replication during S-phase, however, resulted in over-replication and led to chromosome breaks via head-to-tail replication fork collisions that are marked by chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA. Low-level, sporadic induction of G1 replication induced an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation by G1/S deregulation.

Expression of Interferons Lambda 3 and 4 Induces Identical Response in Human Liver Cell Lines Depending Exclusively on Canonical Signaling

Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness

Background The National Institute for Health and Care Excellence and a number of international health technology assessment agencies have recently undertaken appraisals of histology-independent technologies (HITs). A strong and untested assumption inherent in the submissions included identical clinical response across all tumour histologies, including new histologies unrepresented in the trial. Challenging this assumption and exploring the potential for heterogeneity has the potential to impact upon cost-effectiveness. Method Using published response data for a HIT, a Bayesian hierarchical model (BHM) was used to identify heterogeneity in response and to estimate the probability of response for each histology included in single-arm studies, which informed the submission for the HIT, larotrectinib. The probability of response for a new histology was estimated. Results were inputted into a simplified response-based economic model using hypothetical parameters. Histology-independent and histology-specific incremental cost-effectiveness ratios accounting for heterogeneity were generated. Results The results of the BHM show considerable heterogeneity in response rates across histologies. The predicted probability of response estimated by the BHM is 60.9% (95% credible interval 16.0; 91.8%), lower than the naively pooled probability of 74.5%. A mean response probability of 56.9% (0.2; 99.9%) is predicted for an unrepresented histology. Based on the economic analysis, the probability of the hypothetical HIT being cost-effective under the assumption of identical response is 78%. Allowing for heterogeneity, the probability of various approval decisions being cost-effective ranges from 93% to 11%. Conclusions Central to the challenge of reimbursement of HITs is the potential for heterogeneity. This study illustrates how heterogeneity in clinical effectiveness can result in highly variable and uncertain estimates of cost-effectiveness. This analysis can help improve understanding of the consequences of histology-independent versus histology-specific decisions.

Prescribing preferences for hormone sensitive (HR+) metastatic breast cancer (mBC) in the CDK 4/6 inhibitor (CDK 4/6i) era.

e13058 Background: CDK 4/6i is a category 1 guideline-recommended therapy for HR+/HER2- mBC in both first-line (1L) with an aromatase inhibitor and second-line (2L) with fulvestrant and without prior CDK 4/6i. We sought to understand community oncologists’ (c-oncs) prescribing preferences and sequencing for 1L, 2L, and third-line (3L) HR+/HER2- mBC patients across several common clinical scenarios (CS). Methods: C-oncs were presented 4 hypothetical HR+/HER2- mBC clinical scenarios (CS 1-4) via web-based survey. CS differed by menopausal status, prior adjuvant therapy and nature of metastases (mets) (i.e., bulky liver, lung, bone), but otherwise uniform: asymptomatic presentation, PI3K negative, identical response extent and duration in 1L, 2L, and 3L. Treatment preferences: hormonal (H), single agent (SA) or combination chemotherapy (CC) for 1L, 2L, and 3L in each CS were queried. We describe these preference patterns. Results: 47 U.S. c-oncs participated: mean years in practice was 22.7 and mean mBC patients under active treatment was 23.3. Preference for treatment and sequence, regardless of CS, per LOT were: 1L = 71% H, 14% SA, 16% CC; 2L = 51% H, 31% SA, 16% CC; and 3L = 35% H, 59% SA, 6% CC (Table). Of the 71% who preferred 1L H, the CDK4/6i % were: 73% overall, 58% when mets described as bulky liver, 94% when described as bone and or lung. The preference for pre-planned sequential chemo-hormonal therapy in 1L resulted in 63% of initial chemotherapy followed immediately by H; of which CDK 4/6i was preferred in 47%. In total, the initial and post-chemo CDK4/6i 1L preference was 80%. 2L hormonal preferences by frequency were: everolimus + exemestane = 38%, CDK 4/6i + fulvestrant = 20%, fulvestrant = 19%. SA preferences: 2L = capecitabine 46%, taxane 25%; 3L = capecitabine 40%, eribulin 32%. CC preferences included atezolizumab + nab-paclitaxel 24% in 1L and 16% in 2L. Conclusions: 1L HR+/HER2- mBC treatment is highly variable and preferences that warrant further research include: the role of CC, specifically atezolizumab + nab-paclitaxel; repeated CDK4/6i line of therapy; H therapy post CDK4/6i progression; and optimal SA sequencing. [Table: see text]

