Ethical Considerations for the Return of Incidental Findings in Ophthalmic Genomic Research

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Available from PubMed Central (PMC).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757467/Whole genome and whole exome sequencing technologies are being increasingly used in research. However, they have the potential to identify incidental findings (IF), findings not related to the indication of the test, raising questions regarding researchers' responsibilities toward the return of this information to participants. In this study we discuss the ethical considerations related to the return of IF to research participants, emphasizing that the type of the study matters and describing the current practice standards. There are currently no legal obligations for researchers to return IF to participants, but some viewpoints consider that researchers might have an ethical one to return IF of clinical validity and clinical utility and that are actionable. The reality is that most IF are complex to interpret, especially since they were not the indication of the test. The clinical utility often depends on the participants' preferences, which can be challenging to conciliate and relies on participants' understanding. In summary, in the context of a lack of clear guidance, researchers need to have a clear plan for the disclosure or nondisclosure of IF from genomic research, balancing their research goals and resources with the participants' rights and their duty not to harm

Change in hematologic indices over time in pediatric inflammatory bowel disease treated with azathioprine

Azathioprine leads to changes in mean corpuscular volume (MCV) and white blood cell (WBC) indices reflecting efficacy or toxicity. Understanding the interactions between bone marrow stem cells and azathioprine could highlight abnormal response patterns as forerunners for hematologic malig-nancies. This study gives a statistical description of factors influencing the relationship between MCV and WBC in children with inflammatory bowel disease treated with azathioprine. We found that leukopenia preceded macro¬cytosis. Macrocytosis is therefore not a good predictor of leukopenia. Further studies will be necessary to determine the subgroup of patients at increased risk of malignancies based on bone marrow response

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

Developing and enhancing biodiversity monitoring programmes: a collaborative assessment of priorities

1.Biodiversity is changing at unprecedented rates, and it is increasingly important that these changes are quantified through monitoring programmes. Previous recommendations for developing or enhancing these programmes focus either on the end goals, that is the intended use of the data, or on how these goals are achieved, for example through volunteer involvement in citizen science, but not both. These recommendations are rarely prioritized. 2.We used a collaborative approach, involving 52 experts in biodiversity monitoring in the UK, to develop a list of attributes of relevance to any biodiversity monitoring programme and to order these attributes by their priority. We also ranked the attributes according to their importance in monitoring biodiversity in the UK. Experts involved included data users, funders, programme organizers and participants in data collection. They covered expertise in a wide range of taxa. 3.We developed a final list of 25 attributes of biodiversity monitoring schemes, ordered from the most elemental (those essential for monitoring schemes; e.g. articulate the objectives and gain sufficient participants) to the most aspirational (e.g. electronic data capture in the field, reporting change annually). This ordered list is a practical framework which can be used to support the development of monitoring programmes. 4.People's ranking of attributes revealed a difference between those who considered attributes with benefits to end users to be most important (e.g. people from governmental organizations) and those who considered attributes with greatest benefit to participants to be most important (e.g. people involved with volunteer biological recording schemes). This reveals a distinction between focussing on aims and the pragmatism in achieving those aims. 5.Synthesis and applications. The ordered list of attributes developed in this study will assist in prioritizing resources to develop biodiversity monitoring programmes (including citizen science). The potential conflict between end users of data and participants in data collection that we discovered should be addressed by involving the diversity of stakeholders at all stages of programme development. This will maximize the chance of successfully achieving the goals of biodiversity monitoring programmes

Beyond the angle of repose: A review and synthesis of landslide processes in response to rapid uplift, Eel River, Northern California

In mountainous settings, increases in rock uplift are often followed by a commensurate uptick in denudation as rivers incise and steepen hillslopes, making them increasingly prone to landsliding as slope angles approach a limiting value. For decades, the threshold slope model has been invoked to account for landslide-driven increases in sediment flux that limit topographic relief, but the manner by which slope failures organize themselves spatially and temporally in order for erosion to keep pace with rock uplift has not been well documented. Here, we review past work and present new findings from remote sensing, cosmogenic radionuclides, suspended sediment records, and airborne lidar data, to decipher patterns of landslide activity and geomorphic processes related to rapid uplift along the northward-migrating Mendocino Triple Junction in Northern California. From historical air photos and airborne lidar, we estimated the velocity and sediment flux associated with active, slow-moving landslides (or earthflows) in the mélange- and argillite-dominated Eel River watershed using the downslope displacement of surface markers such as trees and shrubs. Although active landslides that directly convey sediment into the channel network account for only 7% of the landscape surface, their sediment flux amounts to more than 50% of the suspended load recorded at downstream sediment gaging stations. These active slides tend to exhibit seasonal variations in velocity as satellite-based interferometry has demonstrated that rapid acceleration commences within 1 to 2 months of the onset of autumn rainfall events before slower deceleration ensues in the spring and summer months. Curiously, this seasonal velocity pattern does not appear to vary with landslide size, suggesting that complex hydrologic–mechanical feedbacks (rather than 1-D pore pressure diffusion) may govern slide dynamics. A new analysis of 14 yrs of discharge and sediment concentration data for the Eel River indicates that the characteristic mid-winter timing of earthflow acceleration corresponds with increased suspended concentration values, suggesting that the seasonal onset of landslide motion each year may be reflected in the export of sediments to the continental margin. The vast majority of active slides exhibit gullied surfaces and the gully networks, which are also seasonally active, may facilitate sediment export although the proportion of material produced by this pathway is poorly known. Along Kekawaka Creek, a prominent tributary to the Eel River, new analyses of catchment-averaged erosion rates derived from cosmogenic radionuclides reveal rapid erosion (0.76 mm/yr) below a prominent knickpoint and slower erosion (0.29 mm/yr) upstream. Such knickpoints are frequently observed in Eel tributaries and are usually comprised of massive (> 10 m) interlocking resistant boulders that likely persist in the landscape for long periods of time (> 105 yr). Upstream of these knickpoints, active landslides tend to be less frequent and average slope angles are slightly gentler than in downstream areas, which indicates that landslide density and average slope angle appear to increase with erosion rate. Lastly, we synthesize evidence for the role of large, catastrophic landslides in regulating sediment flux and landscape form. The emergence of resistant blocks within the mélange bedrock has promoted large catastrophic slides that have dammed the Eel River and perhaps generated outburst events in the past. The frequency and impact of these landslide dams likely depend on the spatial and size distributions of resistant blocks relative to the width and drainage area of adjacent valley networks. Overall, our findings demonstrate that landslides within the Eel River catchment do not occur randomly, but instead exhibit spatial and temporal patterns related to baselevel lowering, climate forcing, and lithologic variations. Combined with recent landscape evolution models that incorporate landslides, these results provide predictive capability for estimating erosion rates and managing hazards in mountainous regions

