Evolution of virulence in opportunistic pathogens: generalism, plasticity, and control

Standard virulence evolution theory assumes that virulence factors are maintained because they aid parasitic exploitation, increasing growth within and/or transmission between hosts. An increasing number of studies now demonstrate that many opportunistic pathogens (OPs) do not conform to these assumptions, with virulence factors maintained instead because of advantages in non-parasitic contexts. Here we review virulence evolution theory in the context of OPs and highlight the importance of incorporating environments outside a focal virulence site. We illustrate that virulence selection is constrained by correlations between these external and focal settings and pinpoint drivers of key environmental correlations, with a focus on generalist strategies and phenotypic plasticity. We end with a summary of key theoretical and empirical challenges to be met for a fuller understanding of OPs

Synergy and Group Size in Microbial Cooperation

Microbes produce many molecules that are important for their growth and development, and the consumption of these secretions by nonproducers has recently become an important paradigm in microbial social evolution. Though the production of these public goods molecules has been studied intensely, little is known of how the benefits accrued and costs incurred depend on the quantity of public good molecules produced. We focus here on the relationship between the shape of the benefit curve and cellular density with a model assuming three types of benefit functions: diminishing, accelerating, and sigmoidal (accelerating then diminishing). We classify the latter two as being synergistic and argue that sigmoidal curves are common in microbial systems. Synergistic benefit curves interact with group sizes to give very different expected evolutionary dynamics. In particular, we show that whether or not and to what extent microbes evolve to produce public goods depends strongly on group size. We show that synergy can create an “evolutionary trap” which can stymie the establishment and maintenance of cooperation. By allowing density dependent regulation of production (quorum sensing), we show how this trap may be avoided. We discuss the implications of our results for experimental design

A comparison of model ensembles for attributing 2012 West African rainfall

In 2012, heavy rainfall resulted in flooding and devastating impacts across West Africa. With many people highly vulnerable to such events in this region, this study investigates whether anthropogenic climate change has influenced such heavy precipitation events. We use a probabilistic event attribution approach to assess the contribution of anthropogenic greenhouse gas emissions, by comparing the probability of such an event occurring in climate model simulations with all known climate forcings to those where natural forcings only are simulated. An ensemble of simulations from 10 models from the Coupled Model Intercomparison Project Phase 5 (CMIP5) is compared to two much larger ensembles of atmosphere-only simulations, from the Met Office model HadGEM3-A and from weather@home with a regional version of HadAM3P. These are used to assess whether the choice of model ensemble influences the attribution statement that can be made. Results show that anthropogenic greenhouse gas emissions have decreased the probability of high precipitation across most of the model ensembles. However, the magnitude and confidence intervals of the decrease depend on the ensemble used, with more certainty in the magnitude in the atmosphere-only model ensembles due to larger ensemble sizes from single models with more constrained simulations. Certainty is greatly decreased when considering a CMIP5 ensemble that can represent the relevant teleconnections due to a decrease in ensemble members. An increase in probability of high precipitation in HadGEM3-A using the observed trend in sea surface temperatures (SSTs) for natural simulations highlights the need to ensure that estimates of natural SSTs are consistent with observed trends in order for results to be robust. Further work is needed to establish how anthropogenic forcings are affecting the rainfall processes in these simulations in order to better understand the differences in the overall effect

What do changing weather and climate shocks and stresses mean for the UK food system?

In light of the publication of Henry Dimbleby’s National Food Strategy (www.nationalfoodstrategy. org/) and the COP26 climate meeting in Glasgow, it is timely to consider the impacts of weather and climate extremes on the UK food system. Climate change-driven changes in extreme weather events are one of the highest-risk future shocks to the UK food system [1], underlining the importance of preparedness across the food chain [2]. Here, we identify major knowledge gaps in the primary impacts of extreme weather and climate change across the UK’s food system, its functioning and their interactions to provide information to support adaptation and resilience planning. Research tends to focus on individual food system activities rather than taking a systematic approach [3, 4]. How- ever, strong evidence exists about the impacts of long- term climate trends and extremes [5] on primary food production [6]. The major knowledge gaps therefore concern post-primary production dimensions [4], notably food system activities between the ‘farm-gate’ and consumption—which are the core focus of this paper (supplementary material S1 available online at stacks.iop.org/ERL/17/051001/mmedia). These constitute major economic and social dimensions but are often the ‘missing middle’ in food system discus- sions. We use the UK food system as an illustrative case study, and consider both global and domestic risks and implications. We present methods, tools and frameworks for systemic analysis of climate impacts on food systems, consider the funding landscape, and highlight priorities for future research

Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells

Erratic Flu Vaccination Emerges from Short-Sighted Behavior in Contact Networks

The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior

Bacterial Cooperation Causes Systematic Errors in Pathogen Risk Assessment due to the Failure of the Independent Action Hypothesis

The Independent Action Hypothesis (IAH) states that pathogenic individuals (cells, spores, virus particles etc.) behave independently of each other, so that each has an independent probability of causing systemic infection or death. The IAH is not just of basic scientific interest; it forms the basis of our current estimates of infectious disease risk in humans. Despite the important role of the IAH in managing disease interventions for food and water-borne pathogens, experimental support for the IAH in bacterial pathogens is indirect at best. Moreover since the IAH was first proposed, cooperative behaviors have been discovered in a wide range of microorganisms, including many pathogens. A fundamental principle of cooperation is that the fitness of individuals is affected by the presence and behaviors of others, which is contrary to the assumption of independent action. In this paper, we test the IAH in Bacillus thuringiensis (B.t), a widely occurring insect pathogen that releases toxins that benefit others in the inoculum, infecting the diamondback moth, Plutella xylostella. By experimentally separating B.t. spores from their toxins, we demonstrate that the IAH fails because there is an interaction between toxin and spore effects on mortality, where the toxin effect is synergistic and cannot be accommodated by independence assumptions. Finally, we show that applying recommended IAH dose-response models to high dose data leads to systematic overestimation of mortality risks at low doses, due to the presence of synergistic pathogen interactions. Our results show that cooperative secretions can easily invalidate the IAH, and that such mechanistic details should be incorporated into pathogen risk analysis

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme