Addressing the challenges to successful recruitment and retention in Alzheimer's disease clinical trials

Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them

Assessment of the genetic diversity of native apple cultivars in the south eastern ranges of the Alps with three selected microsatellite loci

The regional diversity of native apple cultivars in parts of the south eastern ranges of the Alps (Styria, Austria and northern parts of Slovenia) was examined. As the application of conventional pomological methods to characterise cultivars may sometimes be ambiguous, we regard the application of molecular methods to be essential for thorough cultivar diversity assessments. Five hundred samples were collected from different climatic and edaphic regions and analysed using three selected microsatellite loci. With this approach we were able to distinguish 190 named varieties at which we chose 50 as reference varieties. The high diversity of native races suggests that the Southern alpine ranges represent a „hot spot“ of cultivar diversity. This can be attributed to historical effects and the local persistence of a traditional management practice with orchards of widely spaced and old-grown trees of various races. Because these „old“ native races could harbour interesting genetic traits (pathogen resistance, taste, etc.) that will be important in future food production, measures for their conservation are overdue. Our approach will not only show which local cultivars/genotypes require rapid action for their protection, but due to the international nature of our project we can also show which old and untraceable local names in different languages correspond with the same cultivars

Differential Development of the Ventral Visual Cortex Extends Through Adolescence

The ventral temporal cortex (VTC) in humans includes functionally defined regions that preferentially respond to objects, faces, and places. Recent developmental studies suggest that the face selective region in the fusiform gyrus (‘fusiform face area’, FFA) undergoes a prolonged development involving substantial increases in its volume after 7 years of age. However, the endpoint of this development is not known. Here we used functional magnetic resonance imaging (fMRI) to examine the development of face-, object- and place selective regions in the VTC of adolescents (12–16 year olds) and adults (18–40 year olds). We found that the volume of face selective activations in the right fusiform gyrus was substantially larger in adults than in adolescents, and was positively correlated with age. This development was associated with higher response amplitudes and selectivity for faces in face selective regions of VTC and increased differentiation of the distributed response patterns to faces versus non-face stimuli across the entire VTC. Furthermore, right FFA size was positively correlated with face recognition memory performance, but not with recognition memory of objects or places. In contrast, the volume of object- and place selective cortical regions or their response amplitudes did not change across these age groups. Thus, we found a striking and prolonged development of face selectivity across the VTC during adolescence that was specifically associated with proficiency in face recognition memory. These findings have important implications for theories of development and functional specialization in VTC

Magneto-resistance quantum oscillations in a magnetic two-dimensional electron gas

Magneto-transport measurements of Shubnikov-de Haas (SdH) oscillations have been performed on two-dimensional electron gases (2DEGs) confined in CdTe and CdMnTe quantum wells. The quantum oscillations in CdMnTe, where the 2DEG interacts with magnetic Mn ions, can be described by incorporating the electron-Mn exchange interaction into the traditional Lifshitz-Kosevich formalism. The modified spin splitting leads to characteristic beating pattern in the SdH oscillations, the study of which indicates the formation of Mn clusters resulting in direct anti-ferromagnetic Mn-Mn interaction. The Landau level broadening in this system shows a peculiar decrease with increasing temperature, which could be related to statistical fluctuations of the Mn concentration.Comment: 8 pages, 6 figure

Separate processing of texture and form in the ventral stream : evidence from fMRI and visual agnosia.

Real-life visual object recognition requires the processing of more than just geometric (shape, size, and orientation) properties. Surface properties such as color and texture are equally important, particularly for providing information about the material properties of objects. Recent neuroimaging research suggests that geometric and surface properties are dealt with separately, within the lateral occipital cortex (LOC) and the collateral sulcus (CoS), respectively. Here we compared objects that either differed in aspect ratio or in surface texture only, keeping all other visual properties constant. Results on brain-intact participants confirmed that surface texture activates an area in the posterior CoS, quite distinct from the area activated by shape within LOC. We also tested two patients with visual object agnosia, one of whom (DF) performed well on the texture task but at chance on the shape task, while the other (MS) showed the converse pattern. This behavioral double dissociation was matched by a parallel neuroimaging dissociation, with activation in CoS but not LOC in patient DF, and activation in LOC but not CoS in patient MS. These data provide presumptive evidence that the areas respectively activated by shape and texture play a causally necessary role in the perceptual discrimination of these features

Thermalisation time and specific heat of neutron stars crust

We discuss the thermalisation process of the neutron stars crust described by solving the heat transport equation with a microscopic input for the specific heat of baryonic matter. The heat equation is solved with initial conditions specific to a rapid cooling of the core. To calculate the specific heat of inner crust baryonic matter, i.e., nuclear clusters and unbound neutrons, we use the quasiparticle spectrum provided by the Hartree-Fock-Bogoliubov approach at finite temperature. In this framework we analyse the dependence of the crust thermalisation on pairing properties and on cluster structure of inner crust matter. It is shown that the pairing correlations reduce the crust thermalisation time by a very large fraction. The calculations show also that the nuclear clusters have a non-negligible influence on the time evolution of the surface temperature of the neutron star.Comment: 7 pages, 5 figures, submitted to Phys. Rev.

Frameworks for Estimating Causal Effects in Observational Settings: Comparing Confounder Adjustment and Instrumental Variables

To estimate causal effects, analysts performing observational studies in health settings utilize several strategies to mitigate bias due to confounding by indication. There are two broad classes of approaches for these purposes: use of confounders and instrumental variables (IVs). Because such approaches are largely characterized by untestable assumptions, analysts must operate under an indefinite paradigm that these methods will work imperfectly. In this tutorial, we formalize a set of general principles and heuristics for estimating causal effects in the two approaches when the assumptions are potentially violated. This crucially requires reframing the process of observational studies as hypothesizing potential scenarios where the estimates from one approach are less inconsistent than the other. While most of our discussion of methodology centers around the linear setting, we touch upon complexities in non-linear settings and flexible procedures such as target minimum loss-based estimation (TMLE) and double machine learning (DML). To demonstrate the application of our principles, we investigate the use of donepezil off-label for mild cognitive impairment (MCI). We compare and contrast results from confounder and IV methods, traditional and flexible, within our analysis and to a similar observational study and clinical trial