Evolutionary optimisation of antibiotic dosing regimens for bacteria with different levels of resistance.

Antimicrobial resistance is one of the biggest threats to global health, food security, and development. Antibiotic overuse and misuse are the main drivers for the emergence of resistance. It is crucial to optimise the use of existing antibiotics in order to improve medical outcomes, decrease toxicity and reduce the emergence of resistance. We formulate the design of antibiotic dosing regimens as an optimisation problem, and use an evolutionary algorithm suited to continuous optimisation (differential evolution) to solve it. Regimens are represented as vectors of real numbers encoding daily doses, which can vary across the treatment duration. A stochastic mathematical model of bacterial infections with tuneable resistance levels is used to evaluate the effectiveness of evolved regimens. The objective is to minimise the treatment failure rate, subject to a constraint on the maximum total antibiotic used. We consider simulations with different levels of bacterial resistance, two ways of administering the drug (orally and intravenously), as well as coinfections with two strains of bacteria. Our approach produced effective dosing regimens, with an average improvement in lowering the failure rate 30%, when compared with standard fixed-daily-dose regimens with the same total amount of antibiotic.

Metabolic effects of menopause: a cross-sectional characterization of body composition and exercise metabolism.

OBJECTIVES: To evaluate body composition, fat distribution, and metabolism at rest and during exercise in premenopausal, perimenopausal, and postmenopausal women. METHODS: This cross-sectional study in 72 women ages 35 to 60 years evaluated body composition via a fourcompartment model, fat distribution using dual-energy x-ray absorptiometry-derived android to gynoid ratio, metabolic measures via indirect calorimetry, and lifestyle factors using surveys. One-way analyses of variance and one-way analyses of covariance covaried for age and hormone levels (estrogen and progesterone) were used to compare groups. RESULTS: Body fat percent was significantly lower in premenopausal than perimenopausal women (mean difference ± standard error: - 10.29 ± 2.73%, P = 0.026) despite similarities in fat mass and fat-free mass between groups (P≥0.217). Android to gynoid ratio was significantly lower in premenopausal than perimenopausal women (MD ± SE: -0.16 ± 0.05 a.u., P = 0.031). Resting energy expenditure was similar between groups (P = 0.999). Fat oxidation during moderate intensity cycle ergometer exercise was significantly greater in premenopausal than postmenopausal women (MD ± SE: 0.09 ± 0.03 g/min, P = 0.045). The change in respiratory exchange ratio between rest and moderate intensity exercise was significantly lower in premenopausal women than peri- (MD ± SE: -0.05 ± 0.03 a.u., P = 0.035) and postmenopausal women (MD ± SE: -0.06 ± 0.03 a.u., P = 0.040). Premenopausal women reported significantly fewer menopause symptoms than peri- (MD ± SE: -6.58 ± 1.52 symptoms, P = 0.002) and postmenopausal participants (MD ± SE: -4.63 ± 1.52 symptoms, P = 0.044), while similarities between groups were observed for lifestyle factors including diet and physical activity (P>0.999). CONCLUSIONS: Perimenopause may be the most opportune window for lifestyle intervention, as this group experienced the onset of unfavorable body composition and metabolic characteristics. VIDEO SUMMARY: http://links.lww.com/MENO/A932.

When and why direct transmission models can be used for environmentally persistent pathogens.

Variants of the susceptible-infected-removed (SIR) model of Kermack & McKendrick (1927) enjoy wide application in epidemiology, offering simple yet powerful inferential and predictive tools in the study of diverse infectious diseases across human, animal and plant populations. Direct transmission models (DTM) are a subset of these that treat the processes of disease transmission as comprising a series of discrete instantaneous events. Infections transmitted indirectly by persistent environmental pathogens, however, are examples where a DTM description might fail and are perhaps better described by models that comprise explicit environmental transmission routes, so-called environmental transmission models (ETM). In this paper we discuss the stochastic susceptible-exposed-infected-removed (SEIR) DTM and susceptible-exposed-infected-removed-pathogen (SEIR-P) ETM and we show that the former is the timescale separation limit of the latter, with ETM host-disease dynamics increasingly resembling those of a DTM when the pathogen's characteristic timescale is shortened, relative to that of the host population. Using graphical posterior predictive checks (GPPC), we investigate the validity of the SEIR model when fitted to simulated SEIR-P host infection and removal times. Such analyses demonstrate how, in many cases, the SEIR model is robust to departure from direct transmission. Finally, we present a case study of white spot disease (WSD) in penaeid shrimp with rates of environmental transmission and pathogen decay (SEIR-P model parameters) estimated using published results of experiments. Using SEIR and SEIR-P simulations of a hypothetical WSD outbreak management scenario, we demonstrate how relative shortening of the pathogen timescale comes about in practice. With atttempts to remove diseased shrimp from the population every 24h, we see SEIR and SEIR-P model outputs closely conincide. However, when removals are 6-hourly, the two models' mean outputs diverge, with distinct predictions of outbreak size and duration.

