Strong environment X genotype interactions determine the fitness costs of antibiotic resistance in vitro and in an insect model of infection (article)

This is the author accepted manuscript. The final version is available from the American Society for Microbiology via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.2503The acquisition of antibiotic resistance commonly imposes fitness costs, a reduction in the fitness of bacteria in the absence of drugs. These costs have been primarily quantified using in vitro experiments and a small number of in vivo studies in mice, and it is commonly assumed that these diverse methods are consistent. Here, we used an insect model of infection to compare the fitness costs of antibiotic resistance in vivo relative to in vitro conditions. Experiments explored diverse mechanisms of resistance in a Gram-positive pathogen, Bacillus thuringiensis, and a Gram-negative intestinal symbiont, Enterobacter cloacae. Rifampicin resistance in B. thuringiensis showed fitness costs that were typically elevated in vivo, although these were modulated by genotype-environment interactions. In contrast, resistance to cefotaxime via de-repression of AmpC β-lactamase in E. cloacae resulted in undetectable costs in vivo or in vitro, while spontaneous resistance to nalidixic acid, and carriage of the IncP plasmid RP4, imposed costs that increased in vivo. Overall, fitness costs in vitro were a poor predictor of fitness costs in vivo because of strong genotype environment interactions throughout this study. Insect infections provide a cheap and accessible means of assessing fitness consequences of resistance mutations, data that is important to understand the evolution and spread of resistance. This study emphasizes that the fitness costs imposed by particular mutations or different modes of resistance are extremely variable, and that only a subset of these mutations are likely to be prevalent outside of the laboratory.Medical Research Council (MRC

Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth

Objectives: To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity. / Study design: Geographical, prospective population-based cohort study of 1139 infants born LMPT (320/7 to 366/7 weeks' gestation) and 1255 infants born at term (370/7 to 426/7 weeks' gestation). Parent questionnaires were obtained to identify impaired cognitive and language development, behavioral problems, delayed social–emotional competence, autistic features, and clinically significant eating difficulties at 24 months corrected age for 638 (57%) children born LMPT and 765 (62%) children born at term. / Results: Latent class analysis revealed 2 profiles of development among the term group: optimal (84%) and a profile of social, emotional, and behavioral impairments termed “nonoptimal” (16%). These 2 profiles were also identified among the LMPT group (optimal: 67%; nonoptimal: 26%). In the LMPT group, a third profile was identified (7%) that was similar to the phenotype previously identified in infants born very preterm. Nonwhite ethnicity, socioeconomic risk, and not receiving breast milk at hospital discharge were risk factors for nonoptimal outcomes in both groups. Male sex, greater gestational age, and pre-eclampsia were only associated with the preterm phenotype. / Conclusions: Among children born LMPT with parent-reported cognitive or behavioral impairments, most had problems similar to the profile of difficulties observed in children born at term. A smaller proportion of children born LMPT had impairments consistent with the “very preterm phenotype” which are likely to have arisen through a preterm pathway. These results suggest that prematurity may affect development through several etiologic pathways in the late and moderately preterm population

Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study.

