Biobanks and Electronic Health Records: Ethical and Policy Challenges in the Genomic Age

In this paper we discuss the ethical and policy challenges presented by the construction and use of biobanks and electronic health records systems, with a particular focus on how these resources implicate certain types of security concerns for patients, families, health care providers and institutions. These two technology platforms are selected for special emphasis in this paper for two reasons. First and foremost, there is a close connection between them. Indeed, of the many accepted definitions, this one from the German National Bioethics Commission provides a sense of this close connection and the great power and reflects the great power these two separate platforms provide to probe more deeply the connection between genotype and phenotype: "...[B]iobanks are defined as collections of samples of human bodily substances (e.g., cells, tissues, blood or DNA as the physical medium of genetic information) that are or can be associated with personal data and information on their donors." Second, these two topics implicate both clinical ethics issues (those arising at the bedside for health care providers and patients), and human research ethics issues (issues arising for scientists, research subjects, ethics review bodies and regulatory authorities). Both of these sub-specialty areas confront similar and complementary ethical issues; for example, issues arising from the nature and adequacy of informed consent, the sufficiency of systems to protect personal privacy and confidentiality, or the need to balance concerns relating to data security and the need to know. A growing research base supports calls for more attention to these issues, and yet current professional ethics frameworks and policy consultation methods are poorly organized and ill-equipped to anticipate and fully address ethical issues in health information technology generally, or to provide adequate ethical assessment of the tools that elicit these issues. Our strategy is to orient readers to the history and context of these issues, to frame several key challenges for researchers and policy makers, and then to close with several recommendations for next steps.Richard M. Fairbanks Foundation, Indianapolis; Grant #UL1RR025761-01, NCRR/NIH: Indiana Clinical and Translational Sciences Institut

Observation of a Free-Shercliff-Layer Instability in Cylindrical Geometry

We report on observations of a free-Shercliff-layer instability in a Taylor-Couette experiment using a liquid metal over a wide range of Reynolds numbers, $Re\sim 10^3-10^6$. The free Shercliff layer is formed by imposing a sufficiently strong axial magnetic field across a pair of differentially rotating axial endcap rings. This layer is destabilized by a hydrodynamic Kelvin-Helmholtz-type instability, characterized by velocity fluctuations in the $r-\theta$ plane. The instability appears with an Elsasser number above unity, and saturates with an azimuthal mode number $m$ which increases with the Elsasser number. Measurements of the structure agree well with 2D global linear mode analyses and 3D global nonlinear simulations. These observations have implications for a range of rotating MHD systems in which similar shear layers may be produced.Comment: 5 pages, 4 figure

A Bibliometric Analysis of an International Research Ethics Trainee Program

We used bibliometric analysis to evaluate the citations associated with publications by trainees in the Fogarty International Center’s International Research Ethics Education and Curriculum Development program. Papers published between 2004 and 2008 were identified for analysis. The outcome measures were total citations, h-index, and i-10. A total of 328 manuscripts were identified, with a yearly average of 66 publications and 363 citations. The median number of citations per paper is 3 (IQR Q1–Q3:6). 12.6% (n = 53) of papers were cited over 10 times and the h-index is 22, indicating that 22 papers had been cited at least 22 times. The data indicate that trainees have been productive and contributed to the scholarly literature. Future studies to benchmark this performance with other bioethics education programs are required to make interpretation of citation analysis more meaningful

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma.

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC

Dynamical Tide in Solar-Type Binaries

Circularization of late-type main-sequence binaries is usually attributed to turbulent convection, while that of early-type binaries is explained by resonant excitation of g modes. We show that the latter mechanism operates in solar-type stars also and is at least as effective as convection, despite inefficient damping of g modes in the radiative core. The maximum period at which this mechanism can circularize a binary composed of solar-type stars in 10 Gyr is as low as 3 days, if the modes are damped by radiative diffusion only and g-mode resonances are fixed; or as high as 6 days, if one allows for evolution of the resonances and for nonlinear damping near inner turning points. Even the larger theoretical period falls short of the observed transition period by a factor two.Comment: 17 pages, 2 postscript figures, uses aaspp4.sty. Submitted to Ap

Evaluation of Exposure to Arsenic in Residential Soil

In response to concerns regarding arsenic in soil from a pesticide manufacturing plant, we conducted a biomonitoring study on children younger than 7 years of age, the age category of children most exposed to soil. Urine samples from 77 children (47% participation rate) were analyzed for total arsenic and arsenic species related to ingestion of inorganic arsenic. Older individuals also provided urine (n = 362) and toenail (n = 67) samples. Speciated urinary arsenic levels were similar between children (geometric mean, geometric SD, and range: 4.0, 2.2, and 0.89–17.7 μg/L, respectively) and older participants (3.8, 1.9, 0.91–19.9 μg/L) and consistent with unexposed populations. Toenail samples were < 1 mg/kg. Correlations between speciated urinary arsenic and arsenic in soil (r = 0.137, p = 0.39; n = 41) or house dust (r = 0.049, p = 0.73; n = 52) were not significant for children. Similarly, questionnaire responses indicating soil exposure were not associated with increased urinary arsenic levels. Relatively low soil arsenic exposure likely precluded quantification of arsenic exposure above background

