Contrasting evolution of virulence and replication rate in an emerging bacterial pathogen

This is the final version. Available on open access from the National Academy of Sciences via the DOI in this recordData deposition: Data reported in this paper have been deposited in Dryad Digital Repository (doi:10.5061/dryad.km3109k).Host resistance through immune clearance is predicted to favor pathogens that are able to transmit faster and are hence more virulent. Increasing pathogen virulence is, in turn, typically assumed to be mediated by increasing replication rates. However, experiments designed to test how pathogen virulence and replication rates evolve in response to increasing host resistance, as well as the relationship between the two, are rare and lacking for naturally evolving host–pathogen interactions. We inoculated 55 isolates of Mycoplasma gallisepticum, collected over 20 y from outbreak, into house finches (Haemorhous mexicanus) from disease-unexposed populations, which have not evolved protective immunity to M. gallisepticum. We show using 3 different metrics of virulence (body mass loss, symptom severity, and putative mortality rate) that virulence has increased linearly over >150,000 bacterial generations since outbreak (1994 to 2015). By contrast, while replication rates increased from outbreak to the initial spread of resistance (1994 to 2004), no further increases have occurred subsequently (2007 to 2015). Finally, as a consequence, we found that any potential mediating effect of replication rate on virulence evolution was restricted to the period when host resistance was initially increasing in the population. Taken together, our results show that pathogen virulence and replication rates can evolve independently, particularly after the initial spread of host resistance. We hypothesize that the evolution of pathogen virulence can be driven primarily by processes such as immune manipulation after resistance spreads in host populations.Natural Environment Research Council (NERC

Northward advection of Atlantic water in the eastern Nordic Seas over the last 3000 yr

Three marine sediment cores distributed along the Norwegian (MD95-2011), Barents Sea (JM09-KA11-GC), and Svalbard (HH11-134-BC) continental margins have been investigated in order to reconstruct changes in the poleward flow of Atlantic waters (AW) and in the nature of upper surface water masses within the eastern Nordic Seas over the last 3000 yr. These reconstructions are based on a limited set of coccolith proxies: the abundance ratio between Emiliania huxleyi and Coccolithus pelagicus, an index of Atlantic vs. Polar/Arctic surface water masses; and Gephyrocapsa muellerae, a drifted coccolith species from the temperate North Atlantic, whose abundance changes are related to variations in the strength of the North Atlantic Current. The entire investigated area, from 66 to 77 N, was affected by an overall increase in AWflow from 3000 cal yr BP (before present) to the present. The long-term modulation of westerlies’ strength and location, which are essentially driven by the dominant mode of the North Atlantic Oscillation (NAO), is thought to explain the observed dynamics of poleward AW flow. The same mechanism also reconciles the recorded opposite zonal shifts in the location of the Arctic front between the area off western Norway and the western Barents Sea–eastern Fram Strait region. The Little Ice Age (LIA) was governed by deteriorating conditions, with Arctic/Polar waters dominating in the surface off western Svalbard and western Barents Sea, possibly associated with both severe sea ice conditions and a strongly reduced AW strength. A sudden short pulse of resumed high WSC (West Spitsbergen Current) flow interrupted this cold spell in eastern Fram Strait from 330 to 410 cal yr BP. Our dataset not only confirms the high amplitude warming of surface waters at the turn of the 19th century off western Svalbard, it also shows that such a warming was primarily induced by an excess flow of AW which stands as unprecedented over the last 3000 yr

