Efficient Replication of Over 180 Genetic Associations with Self-Reported Medical Data

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for amassing large amounts of medical information in a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we expected to (based on the number of cases in our cohort and reported odds ratios, and excluding a set of associations with contradictory published evidence). Altogether we replicated over 180 previously reported associations, including many for type 2 diabetes, prostate cancer, cholesterol levels, and multiple sclerosis. We found significant variation across categories of conditions in the percentage of expected associations that we were able to replicate, which may reflect systematic inflation of the effects in some initial reports, or differences across diseases in the likelihood of misdiagnosis or misreport. We also demonstrated that we could improve replication success by taking advantage of our recontactable cohort, offering more in-depth questions to refine self-reported diagnoses. Our data suggests that online collection of self-reported data in a recontactable cohort may be a viable method for both broad and deep phenotyping in large populations

Quantitative localized proton-promoted dissolution kinetics of calcite using scanning electrochemical microscopy (SECM)

Scanning electrochemical microscopy (SECM) has been used to determine quantitatively the kinetics of proton-promoted dissolution of the calcite (101̅4) cleavage surface (from natural “Iceland Spar”) at the microscopic scale. By working under conditions where the probe size is much less than the characteristic dislocation spacing (as revealed from etching), it has been possible to measure kinetics mainly in regions of the surface which are free from dislocations, for the first time. To clearly reveal the locations of measurements, studies focused on cleaved “mirror” surfaces, where one of the two faces produced by cleavage was etched freely to reveal defects intersecting the surface, while the other (mirror) face was etched locally (and quantitatively) using SECM to generate high proton fluxes with a 25 μm diameter Pt disk ultramicroelectrode (UME) positioned at a defined (known) distance from a crystal surface. The etch pits formed at various etch times were measured using white light interferometry to ascertain pit dimensions. To determine quantitative dissolution kinetics, a moving boundary finite element model was formulated in which experimental time-dependent pit expansion data formed the input for simulations, from which solution and interfacial concentrations of key chemical species, and interfacial fluxes, could then be determined and visualized. This novel analysis allowed the rate constant for proton attack on calcite, and the order of the reaction with respect to the interfacial proton concentration, to be determined unambiguously. The process was found to be first order in terms of interfacial proton concentration with a rate constant k = 6.3 (± 1.3) × 10–4 m s–1. Significantly, this value is similar to previous macroscopic rate measurements of calcite dissolution which averaged over large areas and many dislocation sites, and where such sites provided a continuous source of steps for dissolution. Since the local measurements reported herein are mainly made in regions without dislocations, this study demonstrates that dislocations and steps that arise from such sites are not needed for fast proton-promoted calcite dissolution. Other sites, such as point defects, which are naturally abundant in calcite, are likely to be key reaction sites

Electrochemistry at nanoscale electrodes : individual single-walled carbon nanotubes (SWNTs) and SWNT-templated metal nanowires

Individual nanowires (NWs) and native single-walled carbon nanotubes (SWNTs) can be readily used as well-defined nanoscale electrodes (NSEs) for voltammetric analysis. Here, the simple photolithography-free fabrication of submillimeter long Au, Pt, and Pd NWs, with sub-100 nm heights, by templated electrodeposition onto ultralong flow-aligned SWNTs is demonstrated. Both individual Au NWs and SWNTs are employed as NSEs for electron-transfer (ET) kinetic quantification, using cyclic voltammetry (CV), in conjunction with a microcapillary-based electrochemical method. A small capillary with internal diameter in the range 30–70 μm, filled with solution containing a redox-active mediator (FcTMA+ ((trimethylammonium)methylferrocene), Fe(CN)64–, or hydrazine) is positioned above the NSE, so that the solution meniscus completes an electrochemical cell. A 3D finite-element model, faithfully reproducing the experimental geometry, is used to both analyze the experimental CVs and derive the rate of heterogeneous ET, using Butler–Volmer kinetics. For a 70 nm height Au NW, intrinsic rate constants, k0, up to ca. 1 cm s–1 can be resolved. Using the same experimental configuration the electrochemistry of individual SWNTs can also be accessed. For FcTMA+/2+ electrolysis the simulated ET kinetic parameters yield very fast ET kinetics (k0 > 2 ± 1 cm s–1). Some deviation between the experimental voltammetry and the idealized model is noted, suggesting that double-layer effects may influence ET at the nanoscale

Dual-barrel conductance micropipet as a new approach to the study of ionic crystal dissolution kinetics

A new approach to the study of ionic crystal dissolution kinetics is described, based on the use of a dual-barrel theta conductance micropipet. The solution in the pipet is undersaturated with respect to the crystal of interest, and when the meniscus at the end of the micropipet makes contact with a selected region of the crystal surface, dissolution occurs causing the solution composition to change. This is observed, with better than 1 ms time resolution, as a change in the ion conductance current, measured across a potential bias between an electrode in each barrel of the pipet. Key attributes of this new technique are: (i) dissolution can be targeted at a single crystal surface; (ii) multiple measurements can be made quickly and easily by moving the pipet to a new location on the surface; (iii) materials with a wide range of kinetics and solubilities are open to study because the duration of dissolution is controlled by the meniscus contact time; (iv) fast kinetics are readily amenable to study because of the intrinsically high mass transport rates within tapered micropipets; (v) the experimental geometry is well-defined, permitting finite element method modeling to allow quantitative analysis of experimental data. Herein, we study the dissolution of NaCl as an example system, with dissolution induced for just a few milliseconds, and estimate a first-order heterogeneous rate constant of 7.5 (±2.5) × 10–5 cm s–1 (equivalent surface dissolution flux ca. 0.5 μmol cm–2 s–1 into a completely undersaturated solution). Ionic crystals form a huge class of materials whose dissolution properties are of considerable interest, and we thus anticipate that this new localized microscale surface approach will have considerable applicability in the future