Postexercise Inflammasome Activation and IL-1ß Production Mitigated by Flavonoid Supplementation in Cyclists.

Inflammasomes are multiprotein signaling platforms of the innate immune system that detect markers of physiological stress and promote the maturation of caspase-1 and interleukin 1 beta (IL-1ß), IL-18, and gasdermin D. This randomized, cross-over trial investigated the influence of 2-week mixed flavonoid (FLAV) versus placebo (PL) supplementation on inflammasome activation and IL-1ß and IL-18 production after 75-km cycling in 22 cyclists (42 ± 1.7 years). Blood samples were collected before and after the 2-week supplementation, and then 0 hr, 1.5 hr, and 21 hr postexercise (176 ± 5.4 min, 73.4 ± 2.0 %VO2max). The supplement (678 mg FLAVs) included quercetin, green tea catechins, and bilberry anthocyanins. The pattern of change in the plasma levels of the inflammasome adaptor oligomer ASC (apoptosis-associated speck-like protein containing caspase recruitment domain) was different between the FLAV and PL trials, with the FLAV ASC levels 52% lower (Cohen's d = 1.06) than PL immediately following 75-km cycling (interaction effect, p = .012). The plasma IL-1ß levels in FLAV were significantly lower than PL (23-42%; Cohen's d = 0.293-0.644) throughout 21 hr of recovery (interaction effect, p = .004). The change in plasma gasdermin D levels were lower immediately postexercise in FLAV versus PL (15% contrast, p = .023; Cohen's d = 0.450). The patterns of change in plasma IL-18 and IL-37 did not differ between the FLAV and PL trials (interaction effects, p = .388, .716, respectively). These data indicate that 2-week FLAV ingestion mitigated inflammasome activation, with a corresponding decrease in IL-1ß release in cyclists after a 75-km cycling time trial. The data from this study support the strategy of ingesting high amounts of FLAV to mitigate postexercise inflammation.

Effects of Whey and Pea Protein Supplementation on Post-Eccentric Exercise Muscle Damage: A Randomized Trial.

This randomized trial compared pea protein, whey protein, and water-only supplementation on muscle damage, inflammation, delayed onset of muscle soreness (DOMS), and physical fitness test performance during a 5-day period after a 90-min eccentric exercise bout in non-athletic non-obese males (n = 92, ages 18-55 years). The two protein sources (0.9 g protein/kg divided into three doses/day) were administered under double blind procedures. The eccentric exercise protocol induced significant muscle damage and soreness, and reduced bench press and 30-s Wingate performance. Whey protein supplementation significantly attenuated post-exercise blood levels for biomarkers of muscle damage compared to water-only, with large effect sizes for creatine kinase and myoglobin during the fourth and fifth days of recovery (Cohen's d > 0.80); pea protein versus water supplementation had an intermediate non-significant effect (Cohen's d < 0.50); and no significant differences between whey and pea protein were found. Whey and pea protein compared to water supplementation had no significant effects on post-exercise DOMS and the fitness tests. In conclusion, high intake of whey protein for 5 days after intensive eccentric exercise mitigated the efflux of muscle damage biomarkers, with the intake of pea protein having an intermediate effect.

Multi-objective evolutionary design of antibiotic treatments.

Antibiotic resistance is one of the major challenges we face in modern times. Antibiotic use, especially their overuse, is the single most important driver of antibiotic resistance. Efforts have been made to reduce unnecessary drug prescriptions, but limited work is devoted to optimising dosage regimes when they are prescribed. The design of antibiotic treatments can be formulated as an optimisation problem where candidate solutions are encoded as vectors of dosages per day. The formulation naturally gives rise to competing objectives, as we want to maximise the treatment effectiveness while minimising the total drug use, the treatment duration and the concentration of antibiotic experienced by the patient. This article combines a recent mathematical model of bacterial growth including both susceptible and resistant bacteria, with a multi-objective evolutionary algorithm in order to automatically design successful antibiotic treatments. We consider alternative formulations combining relevant objectives and constraints. Our approach obtains shorter treatments, with improved success rates and smaller amounts of drug than the standard practice of administering daily fixed doses. These new treatments consistently involve a higher initial dose followed by lower tapered doses.

Correction: Predicting the Potential for Natural Recovery of Atlantic Salmon (Salmo salar L.) Populations following the Introduction of Gyrodactylus salaris Malmberg, 1957 (Monogenea).

[This corrects the article DOI: 10.1371/journal.pone.0169168.].