Rapid antagonistic coevolution in an emerging pathogen and its vertebrate host

This is the final version of the article. Available from Elsevier via the DOI in this record.Host-pathogen coevolution is assumed to play a key role in eco-evolutionary processes, including epidemiological dynamics and the evolution of sexual reproduction [1-4]. Despite this, direct evidence for host-pathogen coevolution is exceptional [5-7], particularly in vertebrate hosts. Indeed, although vertebrate hosts have been shown to evolve in response to pathogens or vice versa [8-12], there is little evidence for the necessary reciprocal changes in the success of both antagonists over time [13]. Here, we generate a time-shift experiment to demonstrate adaptive, reciprocal changes in North American house finches (Haemorhous mexicanus) and their bacterial pathogen, Mycoplasma gallisepticum [14-16]. Our experimental design is made possible by the existence of disease-exposed and unexposed finch populations, which were known to exhibit equivalent responses to experimental inoculation until the recent spread of genetic resistance in the former [14, 17]. While inoculation with pathogen isolates from epidemic outbreak caused comparable sub-lethal eye-swelling in hosts from exposed (hereafter adapted) and unexposed (hereafter ancestral) populations, inoculation with isolates sampled after the spread of resistance were threefold more likely to cause lethal symptoms in hosts from ancestral populations. Similarly, the probability that pathogens successfully established an infection in the primary host and, before inducing death, transmitted to an uninfected sentinel was highest when recent isolates were inoculated in hosts from ancestral populations and lowest when early isolates were inoculated in hosts from adapted populations. Our results demonstrate antagonistic host-pathogen coevolution, with hosts and pathogens displaying increased resistance and virulence in response to each other over time.This research was supported by a Natural Environment Research Council standard grant to C.B. (NE/M00256X)

Characterization of Susceptibility Artifacts in MR-thermometry PRFS-based during Laser Interstitial Thermal Therapy

Magnetic Resonance Thermometry (MRT) is demonstrating huge abilities to guide laser interstitial thermal therapy (LITT) in several organs, such as the brain. Among the methods to perform MRT, Proton Resonance Frequency (PRF) shift holds significant benefits, like tissue independence. Despite its potential, PRF shift-based MRT holds significant challenges affecting the accuracy of reconstructed temperature maps. In particular, susceptibility artifacts due to gas-bubble formation are an important source of error in temperature maps in MRT-guided LITT. This work presents the characterization of the susceptibility artifacts in MRT-guided LITT and the measurement of its size. LITT was performed in gelatin-based phantoms, at 5 W, 2 W, 1 W, and 0.5 W under MRI guidance with a 1.5 T clinical MRI scanner. Temperature images were obtained with a 3D EPI (Echo planar imaging) prototype sequence. Areas of temperature errors were defined as zones of negative temperature variation <-2 degrees C. Moreover, we have analyzed the artifact shape in sagittal, axial and coronal planes. The analysis demonstrates a double-lobe shape for the susceptibility artifact mainly distributed in the sagittal plane. Also, the higher laser power caused a bigger artifact area. Temperature errors of similar to 80 degrees C proved the necessity to avoid susceptibility artifact generation during MRT-guided LITT. The analysis of the influence of the laser power on the artifact has suggested that using low laser power (0.5 W) helps avoid this measurement error

An experimental test in Mallards ( Anas platyrhynchos ) of the effect of incubation and maternal preen oil on eggshell microbial load

Microbial infection is one of the main factors reducing survival in the first stages of life in oviparous species, and recent studies have shown that the avian eggshell harbors an important variety of microorganisms that can rapidly multiply and penetrate the shell, leading to a decrease in hatchability. Here, we report the results of an experiment in which we examined how incubation and maternal preen oil affect the growth of avian eggshell microbes, using the Mallard (Anas platyrhynchos) as a model species. We compared the bacterial and fungal loads on the shell of non-incubated eggs and eggs incubated by females having free or blocked access to their preen gland. An increase of eggshell bacterial loads was observed in all conditions, but bacterial growth was higher on the shell of incubated eggs than on non-incubated eggs. We did not find any significant difference in eggshell bacterial growth for eggs incubated by females with free or blocked access to their preen gland. In addition, fungal growth during our experiment was not affected by incubation or the mother's preen oil. Our findings are in contrast with those of previous studies which showed that incubation limited or had no effect on eggshell bacterial growth. Differences in environmental conditions and/or species ecology may explain the difference between the results of our experiment and those of previous studies. Our study provides the first data on the effect of maternal preen oil on eggshell microorganisms, showing that preen oil does not limit eggshell microbial growth

Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials

Taljaard, M., Goldstein, C. E., Giraudeau, B., Nicholls, S. G., Carroll, K., Hey, S. P., … Weijer, C. (2020). Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials. Clinical Trials. Copyright © The Author(s), 2020. DOI: https://doi.org/10.1177/174077451989679

Treatment of chronic hepatitis C in patients unresponsive to interferon. Interest of re-treatment combining interferon induction therapy and ribavirin (a multicenter pilot study)

Aim About 45% of patients with chronic hepatitis C are unresponsive to the present reference treatment combining pegelated interferon plus ribavirin; before pegylated interferon was available the non-response rate was around 60%. This open multicenter pilot study, initiated before pegylated interferon became available, was designed to evaluate, in patients unresponsive to interferon monotherapy, the rate of biological and virological response and side-effects of the ribivirin- alpha 2b interferon combination. Methods The combination protocol was ribavirin (1 to 1.2 g/d) plus alpha 2b interferon at induction doses (9 MU/d the first week; 4.5 MU/d the eleven following weeks; 3 MU/2 days the 36 following weeks). Results Among the 27 included patients, 17 (63%) were viremia-negative (PCR) after 12 weeks of treatment, 9 (33%) were complete responders (undetectable viremia and normal transaminases) at the end of treatment (48 weeks) and of follow-up (72 weeks). Patients with non-1, non-4 genotypes who derived full benefit from this therapeutic strategy (6/7 (86%) were complete responders: 4/5 with genotype 3 and 2/2 with genotype 5). Quality-of-life was impaired during treatment, especially during the first 12 weeks of high-dose interferon therapy. Conclusion While waiting for new therapeutic possibilities, these good results suggest interferon induction at the beginning of treatment remains a valid option

Experimental evidence for stabilizing selection on virulence in a bacterial pathogen

This is the final version. Available on open access from Wiley via the DOI in this recordData archiving: Data reported in this paper have been deposited in Dryad Digital Repository (https://doi.org/10.5061/dryad.9cnp5hqgh).The virulence‐transmission trade‐off hypothesis has provided a dominant theoretical basis for predicting pathogen virulence evolution, but empirical tests are rare, particularly at pathogen emergence. The central prediction of this hypothesis is that pathogen fitness is maximized at intermediate virulence due to a trade‐off between infection duration and transmission rate. However, obtaining sufficient numbers of pathogen isolates of contrasting virulence to test the shape of relationships between key pathogen traits, and doing so without the confounds of evolved host protective immunity (as expected at emergence), is challenging. Here, we inoculated 55 isolates of the bacterial pathogen, Mycoplasma gallisepticum, into non‐resistant house finches (Haemorhous mexicanus) from populations that have never been exposed to the disease. Isolates were collected over a 20‐year period from outbreak in disease‐exposed populations of house finches and vary markedly in virulence. We found a positive linear relationship between pathogen virulence and transmission rate to an uninfected sentinel, supporting the core assumption of the trade‐off hypothesis. Further, in support of the key prediction, there was no evidence for directional selection on a quantitative proxy of pathogen virulence and, instead, isolates of intermediate virulence were fittest. Surprisingly, however, the positive relationship between virulence and transmission rate was not underpinned by variation in pathogen load or replication rate as is commonly assumed. Our results indicate that selection favors pathogens of intermediate virulence at disease emergence in a novel host species, even when virulence and transmission are not linked to pathogen load.Natural Environment Research Council (NERC

Timeline cluster: a graphical tool to identify risk of bias in cluster randomised trials

Robust evidence of the effectiveness of interventions relating to policy, practice, and organisation of healthcare often comes from well conducted cluster randomised trials. Such trials are, however, prone to recruitment bias depending on whether participants are recruited before the randomisation of clusters and whether the recruiter is blinded to the allocation status. In most cases, participants and trial staff cannot be blinded to the intervention, which might lead to performance and detection bias. Unfortunately, cluster trial reports often do not provide a clear description of the timing of trial processes and blinding, and these aspects are not covered by current reporting tools. This article proposes a graphical tool depicting the time sequence of steps and blinding status in cluster randomised trials. The tool might be helpful at both the protocol and the report writing stages to clarify the process and to help identify potential bias in cluster randomised trials