Antibiotic Killing of Diversely Generated Populations of Nonreplicating Bacteria

ABSTRACTNonreplicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of nonreplicating populations of planktonic bacteria: (i) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (ii) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; and (iii) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations ofStaphylococcus aureusNewman andEscherichia coliK-12 (MG1655) and, respectively, nine and seven different bactericidal antibiotics, we estimated the rates at which these drugs kill these different types of nonreplicating bacteria. In contrast to the common belief that bacteria that are nonreplicating are refractory to antibiotic-mediated killing, all three types of nonreplicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics daptomycin and colistin, respectively. This result indicates that nonreplicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.

Graphical Comparison of Critically Damped Versus Overdamped Free Vibration of Single Degree of Freedom Structure

In most vibration structural problems, the value of damping is less than unity. Such a small amount of damping may increase near or exceed unity under certain special circumstances. Critically damped and overdamped solutions are completed until the final expressions are generated and an indication provided by MATLAB as to how these expressions depend on viscous damping ratios, natural frequencies, and initial conditions. The developed equations of various damping systems, which are commonly employed in vibration analyses, are compared, with several important observations are noted. Natural frequency is of primary importance when controlling the settling time of critically damped and overdamped vibration responses. Initial conditions are also considered main factors that affect critically damped and overdamped vibration peak responses. Damping plays a crucial role in the peak response of an overdamped system. A direct relationship between the damping ratio and the peak response is observed, whereas an inverse relationship exists between the damping ratio and the settling time. Therefore, critically damped and overdamped systems exhibit an identical response in the large scale perspective, whereby they first rise and then fall. In the zoomed scale, the peak response of the overdamped system is lower than that of the critically damped system, and the latter falls faster than the former. No cyclic response is observed, and the vibration statement is abnormally used for both critically damped and overdamped systems.

Antibiotic killing of diversely generated populations of non-replicating bacteria

Non-replicating bacteria are known to be (or at least commonly thought to be) refractory to antibiotics to which they are genetically susceptible. Here, we explore the sensitivity to killing by bactericidal antibiotics of three classes of non-replicating populations of planktonic bacteria; (1) stationary phase, when the concentration of resources and/or nutrients are too low to allow for population growth; (2) persisters, minority subpopulations of susceptible bacteria surviving exposure to bactericidal antibiotics; (3) antibiotic-static cells, bacteria exposed to antibiotics that prevent their replication but kill them slowly if at all, the so-called bacteriostatic drugs. Using experimental populations of Staphylococcus aureus Newman and Escherichia coli K12 (MG1655) and respectively 9 and 7 different bactericidal antibiotics, we estimate the rates at which these drugs kill these different types of non-replicating bacteria. Contrary to the common belief that bacteria that are non-replicating are refractory to antibiotic-mediated killing, all three types of non-replicating populations of these Gram-positive and Gram-negative bacteria are consistently killed by aminoglycosides and the peptide antibiotics, daptomycin and colistin, respectively. This result indicates that non-replicating cells, irrespectively of why they do not replicate, have an almost identical response to bactericidal antibiotics. We discuss the implications of these results to our understanding of the mechanisms of action of antibiotics and the possibility of adding a short-course of aminoglycosides or peptide antibiotics to conventional therapy of bacterial infections.

Investigating Cognitive Effort and Response Quality of Question Formats in Web Surveys Using Paradata

Measuring attitudes and opinions employing agree/disagree (A/D) questions is a common method in social research because it appears to be possible to measure different constructs with identical response scales. However, theoretical considerations suggest that A/D questions require a considerable cognitive processing. Item-specific (IS) questions, in contrast, offer content-related response categories, implying less cognitive processing. To investigate the respective cognitive effort and response quality associated with A/D and IS questions, we conducted a web-based experiment with 1,005 students. Cognitive effort was assessed by response times and answer changes. Response quality, in contrast, was assessed by different indicators such as dropouts. According to our results, single IS questions require higher cognitive effort than single A/D questions in terms of response times. Moreover, our findings show substantial differences in processing single and grid questions.