The Search for Stable, Massive, Elementary Particles

In this paper we review the experimental and observational searches for stable, massive, elementary particles other than the electron and proton. The particles may be neutral, may have unit charge or may have fractional charge. They may interact through the strong, electromagnetic, weak or gravitational forces or through some unknown force. The purpose of this review is to provide a guide for future searches - what is known, what is not known, and what appear to be the most fruitful areas for new searches. A variety of experimental and observational methods such as accelerator experiments, cosmic ray studies, searches for exotic particles in bulk matter and searches using astrophysical observations is included in this review.Comment: 34 pages, 8 eps figure

Tracing the colonization history of the Indian Ocean scops-owls (Strigiformes: Otus) with further insight into the spatio-temporal origin of the Malagasy avifauna

<p>Abstract</p> <p>Background</p> <p>The island of Madagascar and surrounding volcanic and coralline islands are considered to form a biodiversity hotspot with large numbers of unique taxa. The origin of this endemic fauna can be explained by two different factors: vicariance or over-water-dispersal. Deciphering which factor explains the current distributional pattern of a given taxonomic group requires robust phylogenies as well as estimates of divergence times. The lineage of Indian Ocean scops-owls (<it>Otus</it>: Strigidae) includes six or seven species that are endemic to Madagascar and portions of the Comoros and Seychelles archipelagos; little is known about the species limits, biogeographic affinities and relationships to each other. In the present study, using DNA sequence data gathered from six loci, we examine the biogeographic history of the Indian Ocean scops-owls. We also compare the pattern and timing of colonization of the Indian Ocean islands by scops-owls with divergence times already proposed for other bird taxa.</p> <p>Results</p> <p>Our analyses revealed that Indian Ocean islands scops-owls do not form a monophyletic assemblage: the Seychelles <it>Otus insularis </it>is genetically closer to the South-East Asian endemic <it>O. sunia </it>than to species from the Comoros and Madagascar. The Pemba Scops-owls <it>O. pembaensis</it>, often considered closely related to, if not conspecific with <it>O. rutilus </it>of Madagascar, is instead closely related to the African mainland <it>O. senegalensis</it>. Relationships among the Indian Ocean taxa from the Comoros and Madagascar are unresolved, despite the analysis of over 4000 bp, suggesting a diversification burst after the initial colonization event. We also highlight one case of putative back-colonization to the Asian mainland from an island ancestor (<it>O. sunia</it>). Our divergence date estimates, using a Bayesian relaxed clock method, suggest that all these events occurred during the last 3.6 myr; albeit colonization of the Indian Ocean islands were not synchronous, <it>O. pembaensis </it>diverged from <it>O. senegalensis </it>about 1.7 mya while species from Madagascar and the Comoro diverged from their continental sister-group about 3.6 mya. We highlight that our estimates coincide with estimates of diversification from other bird lineages.</p> <p>Conclusion</p> <p>Our analyses revealed the occurrence of multiple synchronous colonization events of the Indian Ocean islands by scops-owls, at a time when faunistic exchanges involving Madagascar was common as a result of lowered sea-level that would have allowed the formation of stepping-stone islands. Patterns of diversification that emerged from the scops-owls data are: 1) a star-like pattern concerning the order of colonization of the Indian Ocean islands and 2) the high genetic distinctiveness among all Indian Ocean taxa, reinforcing their recognition as distinct species.</p

Distribution, Elimination, and Biopersistence to 90 Days of a Systemically Introduced 30 nm Ceria-Engineered Nanomaterial in Rats

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were quantified for 2 weeks. Nine organs were weighed and samples collected from 14 tissues/organs/systems, blood and cerebrospinal fluid for cerium determination. Histology and oxidative stress were assessed. Less than 1% of the nanoceria was excreted in the first 2 weeks, 98% in feces. Body weight gain was initially impaired. Spleen weight was significantly increased in some ceria-treated groups, associated with abnormalities. Ceria was primarily retained in the spleen, liver, and bone marrow. There was little decrease of ceria in any tissue over the 90 days. Granulomas were observed in the liver. Time-dependent oxidative stress changes were seen in the liver and spleen. Nanoscale ceria was persistently retained by organs of the mononuclear phagocyte system, associated with adverse changes. The results support concern about the long-term fate and adverse effects of inert nanoscale metal oxides that distribute throughout the body, are persistently retained, and produce adverse changes

Bayesian Methods for Exoplanet Science

Exoplanet research is carried out at the limits of the capabilities of current telescopes and instruments. The studied signals are weak, and often embedded in complex systematics from instrumental, telluric, and astrophysical sources. Combining repeated observations of periodic events, simultaneous observations with multiple telescopes, different observation techniques, and existing information from theory and prior research can help to disentangle the systematics from the planetary signals, and offers synergistic advantages over analysing observations separately. Bayesian inference provides a self-consistent statistical framework that addresses both the necessity for complex systematics models, and the need to combine prior information and heterogeneous observations. This chapter offers a brief introduction to Bayesian inference in the context of exoplanet research, with focus on time series analysis, and finishes with an overview of a set of freely available programming libraries.Comment: Invited revie