Extreme Dysbiosis of the Microbiome in Critical Illness.

Critical illness is hypothesized to associate with loss of "health-promoting" commensal microbes and overgrowth of pathogenic bacteria (dysbiosis). This dysbiosis is believed to increase susceptibility to nosocomial infections, sepsis, and organ failure. A trial with prospective monitoring of the intensive care unit (ICU) patient microbiome using culture-independent techniques to confirm and characterize this dysbiosis is thus urgently needed. Characterizing ICU patient microbiome changes may provide first steps toward the development of diagnostic and therapeutic interventions using microbiome signatures. To characterize the ICU patient microbiome, we collected fecal, oral, and skin samples from 115 mixed ICU patients across four centers in the United States and Canada. Samples were collected at two time points: within 48 h of ICU admission, and at ICU discharge or on ICU day 10. Sample collection and processing were performed according to Earth Microbiome Project protocols. We applied SourceTracker to assess the source composition of ICU patient samples by using Qiita, including samples from the American Gut Project (AGP), mammalian corpse decomposition samples, childhood (Global Gut study), and house surfaces. Our results demonstrate that critical illness leads to significant and rapid dysbiosis. Many taxons significantly depleted from ICU patients versus AGP healthy controls are key "health-promoting" organisms, and overgrowth of known pathogens was frequent. Source compositions of ICU patient samples are largely uncharacteristic of the expected community type. Between time points and within a patient, the source composition changed dramatically. Our initial results show great promise for microbiome signatures as diagnostic markers and guides to therapeutic interventions in the ICU to repopulate the normal, "health-promoting" microbiome and thereby improve patient outcomes. IMPORTANCE Critical illness may be associated with the loss of normal, "health promoting" bacteria, allowing overgrowth of disease-promoting pathogenic bacteria (dysbiosis), which, in turn, makes patients susceptible to hospital-acquired infections, sepsis, and organ failure. This has significant world health implications, because sepsis is becoming a leading cause of death worldwide, and hospital-acquired infections contribute to significant illness and increased costs. Thus, a trial that monitors the ICU patient microbiome to confirm and characterize this hypothesis is urgently needed. Our study analyzed the microbiomes of 115 critically ill subjects and demonstrated rapid dysbiosis from unexpected environmental sources after ICU admission. These data may provide the first steps toward defining targeted therapies that correct potentially "illness-promoting" dysbiosis with probiotics or with targeted, multimicrobe synthetic "stool pills" that restore a healthy microbiome in the ICU setting to improve patient outcomes

Patch behaviour and predictability propierties of modelled finite-amplitude sand ridges on the inner shelf

The long-term evolution of shoreface-connected sand ridges is investigated with a nonlinear spectral model which governs the dynamics of waves, currents, sediment transport and the bed level on the inner shelf. Wave variables are calculated with a shoaling-refraction model instead of using a parameterisation. The spectral model describes the time evolution of amplitudes of known eigenmodes of the linearised system. Bottom pattern formation occurs if the transverse bottom slope of the inner shelf, β, exceeds a critical value βc. For fixed model parameters the sensitivity of the properties of modelled sand ridges to changes in the number (N−1) of resolved subharmonics (of the initially fastest growing mode) is investigated. For any N the model shows the growth and subsequent saturation of the height of the sand ridges. The saturation time scale is several thousands of years, which suggests that observed sand ridges have not reached their saturated stage yet. The migration speed of the ridges and the average longshore spacing between successive crests in the saturated state differ from those in the initial state. Analysis of the potential energy balance of the ridges reveals that bed slope-induced sediment transport is crucial for the saturation process. In the transient stage the shoreface-connected ridges occur in patches. The overall characteristics of the bedforms (saturation time, final maximum height, average longshore spacing, migration speed) hardly vary with N. However, individual time series of modal amplitudes and bottom patterns strongly depend on N, thereby implying that the detailed evolution of sand ridges can only be predicted over a limited time interval. Additional experiments show that the critical bed slope βc increases with larger offshore angles of wave incidence, larger offshore wave heights and longer wave periods, and that the corresponding maximum height of the ridges decreases whilst the saturation time increases.Postprint (published version

T-profiler: scoring the activity of predefined groups of genes using gene expression data

One of the key challenges in the analysis of gene expression data is how to relate the expression level of individual genes to the underlying transcriptional programs and cellular state. Here we describe T-profiler, a tool that uses the t-test to score changes in the average activity of predefined groups of genes. The gene groups are defined based on Gene Ontology categorization, ChIP-chip experiments, upstream matches to a consensus transcription factor binding motif or location on the same chromosome. If desired, an iterative procedure can be used to select a single, optimal representative from sets of overlapping gene groups. T-profiler makes it possible to interpret microarray data in a way that is both intuitive and statistically rigorous, without the need to combine experiments or choose parameters. Currently, gene expression data from Saccharomyces cerevisiae and Candida albicans are supported. Users can upload their microarray data for analysis on the web at

Scaling mechanisms of energy communities: A comparison of 28 initiatives

Energy communities have mushroomed over the past decades. These initiatives have scaled, that is replicated their experiences, expanded membership, and diversified involved actors and technologies. The picture existing literature paints is hopeful that the scaling of local-scale action may translate into global-scale impact and thus effectively contribute to combating climate change. However, important gaps remain in understanding the (combinations of) conditions which are necessary for scaling with this goal in mind. This article pushes the boundaries of knowledge further by examining and comparing 28 energy communities through a fuzzy set Qualitative Comparative Analysis (QCA) and by identifying the necessary conditions of actionable scaling mechanisms. Our analysis identifies a high number (8) of necessary (combinations of) conditions for scaling. Addressing a strong need amongst policy makers to facilitate broader scaling of community initiatives, this article offers concrete insights on mechanisms that need to be in place to scale energy communities. Insights are developed on – for example – the type of capacity support needed, support structures and the tools needed for connecting communities with each other. These insights help corroborate empirically, for the first time the crucial leverage points that will support strategies for upscaling the impact of energy communities, and will enable them to flourish as an essential element of the global climate governance system