Predicting the Potential for Natural Recovery of Atlantic Salmon (Salmo salar L.) Populations following the Introduction of Gyrodactylus salaris Malmberg, 1957 (Monogenea).

Gyrodactylus salaris (Monogenea, Platyhelminthes) is a notifiable freshwater pathogen responsible for causing catastrophic damage to wild Atlantic salmon stocks, most notably in Norway. In some strains of Baltic salmon (e.g., from the river Neva) however, the impact is greatly reduced due to some form of innate resistance that regulates parasite numbers, resulting in fewer host mortalities. Gyrodactylus salaris is known from 17 European states; its status in a further 35 states remains unknown; the UK, the Republic of Ireland and certain watersheds in Finland are free of the parasite. Thus, the parasite poses a serious threat if it emerges in Atlantic salmon rearing regions throughout Europe. At present, infections are generally controlled via extreme measures such as the treatment of entire river catchments with the biocide rotenone, in order to remove all hosts, before restocking with the original genetic stock. The use of rotenone in this way in EU countries is unlikely as it would be in contravention of the Water Framework Directive. Not only are such treatments economically and environmentally costly, they also eradicate the potential for any host/parasite evolutionary process to occur. Based on previous studies, UK salmon stocks have been shown to be highly susceptible to infection, analogous to Norwegian stocks. The present study investigates the impact of a G. salaris outbreak within a naïve salmon population in order to determine long-term consequences of infection and the likelihood of coexistence. Simulation of the salmon/ G. salaris system was carried out via a deterministic mathematical modelling approach to examine the dynamics of host-pathogen interactions. Results indicated that in order for highly susceptible Atlantic strains to evolve a resistance, both a moderate-strong deceleratingly costly trade-off on birth rate and a lower overall cost of the immune response are required. The present study provides insights into the potential long term impact of G. salaris if introduced into G. salaris-free territories and suggests that in the absence of external controls salmon populations are likely to recover to high densities nearing 90% of that observed pre-infection.

Reproductive trade-offs may moderate the impact of Gyrodactylus salaris in warmer climates.

Gyrodactylus salaris is a notifiable freshwater ectoparasite of salmonids. Its primary host is Atlantic salmon (Salmo salar), upon which infections can cause death, and have led to massive declines in salmon numbers in Norway, where the parasite is widespread. Different strains of S. salar vary in their susceptibility, with Atlantic strains (such as those found in Norway) exhibiting no resistance to the parasite, and Baltic strains demonstrating an innate resistance sufficient to regulate parasite numbers on the host causing it to either die out or persist at a low level. In this study, Leslie matrix and compartmental models were used to generate data that demonstrated the population growth of G. salaris on an individual host is dependent on the total number of offspring per parasite, its longevity and the timing of its births. The data demonstrated that the key factor determining the rate of G. salaris population growth is the time at which the parasite first gives birth, with rapid birth rate giving rise to large population size. Furthermore, it was shown that though the parasite can give birth up to four times, only two births are required for the population to persist as long as the first birth occurs before a parasite is three days old. As temperature is known to influence the timing of the parasite's first birth, greater impact may be predicted if introduced to countries with warmer climates than Norway, such as the UK and Ireland which are currently recognised to be free of G. salaris. However, the outputs from the models developed in this study suggest that temperature induced trade-offs between the total number of offspring the parasite gives birth to and the first birth timing may prevent increased population growth rates over those observed in Norway.

Can possible evolutionary outcomes be determined directly from the population dynamics?

Traditionally, to determine the possible evolutionary behaviour of an ecological system using adaptive dynamics, it is necessary to calculate the fitness and its derivatives at a singular point. We investigate the claim that the possible evolutionary behaviour can be predicted directly from the population dynamics, without the need for calculation, by applying three criteria - one based on the form of the density dependent rates and two on the role played by the evolving parameters. Taking a general continuous time model, with broad ecological range, we show that the claim is true. Initially, we assume that individuals enter in class 1 and move through population classes sequentially; later we relax these assumptions and find that the criteria still apply. However, when we consider models where the evolving parameters appear non-linearly in the dynamics, we find some aspects of the criteria fail; useful but weaker results on possible evolutionary behaviour now apply.

The influence of trade-off shape on evolutionary behaviour in classical ecological scenarios.

