Known unknowns: building an ethics of uncertainty into genomic medicine

Background Genomic testing has reached the point where, technically at least, it can be cheaper to undertake panel-, exome- or whole genome testing than it is to sequence a single gene. An attribute of these approaches is that information gleaned will often have uncertain significance. In addition to the challenges this presents for pre-test counseling and informed consent, a further consideration emerges over how - ethically - we should conceive of and respond to this uncertainty. To date, the ethical aspects of uncertainty in genomics have remained under-explored. Discussion In this paper, we draft a conceptual and ethical response to the question of how to conceive of and respond to uncertainty in genomic medicine. After introducing the problem, we articulate a concept of ‘genomic uncertainty’. Drawing on this, together with exemplar clinical cases and related empirical literature, we then critique the presumption that uncertainty is always problematic and something to be avoided, or eradicated. We conclude by outlining an ‘ethics of genomic uncertainty’; describing how we might handle uncertainty in genomic medicine. This involves fostering resilience, welfare, autonomy and solidarity. Conclusions Uncertainty will be an inherent aspect of clinical practice in genomics for some time to come. Genomic testing should not be offered with the explicit aim to reduce uncertainty. Rather, uncertainty should be appraised, adapted to and communicated about as part of the process of offering and providing genomic information. Keywords Ethics Uncertainty Genomics Clinical genomics Massively parallel sequencing Genome sequencing Genomic testing Genetic counseling Rare diseases Variants of uncertain significanc

Mathematical modelling of chemical agent removal by reaction with an immiscible cleanser

When a hazardous chemical agent has soaked into a porous medium, such as concrete, it can be difficult to neutralise. One removal method is chemical decontamination, where a cleanser is applied to react with and neutralise the agent, forming less harmful reaction products. There are often several cleansers that could be used to neutralise the same agent, so it is important to identify the cleanser features associated with fast and effective decontamination. As many cleansers are aqueous solutions while many agents are immiscible with water, the decontamination reaction often takes place at the interface between two phases. In this paper, we develop and analyse a mathematical model of a decontamination reaction between a neat agent and an immiscible cleanser solution. We assume that the reaction product is soluble in both the cleanser phase and the agent phase. At the moving boundary between the two phases, we obtain coupling conditions from mass conservation arguments and the oil–water partition coefficient of the product. We analyse our model using both asymptotic and numerical methods, and investigate how different features of a cleanser affect the time taken to remove the agent. Our results reveal the existence of two regimes characterised by different rate-limiting transport processes, and we identify the key parameters that control the removal time in each regime. In particular, we find that the oil–water partition coefficient of the reaction product is significantly more important in determining the removal time than the effective reaction rate

The Water–Amorphous Calcium Carbonate Interface and Its Interactions with Amino Acids

Amorphous calcium carbonate is often the first phase to precipitate during the mineralisation of calcium carbonate, before the formation of one of the crystalline polymorphs. In vivo, this phase is believed to be essential for the manufacture of minerals displaying non-equilibrium morphologies. The precipitation of this, usually transient, phase and its subsequent transformation into one of the crystalline polymorphs can be controlled by organic molecules. Here, we present a series of Molecular Dynamics simulations that explore the amorphous calcium carbonate – water interface, the attachment of amino acids onto both hydrous and anhydrous amorphous calcium carbonate and their effect on the surface. The results show that surface ions have a different coordination number distribution from bulk ions and can diffuse up to two orders of magnitude faster than their bulk counterparts, suggesting that crystallisation is much more likely to occur in this region. All the amino acids investigated bind to the amorphous calcium carbonate surfaces. However, acidic amino acids have a clear preference for the surface of amorphous CaCO3.H2O. The favoured mode of interaction of the amino acids is through amine and/or guanidine moieties. The important ramifications of the results for our understanding of protein-mineral interactions are discussed

Using simulation to understand the structure and properties of hydrated amorphous calcium carbonate

We report results from studies using four different protocols to prepare hydrated amorphous calcium carbonate, ranging from random initial structures to melting hydrated mineral structures. All protocols give good agreement with experimental X-ray structure factors. However, the thermodynamic properties, ion coordination environments, and distribution of water for the structures produced by the protocols show statistically significant variation depending on the protocols used. We discuss the diffusivity of water through the various structures and its relation to experiments. We show that one protocol (based on melting ikaite) gives a structure where the water is mobile, due to the presence of porosity in the amorphous structure. We conclude that our models of hydrated amorphous calcium carbonate do give a range of behaviour that resembles that observed experimentally, although the variation is less marked in the simulations than in experiments

Contexting Koreans: Does the High/Low Model Work?

