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

Protection Against a Bovine Viral Diarrhea Virus (BVDV) Type 1 Challenge in Calves Vaccinated with a Bovine Herpesvirus-1 (BHV-1)-BVDV Recombinant

A recently developed recombinant bovine herpesvirus 1 (BHV-1) virus containing the envelope protein gp53 of bovine viral diarrhea virus (BVDV) type 1, BHV-1 (v1V31), was assessed for its ability to protect against BVDV in calves. Four calves were vaccinated intranasally with the recombinant BHV-1-BVDV vaccine and did not exhibit any clinical signs following vaccination. The vaccine virus was recovered from all vaccinated calves on days 8 through 10 and the replication appeared to be restricted to nasal passages. Twenty-eight days after vaccination, the four vaccinated and four control calves were challenged with the type 1 BVDV, strain NY-1. All calves had slight temperature elevations but the clinical signs were more severe in the control calves. The platelet counts were significantly depressed in the control calves. Prior to challenge, neither group had BVDV serum neutralizing antibody. The vaccinated calves developed higher serum antibody levels 2 months following challenge, indicating a secondary immune response. Necropsy was performed six weeks following infection. No latent BHV-1 virus was detected from the trigeminal ganglion of any of the vaccinated calves. The recombinant BHV-1 virus vaccine containing a single BVDV protein provided partial protection against BVDV infection

Brucella abortus siderophore 2,3-dihydroxybenzoic acid protects brucellae from killing by macrophages

Addition of 2,3-dihydroxybenzoic acid, a siderophore produced by Brucella abortus, to macrophage cultures prevented intracellular killing of brucellae during the first 12 h after infection and increased the number of intracellular brucellae recovered at 48 h after infection. The protective effect could be demonstrated with inflammatory macrophages, interferon-gamma-activated macrophages and with macrophages supplemented with iron, shown elsewhere to facilitate killing of B abortus

Charge Screening Effect in Metallic Carbon Nanotubes

Charge screening effect in metallic carbon nanotubes is investigated in a model including the one-dimensional long-range Coulomb interaction. It is pointed out that an external charge which is being fixed spatially is screened by internal electrons so that the resulting object becomes electrically neutral. We found that the screening length is given by about the diameter of a nanotube.Comment: 11 pages, 6 figure

Observational Consequences of a Landscape

In this paper we consider the implications of the "landscape" paradigm for the large scale properties of the universe. The most direct implication of a rich landscape is that our local universe was born in a tunnelling event from a neighboring vacuum. This would imply that we live in an open FRW universe with negative spatial curvature. We argue that the "overshoot" problem, which in other settings would make it difficult to achieve slow roll inflation, actually favors such a cosmology. We consider anthropic bounds on the value of the curvature and on the parameters of inflation. When supplemented by statistical arguments these bounds suggest that the number of inflationary efolds is not very much larger than the observed lower bound. Although not statistically favored, the likelihood that the number of efolds is close to the bound set by observations is not negligible. The possible signatures of such a low number of efolds are briefly described.Comment: 21 pages, 4 figures v2: references adde

Circumstellar interaction in supernovae in dense environments - an observational perspective

In a supernova explosion, the ejecta interacting with the surrounding circumstellar medium (CSM) give rise to variety of radiation. Since CSM is created from the mass lost from the progenitor star, it carries footprints of the late time evolution of the star. This is one of the unique ways to get a handle on the nature of the progenitor star system. Here, I will focus mainly on the supernovae (SNe) exploding in dense environments, a.k.a. Type IIn SNe. Radio and X-ray emission from this class of SNe have revealed important modifications in their radiation properties, due to the presence of high density CSM. Forward shock dominance of the X-ray emission, internal free-free absorption of the radio emission, episodic or non-steady mass loss rate, asymmetry in the explosion seem to be common properties of this class of SNe.Comment: Fixed minor typos. 31 pages, 9 figures, accepted for publication in Space Science Reviews. Chapter in International Space Science Institute (ISSI) Book on "Supernovae" to be published in Space Science Reviews by Springe

Field Measurements of Terrestrial and Martian Dust Devils

Surface-based measurements of terrestrial and martian dust devils/convective vortices provided from mobile and stationary platforms are discussed. Imaging of terrestrial dust devils has quantified their rotational and vertical wind speeds, translation speeds, dimensions, dust load, and frequency of occurrence. Imaging of martian dust devils has provided translation speeds and constraints on dimensions, but only limited constraints on vertical motion within a vortex. The longer mission durations on Mars afforded by long operating robotic landers and rovers have provided statistical quantification of vortex occurrence (time-of-sol, and recently seasonal) that has until recently not been a primary outcome of more temporally limited terrestrial dust devil measurement campaigns. Terrestrial measurement campaigns have included a more extensive range of measured vortex parameters (pressure, wind, morphology, etc.) than have martian opportunities, with electric field and direct measure of dust abundance not yet obtained on Mars. No martian robotic mission has yet provided contemporaneous high frequency wind and pressure measurements. Comparison of measured terrestrial and martian dust devil characteristics suggests that martian dust devils are larger and possess faster maximum rotational wind speeds, that the absolute magnitude of the pressure deficit within a terrestrial dust devil is an order of magnitude greater than a martian dust devil, and that the time-of-day variation in vortex frequency is similar. Recent terrestrial investigations have demonstrated the presence of diagnostic dust devil signals within seismic and infrasound measurements; an upcoming Mars robotic mission will obtain similar measurement types

Parkinson's disease age at onset genome-wide association study : Defining heritability, genetic loci, and α-synuclein mechanisms

Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe

Meaningful Metrics for Evaluating Eventual Consistency

Abstract. Optimistic replication is a fundamental technique for supporting collaborative work practices in mobile environments. However, eventual consistency, in contrast to immediate strong consistency in pessimistic replication, is much harder to evaluate. This paper analyzes different metrics for measuring the effectiveness of eventually consistent systems. Using results from a simulated environment of relevant optimistic replication protocols, we show that each metric hides previously undocumented side effects. These add considerable imprecision to any evaluation that exclusively relies on a single metric. Hence, we advocate a combined methodology comprising three complementary metrics: commit ratio, average agreement delay and average commit delay.