Trade-off shapes are crucial to evolutionary outcomes. However, due to different ecological feedbacks their implications may depend not only on the trade-off being considered but also the ecological scenario. Here, we apply a novel geometric technique, trade-off and invasion plots (TIPs), to examine in detail how the shape of trade-off relationships affect evolutionary outcomes under a range of classic ecological scenarios including Lotka-Volterra type and host-parasite interactions. We choose models of increasing complexity in order to gain an insight into the features of ecological systems that determine the evolutionary outcomes. In particular we focus on when evolutionary attractors, repellors and branching points occur and how this depends on whether the costs are accelerating (benefits become 'increasingly' costly), decelerating (benefits become 'decreasingly' costly) or constant. In all cases strongly accelerating costs lead to attractors while strongly decelerating ones lead to repellors, but with weaker relationships, this no longer holds. For some systems weakly accelerating costs may lead to repellors and decelerating costs may lead to attractors. In many scenarios it is weakly decelerating costs that lead to branching points, but weakly accelerating and linear costs may also lead to disruptive selection in particular ecological scenarios. Using our models we suggest a classification of ecological interactions, based on three distinct criteria, that can produce one of four fundamental TIPs which allow for different evolutionary behaviour. This provides a baseline theory which may inform the prediction of evolutionary outcomes in similar yet unexplored ecological scenarios. In addition we discuss the implications of our results to a number of specific life-history trade-offs in the classic ecological scenarios represented by our models.

When is evolutionary branching in predator-prey systems possible with an explicit carrying capacity?

In this study we use the theory of adaptive dynamics firstly to explore the differences in evolutionary behaviour of a generalist predator (or more specifically an omnivorous or intraguild predator) in a predator-prey model, with a Holling Type II functional response, when two distinct forms for the carrying capacity are used. The first of these involves the carrying capacity as an emergent property, whilst in the second it appears explicitly in the dynamics. The resultant effect this has on the intraspecific competition in each case is compared. Taking an identical trade-off in each case, we find that only with an emergent carrying capacity is evolutionary branching possible. Our study then concentrates solely on the case where the carrying capacity appears explicitly. Using the same model as above, but choosing alternate trade-offs, we find branching can occur with an explicit carrying capacity. Our investigation finishes by taking a more general functional response in an attempt to derive a condition for when branching can or cannot occur. For a predator-prey model, branching cannot occur if the functional response can be separated into two components, one a function of the population densities, X and Z, and the other a function of the evolving parameter z (traded off against the intrinsic growth rate), i.e. if F(z,X,Z) = F(1)(z)F(2)(X,Z). This search for evolutionary branching is motivated by its possible role in speciation.

The phagocytic capacity of neurones.

Phagocytosis is defined as the ingestion of particulates over 0.5 microm in diameter and is associated with cells of the immune system such as macrophages or monocytes. Neurones are not generally recognized to be phagocytic. Using light, confocal, time-lapse and electron microscopy, we carried out a wide range of in-vitro and in-vivo experiments to examine the phagocytic capacity of different neuronal cell types. We demonstrated phagocytosis of material by neurones, including cell debris and synthetic particles up to 2.8 microm in diameter. We showed phagocytosis in different neuronal types, and demonstrated that debris can be transported from neurite extremities to cell bodies and persist within neurones. Flow cytometry analysis demonstrated the lack of certain complement receptors on neurones but the presence of others, including integrin receptors known to mediate macrophage phagocytosis, indicating that a restricted set of phagocytosis receptors may mediate this process. Neuronal phagocytosis occurs in vitro and in vivo, and we propose that this is a more widespread and significant process than previously recognized. Neuronal phagocytosis may explain certain inclusions in neurones during disease, cell-to-cell spread of disease, neuronal death during disease progression and provide a potential mechanism for therapeutic intervention through the delivery of particulate drug carriers.

The geometric theory of adaptive evolution: trade-off and invasion plots.

The purpose of this paper is to take an entirely geometrical path to determine the evolutionary properties of ecological systems subject to trade-offs. In particular we classify evolutionary singularities in a geometrical fashion. To achieve this, we study trade-off and invasion plots (TIPs) which show graphically the outcome of evolution from the relationship between three curves. The first invasion boundary (curve) has one strain as resident and the other strain as putative invader and the second has the roles of the strains reversed. The parameter values for one strain are used as the origin with those of the second strain varying. The third curve represents the trade-off. All three curves pass through the origin or tip of the TIP. We show that at this point the invasion boundaries are tangential. At a singular TIP, in which the origin is an evolutionary singularity, the invasion boundaries and trade-off curve are all tangential. The curvature of the trade-off curve determines the region in which it enters the singular TIP. Each of these regions has particular evolutionary properties (EUS, CS, SPR and MI). Thus we determine by direct geometric argument conditions for each of these properties in terms of the relative curvatures of the trade-off curve and invasion boundaries. We show that these conditions are equivalent to the standard partial derivative conditions of adaptive dynamics. The significance of our results is that we can determine whether the singular strategy is an attractor, branching point, repellor, etc. simply by observing in which region the trade-off curve enters the singular TIP. In particular we find that, if and only if the TIP has a region of mutual invadability, is it possible for the singular strategy to be a branching point. We illustrate the theory with an example and point the way forward.