Psychological, behavioral and social effects of disclosing Alzheimer's disease biomarkers to research participants

BACKGROUND: Current Alzheimer's disease (AD) research initiatives focus on cognitively healthy individuals with biomarkers that are associated with the development of AD. It is unclear whether biomarker results should be returned to research participants and what the psychological, behavioral and social effects of disclosure are. This systematic review therefore examines the psychological, behavioral and social effects of disclosing genetic and nongenetic AD-related biomarkers to cognitively healthy research participants. METHODS: We performed a systematic literature search in eight scientific databases. Three independent reviewers screened the identified records and selected relevant articles. Results extracted from the included articles were aggregated and presented per effect group. RESULTS: Fourteen studies met the inclusion criteria and were included in the data synthesis. None of the identified studies examined the effects of disclosing nongenetic biomarkers. All studies but one concerned the disclosure of APOE genotype and were conducted in the USA. Study populations consisted largely of cognitively healthy first-degree relatives of AD patients. In this group, disclosure of an increased risk was not associated with anxiety, depression or changes in perceived risk in relation to family history. Disclosure of an increased risk did lead to an increase in specific test-related distress levels, health-related behavior changes and long-term care insurance uptake and possibly diminished memory functioning. CONCLUSION: In cognitively healthy research participants with a first-degree relative with AD, disclosure of APOE ε4-positivity does not lead to elevated anxiety and depression levels, but does increase test-related distress and results in behavior changes concerning insurance and health. We did not find studies reporting the effects of disclosing nongenetic biomarkers and only one study included people without a family history of AD. Empirical studies on the effects of disclosing nongenetic biomarkers and of disclosure to persons without a family history of AD are urgently needed. TRIAL REGISTRATION: PROSPERO international prospective register for systematic reviews CRD42016035388 . Registered 19 February 2016

Evaluation of the response behaviour of unconfined cemented materials under dynamic loading

There is a significant increase in traffic loading on most roads in the developing African countries, and South Africa is one of them. Often this increased traffic loading results in the premature failure of pavement structures. Mechanistic-empirical (M-E) design methods based on fundamental principles are better able to accommodate changes in the design environment. The successful use of design methods depends on the accuracy of the input material parameters. Therefore, as design is moving towards M-E design methods, there is a need for the material parameters to reflect the actual pavement response to dynamic loads. The objective of this paper is to report on the investigation of the response of cement-stabilised sub-base layers to dynamic load by evaluating stiffness at a known strain level. This stiffness was compared with those derived from unconfined compressive strength (UCS) tests performed at static load. The strain and stiffness values were also evaluated against compacted density, cement content, moisture content and material type. It was found that stiffness of some of the cement-stabilised sub-base layers may possibly be overestimated through the use of static loads.Tshwane University of Technology, the National Department of Transport’s Northern Transportation Centre of Development, Geostrada Materials Engineering Laboratory and Aurecon.http://www.journals.co.za/ej/ejour_civileng.htmlhb201

Expression of the wheat multipathogen resistance hexose transporter Lr67res is associated with anion fluxes

OnlinePublMany disease resistance genes in wheat (Triticum aestivum L.) confer strong resistance to specific pathogen races or strains, and only a small number of genes confer multipathogen resistance. The Leaf rust resistance 67 (Lr67) gene fits into the latter category as it confers partial resistance to multiple biotrophic fungal pathogens in wheat and encodes a Sugar Transport Protein 13 (STP13) family hexose-proton symporter variant. Two mutations (G144R, V387L) in the resistant variant, Lr67res, differentiate it from the susceptible Lr67sus variant. The molecular function of the Lr67res protein is not understood, and this study aimed to broaden our knowledge on this topic. Biophysical analysis of the wheat Lr67sus and Lr67res protein variants was performed using Xenopus laevis oocytes as a heterologous expression system. Oocytes injected with Lr67sus displayed properties typically associated with proton-coupled sugar transport proteins—glucose-dependent inward currents, a Km of 110 ± 10 µM glucose, and a substrate selectivity permitting the transport of pentoses and hexoses. By contrast, Lr67res induced much larger sugar-independent inward currents in oocytes, implicating an alternative function. Since Lr67res is a mutated hexose-proton symporter, the possibility of protons underlying these currents was investigated but rejected. Instead, currents in Lr67res oocytes appeared to be dominated by anions. This conclusion was supported by electrophysiology and 36Cl− uptake studies and the similarities with oocytes expressing the known chloride channel from Torpedo marmorata, TmClC-0. This study provides insights into the function of an important disease resistance gene in wheat, which can be used to determine how this gene variant underpins disease resistance in planta.Ricky J. Milne, Katherine E. Dibley, Jayakumar Bose, Anthony R. Ashton, Peter R. Ryan, Stephen D. Tyerman, and Evans S. Laguda

Factors Influencing the Participation of Older People in Clinical Trials : Data Analysis from the MAVIS Trial

Peer reviewedPostprin

Rotating inclined cylinder and the effect of the tilt angle on vortices

We study numerically some possible vortex configurations in a rotating cylinder that is tilted with respect to the rotation axis and where different numbers of vortices can be present at given rotation velocity. In a long cylinder at small tilt angles the vortices tend to align along the cylinder axis and not along the rotation axis. We also show that the axial flow along the cylinder axis, caused by the tilt, will result in the Ostermeier-Glaberson instability above some critical tilt angle. When the vortices become unstable the final state often appears to be a dynamical steady state, which may contain turbulent regions where new vortices are constantly created. These new vortices push other vortices in regions with laminar flow towards the top and bottom ends of the cylinder where they finally annihilate. Experimentally the inclined cylinder could be a convenient environment to create long lasting turbulence with a polarization which can be adjusted with the tilt angle.Comment: 10 pages, 10 figure

Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle

Changes in Serological Immunology Measures in UK and Kenyan Adults Post-controlled Human Malaria Infection.

Background: The timing of infection is closely determined in controlled human malaria infection (CHMI) studies, and as such they provide a unique opportunity to dissect changes in immunological responses before and after a single infection. The first Kenyan Challenge Study (KCS) (Pan African Clinical Trial Registry: PACTR20121100033272) was performed in 2013 with the aim of establishing the CHMI model in Kenya. This study used aseptic, cryopreserved, attenuated Plasmodium falciparum sporozoites administered by needle and syringe (PfSPZ Challenge) and was the first to evaluate parasite dynamics post-CHMI in individuals with varying degrees of prior exposure to malaria. Methods: We describe detailed serological and functional immunological responses pre- and post-CHMI for participants in the KCS and compare these with those from malaria-naïve UK volunteers who also underwent CHMI (VAC049) (ClinicalTrials.gov NCT01465048) using PfSPZ Challenge. We assessed antibody responses to three key blood-stage merozoite antigens [merozoite surface protein 1 (MSP1), apical membrane protein 1 (AMA1), and reticulocyte-binding protein homolog 5 (RH5)] and functional activity using two candidate measures of anti-merozoite immunity; the growth inhibition activity (GIA) assay and the antibody-dependent respiratory burst activity (ADRB) assay. Results:Clear serological differences were observed pre- and post-CHMI by ELISA between malaria-naïve UK volunteers in VAC049, and Kenyan volunteers who had prior malaria exposure. Antibodies to AMA1 and schizont extract correlated with parasite multiplication rate (PMR) post-CHMI in KCS. Serum from volunteer 110 in KCS, who demonstrated a dramatically reduced PMR in vivo, had no in vitro GIA prior to CHMI but the highest level of ADRB activity. A significant difference in ADRB activity was seen between KCS volunteers with minimal and definite prior exposure to malaria and significant increases were seen in ADRB activity post-CHMI in Kenyan volunteers. Quinine and atovaquone/proguanil, previously assumed to be removed by IgG purification, were identified as likely giving rise to aberrantly high in vitro GIA results. Conclusions: The ADRB activity assay is a promising functional assay that warrants further investigation as a measure of prior exposure to malaria and predictor of control of parasite growth. The CHMI model can be used to evaluate potential measures of naturally-acquired immunity to malaria

Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer

Background: Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface. Methods: From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists. Findings: The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists. Interpretation: Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input

Implications of H.E.S.S. observations of pulsar wind nebulae

In this review paper on pulsar wind nebulae (PWN) we discuss the properties of such nebulae within the context of containment against cross-field diffusion (versus normal advection), the effect of reverse shocks on the evolution of offset ``Vela-like'' PWN, constraints on maximum particle energetics, magnetic field strength estimates based on spectral and spatial properties, and the implication of such field estimates on the composition of the wind. A significant part of the discussion is based on the High Energy Stereoscopic System ({\it H.E.S.S.} or {\it HESS}) detection of the two evolved pulsar wind nebulae Vela X (cocoon) and HESS J1825-137. In the case of Vela X (cocoon) we also review evidence of a hadronic versus a leptonic interpretation, showing that a leptonic interpretation is favored for the {\it HESS} signal. The constraints discussed in this review paper sets a general framework for the interpretation of a number of offset, filled-center nebulae seen by {\it HESS}. These sources are found along the galactic plane with galactic latitudes $|b|\sim 0$, where significant amounts of molecular gas is found. In these regions, we find that the interstellar medium is inhomogeneous, which has an effect on the morphology of supernova shock expansion. One consequence of this effect is the formation of offset pulsar wind nebulae as observed.Comment: to appear in Springer Lecture Notes on Neutron Stars and Pulsars: 40 years after their discovery, eds. W. Becke

Classification of Supernovae

The current classification scheme for supernovae is presented. The main observational features of the supernova types are described and the physical implications briefly addressed. Differences between the homogeneous thermonuclear type Ia and similarities among the heterogeneous core collapse type Ib, Ic and II are highlighted. Transforming type IIb, narrow line type IIn, supernovae associated with GRBs and few peculiar objects are also discussed.Comment: 16 Pages, 4 figures, to be published in "Supernovae and Gamma-Ray Bursters," ed. Kurt W. Weile