iPS Cells for Modelling and Treatment of Retinal Diseases

For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration

Chemical tagging can work: Identification of stellar phase-space structures purely by chemical-abundance similarity

Chemical tagging promises to use detailed abundance measurements to identify spatially separated stars that were in fact born together (in the same molecular cloud), long ago. This idea has not yielded much practical success, presumably because of the noise and incompleteness in chemical-abundance measurements. We have succeeded in substantially improving spectroscopic measurements with The Cannon, which has now delivered 15 individual abundances for ~100,000 stars observed as part of the APOGEE spectroscopic survey, with precisions around 0.04 dex. We test the chemical-tagging hypothesis by looking at clusters in abundance space and confirming that they are clustered in phase space. We identify (by the k-means algorithm) overdensities of stars in the 15-dimensional chemical-abundance space delivered by The Cannon, and plot the associated stars in phase space. We use only abundance-space information (no positional information) to identify stellar groups. We find that clusters in abundance space are indeed clusters in phase space. We recover some known phase-space clusters and find other interesting structures. This is the first-ever project to identify phase-space structures at survey-scale by blind search purely in abundance space; it verifies the precision of the abundance measurements delivered by The Cannon; the prospects for future data sets appear very good.Comment: accepted for publication in the Ap

Role of the TCF4 gene intronic variant in normal variation of corneal endothelium

PURPOSE: To identify early features of Fuchs endothelial dystrophy (FED) in carriers of the rs613872(G) transcription factor 4 gene (TCF4) aged 20 to 21 years. METHODS: Prospective cohort study of people aged 20 to 21 years previously enrolled in the Western Australia Pregnancy (Raine) Cohort. Specular microscopy was performed using a noncontact specular microscopy (EM-3000; Tomey, Nagoya, Japan). Individual genotype data were extracted from the genome-wide Illumina 660 Quad Array. Analysis of the association between the rs613872 risk allele in TCF4 and specular microscopic measurements was conducted. RESULTS: Association between the rs613872 risk allele and corneal endothelial cell density (CD) as well as the coefficient of variation in cell shape was the main outcome measure. Genotype and specular microscopic data were available for a total of 445 participants (46% women). The median CD was 2851 and 2850 cells per square millimeter in the right and left eyes, respectively. No significant differences between intereye variability in endothelial CD were seen (right eye to left eye correlation = 0.64); however, a significant difference in variability of endothelial CD between men and women was observed (male: OD, 2839 ± 124 cells/mm and OS, 2845 ± 124 cells/mm vs. female: OD, 2838 ± 134 cells/mm and OS, 2842 ± 132 cells/mm; OD, P = 0.0013 and OS, P = 0.0016). Eleven individuals were homozygous for the rs613872 risk allele. We found no association between rs613872 genotype and CD or coefficient of variation. One of 11 homozygous GG individuals was found to have a gutta in 1 sample field on specular microscopy, whereas 2 of 297 TT individuals also had a gutta each in 1 sample field. CONCLUSIONS: We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial CD or variation in cell morphology in a healthy young adult population. Copyrigh

Mutations in the EPHA2 gene are a major contributor to inherited cataracts in South-Eastern Australia.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C.T in the EPHA2 gene and the previously reported splice mutation c.2826-9G.A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract

Policy options for the world’s primary forests in multilateral environmental agreements

We identify policies that would provide a solid foundation in key international negotiations to ensure that primary forests persist into the 21st Century. A novel compilation of primary forest cover and other data revealed that protection of primary forests is a matter of global concern being equally distributed between developed and developing countries. Almost all (98%) of primary forest is found within 25 countries with around half in five developed ones (USA, Canada, Russia, Australia, and NZ). Only approximate to 22% of primary forest is found in IUCN Protected Areas Categories I-VI, which is approximately 5% of preagriculture natural forest cover. Rates of deforestation and forest degradation are rapid and extensive, and the long-term integrity of primary forest cannot be assumed. We recommend four new actions that could be included in climate change, biodiversity, and sustainable development negotiations: (1) recognize primary forests as a matter of global concern within international negotiations; (2) incorporate primary forests into environmental accounting; (3) prioritize the principle of avoided loss; and (4) universally accept the important role of indigenous and community conserved areas. In the absence of specific policies for primary forest protection, their unique biodiversity values and ecosystem services will continue to erode