Structural correlations in heterogeneous electron transfer at monolayer and multilayer graphene electrodes

As a new form of carbon, graphene is attracting intense interest as an electrode material with widespread applications. In the present study, the heterogeneous electron transfer (ET) activity of graphene is investigated using scanning electrochemical cell microscopy (SECCM), which allows electrochemical currents to be mapped at high spatial resolution across a surface for correlation with the corresponding structure and properties of the graphene surface. We establish that the rate of heterogeneous ET at graphene increases systematically with the number of graphene layers, and show that the stacking in multilayers also has a subtle influence on ET kinetics. © 2012 American Chemical Society

Gendered endings: Narratives of male and female suicides in the South African Lowveld

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s11013-012-9258-y. Copyright @ Springer Science+Business Media, LLC 2012.Durkheim’s classical theory of suicide rates being a negative index of social solidarity downplays the salience of gendered concerns in suicide. But gendered inequalities have had a negative impact: worldwide significantly more men than women perpetrate fatal suicides. Drawing on narratives of 52 fatal suicides in Bushbuckridge, South Africa, this article suggests that Bourdieu’s concepts of ‘symbolic violence’ and ‘masculine domination’ provide a more appropriate framework for understanding this paradox. I show that the thwarting of investments in dominant masculine positions have been the major precursor to suicides by men. Men tended to take their own lives as a means of escape. By contrast, women perpetrated suicide to protest against the miserable consequences of being dominated by men. However, contra the assumption of Bourdieu’s concept of ‘habitus’, the narrators of suicide stories did reflect critically upon gender constructs

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Notes on a scandal: the official enquiry into deviance and corruption in New Zealand police

Since 2004, the New Zealand Police Service has been engulfed by a series of scandals relating to allegations that officers have committed rape and sexual assault and conducted inappropriate sexual relations with vulnerable people. Moreover, it has been claimed that other officers engaged in corrupt practices to thwart the investigation and prosecution of criminal behaviour of police officers. In 2007, a Commission of Inquiry report established a program of reform intended to shape the future direction of the police service. This article provides an overview of these scandals, the context in which they have emerged, and the political and policing response to them. The analysis contained in the Commission report is compared with that offered by comparable investigations of police deviance and corruption in other countries. The methodological and conceptual limitations of the Commission are outlined and the prospects of the recommendations are considered

Evolution of oxygen isotopic composition in the inner solar nebula

Changes in the chemical and isotopic composition of the solar nebula with time are reflected in the properties of different constituents that are preserved in chondritic meteorites. CR carbonaceous chondrites are among the most primitive of all chondrite types and must have preserved solar nebula records largely unchanged. We have analyzed the oxygen and magnesium isotopes in a range of the CR constituents of different formation temperatures and ages, including refractory inclusions and chondrules of various types. The results provide new constraints on the time variation of the oxygen isotopic composition of the inner (<5 AU) solar nebula - the region where refractory inclusions and chondrules most likely formed. A chronology based on the decay of short-lived 26Al (t1/2 ~ 0.73 Ma) indicates that the inner solar nebula gas was 16O-rich when refractory inclusions formed, but less than 0.8 Ma later, gas in the inner solar nebula became 16O-poor and this state persisted at least until CR chondrules formed ~1-2 Myr later. We suggest that the inner solar nebula became 16O-poor because meter-size icy bodies, which were enriched in 17,18O due to isotopic self-shielding during the ultraviolet photo dissociation of CO in the protosolar molecular cloud or protoplanetary disk, agglomerated outside the snowline, drifted rapidly towards the Sun, and evaporated at the snowline. This led to significant enrichment in 16O-depleted water, which then spread through the inner solar system. Astronomical studies of the spatial and/or temporal variations of water abundance in protoplanetary disks may clarify these processes.Comment: 27 pages, 5 figure

On the Analysis of Phylogenetically Paired Designs

As phylogenetically controlled experimental designs become increasingly common in ecology, the need arises for a standardized statistical treatment of these datasets. Phylogenetically paired designs circumvent the need for resolved phylogenies and have been used to compare species groups, particularly in the areas of invasion biology and adaptation. Despite the widespread use of this approach, the statistical analysis of paired designs has not been critically evaluated. We propose a mixed model approach that includes random effects for pair and species. These random effects introduce a “two-layer” compound symmetry variance structure that captures both the correlations between observations on related species within a pair as well as the correlations between the repeated measurements within species. We conducted a simulation study to assess the effect of model misspecification on Type I and II error rates. We also provide an illustrative example with data containing taxonomically similar species and several outcome variables of interest. We found that a mixed model with species and pair as random effects performed better in these phylogenetically explicit simulations than two commonly used reference models (no or single random effect) by optimizing Type I error rates and power. The proposed mixed model produces acceptable Type I and II error rates despite the absence of a phylogenetic tree. This design can be generalized to a variety of datasets to analyze repeated measurements in clusters of related subjects/species