Detecting Regulatory Mechanisms in Endocrine Time Series Measurements

The regulatory mechanisms underlying pulsatile secretion are complex, especially as it is partly controlled by other hormones and the combined action of multiple agents. Regulatory relations between hormones are not directly observable but may be deduced from time series measurements of plasma hormone concentrations. Variation in plasma hormone levels are the resultant of secretion and clearance from the circulation. A strategy is proposed to extract inhibition, activation, thresholds and circadian synchronicity from concentration data, using particular association methods. Time delayed associations between hormone concentrations and/or extracted secretion pulse profiles reveal the information on regulatory mechanisms. The above mentioned regulatory mechanisms are illustrated with simulated data. Additionally, data from a lean cohort of healthy control subjects is used to illustrate activation (ACTH and cortisol) and circadian synchronicity (ACTH and TSH) in real data. The simulation and the real data both consist of 145 equidistant samples per individual, matching a 24-hr time span with 10 minute intervals. The results of the simulation and the real data are in concordance

Prospect theory, mitigation and adaptation to climate change

Climate change is one of the most pressing challenges in current environmental policy. Appropriate policies intended to stimulate efficient adaptation and mitigation should not exclusively rely on the assumption of the homo oeconomicus, but take advantage of well-researched alternative behavioural patterns. Prospect theory provides a number of climate-relevant insights, such as the notion that evaluations of outcomes are reference dependent, and the relevance of perceived certainty of outcomes. This paper systematically reviews what prospect theory can offer to analyse mitigation and adaptation. It is shown that accounting for reference dependence and certainty effects contributes to a better understanding of some well-known puzzles in the climate debate, including (but not limited to) the different uptake of mitigation and adaptation amongst individuals and nations, the role of technical vs. financial adaptation, and the apparent preference for hard protection measures in coastal adaptation. Finally, concrete possibilities for empirical research on these effects are proposed

Whole genome sequencing of 378 prostate cancer metastases reveals tissue selectivity for mismatch deficiency with potential therapeutic implications

Background: Survival of patients with metastatic castration-resistant prostate cancer (mCRPC) depends on the site of metastatic dissemination. Methods: Patients with mCRPC were prospectively included in the CPCT-02 metastatic site biopsy study. We evaluated whole genome sequencing (WGS) of 378 mCRPC metastases to understand the genetic traits that affect metastatic site distribution. Results: Our findings revealed that RB1, PIK3CA, JAK1, RNF43, and TP53 mutations are the most frequent genetic determinants associated with site selectivity for metastatic outgrowth. Furthermore, we explored mutations in the non-coding genome and found that androgen receptor (AR) chromatin binding sites implicated in metastatic prostate cancer differ in mutation frequencies between metastatic sites, converging on pathways that impact DNA repair. Notably, liver and visceral metastases have a higher tumor mutational load (TML) than bone and lymph node metastases, independent of genetic traits associated with neuroendocrine differentiation. We found that TML is strongly associated with DNA mismatch repair (MMR)-deficiency features in these organs. Conclusions: Our results revealed gene mutations that are significantly associated with metastatic site selectivity and that frequencies of non-coding mutations at AR chromatin binding sites differ between metastatic sites. Immunotherapeutics are thus far unsuccessful in unselected mCRPC patients. We found a higher TML in liver and visceral metastases compared to bone and lymph node metastases. As immunotherapeutics response is associated with mutational burden, these findings may assist in selecting mCRPC patients for immunotherapy treatment based on organs affected by metastatic disease. Trial registration number: NCT01855477.</p

Why and how do political actors pursue risky welfare state reforms?

Why and how do political actors pursue risky welfare state reforms, in spite of the institutional mechanisms and political resistance that counteract change? This is one of the key puzzles of contemporary welfare state research, which is brought about by the absence of a complete account that identifies both the cause and causal mechanisms of risky reforms. In this article we offer a remedy for this lacuna. Prospect theory teaches us that political actors will only undertake risky reforms if they consider themselves to be in a losses domain, that is when their current situation is unacceptable. Next, we discuss the strategies that political actors use to avoid the blame associated with risky reforms. These provide the causal mechanisms linking cause and effect. The sudden outburst of risky reforms in formerly 'immovable' Italy provides an empirical illustration of our account. Copyright © 2007 Sage Publications

Global urbanization and food production in direct competition for land: Leverage places to mitigate impacts on SDG2 and on the Earth System

Global urbanization and food production are in direct competition for land. This paper carries out a critical review of how displacing crop production from urban and peri-urban land to other areas – because of issues related to soil quality – will demand a substantially larger proportion of the Earth’s terrestrial land surface than the surface area lost to urban encroachment. Such relationships may trigger further distancing effects and unfair social-ecological teleconnections. It risks also setting in motion amplifying effects within the Earth System. In combination, such multiple stressors set the scene for food riots in cities of the Global South. Our review identifies viable leverage points on which to act in order to navigate urban expansion away from fertile croplands. We first elaborate on the political complexities in declaring urban and peri-urban lands with fertile soils as one global commons. We find that the combination of an advisory global policy aligned with regional policies enabling robust common properties rights for bottom-up actors and movements in urban and peri-urban agriculture (UPA) as multi-level leverage places to intervene. To substantiate the ability of aligning global advisory policy with regional planning, we review both past and contemporary examples where empowering local social-ecological UPA practices and circular economies have had a stimulating effect on urban resilience and helped preserve, restore, and maintain urban lands with healthy soils