OBJECTIVE: To examine the timing and duration of RSV bronchiolitis hospital admission among term and preterm infants in England and to identify risk factors for bronchiolitis admission. DESIGN: A population-based birth cohort with follow-up to age 1 year, using the Hospital Episode Statistics database. SETTING: 71 hospitals across England. PARTICIPANTS: We identified 296618 individual birth records from 2007/08 and linked to subsequent hospital admission records during the first year of life. RESULTS: In our cohort there were 7189 hospital admissions with a diagnosis of bronchiolitis, 24.2 admissions per 1000 infants under 1 year (95%CI 23.7-24.8), of which 15% (1050/7189) were born preterm (47.3 bronchiolitis admissions per 1000 preterm infants (95% CI 44.4-50.2)). The peak age group for bronchiolitis admissions was infants aged 1 month and the median was age 120 days (IQR = 61-209 days). The median length of stay was 1 day (IQR = 0-3). The relative risk (RR) of a bronchiolitis admission was higher among infants with known risk factors for severe RSV infection, including those born preterm (RR = 1.9, 95% CI 1.8-2.0) compared with infants born at term. Other conditions also significantly increased risk of bronchiolitis admission, including Down's syndrome (RR = 2.5, 95% CI 1.7-3.7) and cerebral palsy (RR = 2.4, 95% CI 1.5-4.0). CONCLUSIONS: Most (85%) of the infants who are admitted to hospital with bronchiolitis in England are born at term, with no known predisposing risk factors for severe RSV infection, although risk of admission is higher in known risk groups. The early age of bronchiolitis admissions has important implications for the potential impact and timing of future active and passive immunisations. More research is needed to explain why babies born with Down's syndrome and cerebral palsy are also at higher risk of hospital admission with RSV bronchiolitis

Explaining Evidence Denial as Motivated Pragmatically Rational Epistemic Irrationality

This paper introduces a model for evidence denial that explains this behavior as a manifestation of rationality and it is based on the contention that social values (measurable as utilities) often underwrite these sorts of responses. Moreover, it is contended that the value associated with group membership in particular can override epistemic reason when the expected utility of a belief or belief system is great. However, it is also true that it appears to be the case that it is still possible for such unreasonable believers to reverse this sort of dogmatism and to change their beliefs in a way that is epistemically rational. The conjecture made here is that we should expect this to happen only when the expected utility of the beliefs in question dips below a threshold where the utility value of continued dogmatism and the associated group membership is no longer sufficient to motivate defusing the counter-evidence that tells against such epistemically irrational beliefs

Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study.

OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point

Probabilistic single function dual process theory and logic programming as approaches to non-monotonicity in human vs. artificial reasoning

In this paper, it is argued that single function dual process theory is a more credible psychological account of non-monotonicity in human conditional reasoning than recent attempts to apply logic programming (LP) approaches in artificial intelligence to these data. LP is introduced and among other critiques, it is argued that it is psychologically unrealistic in a similar way to hash coding in the classicism vs. connectionism debate. Second, it is argued that causal Bayes nets provide a framework for modelling probabilistic conditional inference in System 2 that can deal with patterns of inference LP cannot. Third, we offer some speculations on how the cognitive system may avoid problems for System 1 identified by Fodor in 1983. We conclude that while many problems remain, the probabilistic single function dual processing theory is to be preferred over LP as an account of the non-monotonicity of human reasoning

Ripples in a pond: Do social work students need to learn about terrorism?

In the face of heightened awareness of terrorism, however it is defined, the challenges for social work are legion. Social work roles may include working with the military to ensure the well-being of service-men and women and their families when bereaved or injured, as well as being prepared to support the public within the emergency context of an overt act of terrorism. This paper reviews some of the literature concerning how social work responds to confl ict and terrorism before reporting a smallscale qualitative study examining the views of social work students, on a qualifying programme in the UK, of terrorism and the need for knowledge and understanding as part of their education

High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease

BACKGROUND: The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases. METHODS: We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used. RESULTS: We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis. CONCLUSION: Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naïve methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease

Physical Attractiveness and Altruism in Two Modified Dictator Games

Several studies find that male individuals are more altruistic toward attractive women, suggesting altruism may serve as a courtship display. Many studies exploring this phenomenon have used vignettes and facial images. We tested the sexual selection hypothesis as an explanation for altruistic behavior, where players played the dictator game with “live” participants. Two studies were conducted (Study 1, n = 212; Study 2, n = 188) where we manipulated stakes and anonymity between participants to explore the relationship between the dictator’s allocations and their perceived attractiveness of the recipient. We found no relationship between attractiveness and altruism. Dictators were consistently fair when allocating stakes, irrespective of the recipients’ attractiveness