South Korea is assumed to be a high-context culture with extensive shared information and an emphasis on relationships in doing business. The follow ing study reported here tests this assumption and illustrates similarities and differences between Korean and American writers in an attempt to document language differences between high- and low- context societies. Data in the texts studied did not confirm the high/low contextfeatures expected. South Korean texts showed more similarities to than differences from the American texts, and the language features found suggest a more complex context situa tion than the high/low context model may be able to accommodate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66563/2/10.1177_108056999806100403.pd

Product Groups, Discrete Symmetries, and Grand Unification

We study grand unified theories based on an SU(5)xSU(5) gauge group in which the GUT scale, M_{GUT}, is the VEV of an exact or approximate modulus, and in which fast proton decay is avoided through a combination of a large triplet mass and small triplet couplings. These features are achieved by discrete symmetries. In many of our models, M_{GUT} is generated naturally by the balance of higher dimension terms that lift the GUT modulus potential, and soft supersymmetry breaking masses. The theories often lead to interesting patterns of quark and lepton masses. We also discuss some distinctions between grand unified theories and string unification.Comment: 23 pages; no figures; revtex

Ecosystem Capacity for Microbial Biodegradation of Munitions Compounds and Phenanthrene in Three Coastal Waterways in North Carolina, United States

Munitions compounds (i.e., 2,4,6-trinitrotoluene (TNT), octahy-dro-1,3,5,7-tetranitro-1,3,5,7-tetrazocin (HMX), and hexadydro-1,3,5-trinitro-1,3,5-triazin (RDX), also called energetics) were originally believed to be recalcitrant to microbial biodegradation based on historical groundwater chemical attenuation data and laboratory culture work. More recently, it has been established that natural bacterial assemblages in coastal waters and sediment can rapidly metabolize these organic nitrogen sources and even incorporate their carbon and nitrogen into bacterial biomass. Here, we report on the capacity of natural microbial assemblages in three coastal North Carolina (United States) estuaries to metabolize energetics and phenanthrene (PHE), a proxy for terrestrial aromatic compounds. Microbial assemblages generally had the highest ecosystem capacity (mass of the compound mineralized per average estuarine residence time) for HMX (21-5463 kg) RDX (1.4-5821 kg) PHE (0.29-660 kg) TNT (0.25-451 kg). Increasing antecedent precipitation tended to decrease the ecosystem capacity to mineralize TNT in the Newport River Estuary, and PHE and TNT mineralization were often highest with increasing salinity. There was some evidence from the New River Estuary that increased N-demand (due to a phytoplankton bloom) is associated with increased energetic mineralization rates. Using this type of analysis to determine the ecosystem capacity to metabolize energetics can explain why these compounds are rarely detected in seawater and marine sediment, despite the known presence of unexploded ordnance or recent use in military training exercises. Overall, measuring the ecosystem capacity may help predict the effects of climate change (warming and altered precipitation patterns) and other perturbations on exotic compound fate and transport within ecosystems and provide critical information for managers and decision-makers to develop management strategies based on these changes

Riverine Discharge and Phytoplankton Biomass Control Dissolved and Particulate Organic Matter Dynamics over Spatial and Temporal Scales in the Neuse River Estuary, North Carolina

Estuaries function as important transporters, transformers, and producers of organic matter (OM). Along the freshwater to saltwater gradient, the composition of OM is influenced by physical and biogeochemical processes that change spatially and temporally, making it difficult to constrain OM in these ecosystems. In addition, many of the environmental parameters (temperature, precipitation, riverine discharge) controlling OM are expected to change due to climate change. To better understand the environmental drivers of OM quantity (concentration) and quality (absorbance, fluorescence), we assessed both dissolved OM (DOM) and particulate OM (POM) spatially, along the freshwater to saltwater gradient and temporally, for a full year. We found seasonal differences in salinity throughout the estuary due to elevated riverine discharge during the late fall to early spring, with corresponding changes to OM quantity and quality. Using redundancy analysis, we found DOM covaried with salinity (adjusted r2 = 0.35, 0.41 for surface and bottom), indicating terrestrial sources of DOM in riverine discharge were the dominant DOM sources throughout the estuary, while POM covaried with environmental indictors of terrestrial sources (turbidity, adjusted r2 = 0.16, 0.23 for surface and bottom) as well as phytoplankton biomass (chlorophyll-a, adjusted r2 = 0.25, 0.14 for surface and bottom). Responses in OM quantity and quality observed during the period of elevated discharge were similar to studies assessing OM quality following extreme storm events suggesting that regional changes in precipitation, as predicted by climate change, will be as important in changing the estuarine OM pool as episodic storm events in the future

New Air Quality Targets & Interim Goals for Fine Particulate Matter – PM2.5: Implications for the West Midlands

This document provides a comprehensive overview of the implications of more stringent PM2.5 targets on air quality and public health in the West Midlands. By examining the sources and levels of PM2.5 pollution, exploring potential air quality scenarios and strategies, and estimating the health burden, this document seeks to inform stakeholders and decision makers in their efforts to improve air quality and reduce associated health risks and inequalities