Insensitivity to loss predicts apathy in Huntington's disease

Background Apathy is a deficit in goal‐directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. Methods We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward‐effort calculations, instrumental learning, and response to reward and loss. Results Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward‐related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. Discussion We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward‐effort calculations did not contribute to apathy

An Introduction to Glaciated Margins::The Sedimentary and Geophysical Archive

A glaciated margin is a continental margin that has been occupied by a large ice mass, such that glacial processes and slope processes conspire to produce a thick sedimentary record. Ice masses take an active role in sculpting, redistributing and reorganizing the sediment that they erode on the continental shelf, and act as a supply route to large fan systems (e.g. trough mouth fans, submarine fans) on the continental slope and continental rise. To many researchers, the term ‘glaciated margin’ is synonymous with modern day areas fringing Antarctica and the Arctic shelf systems, yet the geological record contains ancient examples ranging in age from Precambrian to Cenozoic. In the pre-Pleistocene record, there is a tendency for the configuration of the tectonic plates to become increasingly obscure with age. For instance, in the Neoproterozoic record, not everyone agrees on the location of rift margins and some fundamental continental boundaries remain unclear. Given these issues, this introductory paper has two simple aims: (1) to provide a brief commentary of relevant Geological Society publications on glaciated margins, with the landmark papers highlighted and (2) to explain the contents of this volume

PENGARUH PENGGUNAAN ETIKET BRAILLE TERHADAP PEMAHAMAN DAN KEPATUHAN MINUM OBAT PADA PASIEN PENYANDANG TUNANETRA DI PUSKESMAS JANTI KOTA MALANG

Tunanetra adalah tidak berfungsinya indra penglihatan yaitu mata karena kecelakaan atau kecacatan. Menyebabkan tunanetra sulit memahami aturan minum obat setiap harinya ini memicu pengaruh pemahaman dan kepatuhan minum obat pasien penyandang tunanetra. Penelitian ini bertujuan untuk mengetahui pengaruh penggunaan etiket Braille terhadap tingkat kepahaman dan kepatuhan aturan minum obat. Jenis penelitian termasuk metode Pra-eskperimen dengan rancangan perbandingan kelompok statis (Static Group Comprarison),dengan pengambilan sampel Consecutive sampling, instrument penelitian dengan kuesioner kepada 30 responden. Hasil penelitian menunjukkan tingkat pemahaman pada kelompok kontrol 61,67%, sementara kelompok perlakuan sebesar 100%. Untuk kepatuhan kelompok kontrol sebesar 3,65%, dan kelompok perlakuan sebesar 7,92%. Hasil uji Mann Whitey didapat nilai p signifikansi 0,000 < 0,05 terhadap pengaruh penggunaan etiket Braille terhadap pemahaman dan kepatuhan minum obat. Kata Kunci : Pemahaman, Kepatuhan, Aturan Minum Obat, Etiket Braille, Tunanetra, Puskesma

Automated lesion segmentation with BIANCA: Impact of population-level features, classification algorithm and locally adaptive thresholding

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions. In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature with respect to K-nearest neighbour algorithm (currently used for lesion probability map estimation in BIANCA). Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort, a vascular cohort and the cohorts available publicly as a part of a segmentation challenge. We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance, when compared to the global thresholding. It allowed to detect more deep lesions and provided better segmentation of periventricular lesion boundaries, despite the differences in the lesion spatial distribution and load across datasets. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease, and healthy controls, showing that LOCATE adapts well to wide variations in lesion load and spatial distribution

3D macro- and microfabric analyses of Neoproterozoic diamictites from the Valjean Hills, California (United States)

The Cryogenian interval (720–635 Ma) is famous for a rich archive of diamictites, many of which were deposited during glaciations. Classic examples are exposed in the Kingston Peak Formation of the Valjean Hills, near Death Valley (United States), with previous work pointing to multiple glacial cycles in other outcrop belts. Within any glacial period, diamictites are widespread, and in addition, their mechanics of deposition are highly variable. Some are massive in appearance at outcrop or in hand specimens and apparently lack any information that allows their mode of emplacement to be elucidated. Yet, the correct interpretation for deep-time successions in this area is especially important, since it is debated whether the diamictites are either associated with a tectonically driven origin, associated with rifting at the south-western Laurentian margin alongside slope-controlled gravitational mass movement, or predominantly deposited as (sub)glacial diamictites. In this paper, we demonstrate how diamictite texture can be objectively quantified based on clast orientations, at both macroscale and microscale (micromorphology), guiding interpretations. Our method is based on a technique used for Quaternary sediments, by mapping the apparent longest axes of skeleton grains (ranging from fine-grained sand to fine-grained pebbles) in oriented thin sections and reconstructing their microfabric in a 3D space coupled with macrofabric data for each diamictite. In this way, we could identify a bimodal signal in the orientation of the longest axes for each sample. Evidence for shearing and soft sediment deformation supports either subaqueous or subglacial deposition with deformation induced by basal sliding with a paleoflow directed toward the southeast. Our combined approach of micro- and macrofabric analyses can also encourage acquiring accurate fabric data for seemingly structureless diamictites from other deep-time rock archives in an objective manner

New Perspectives on Glacial Geomorphology in Earth's Deep Time Record

International audienceThe deep time (pre-Quaternary) glacial record is an important means to understand the growth, development, and recession of the global cryosphere on very long timescales (10 6-10 8 Myr). Sedimentological description and interpretation of outcrops has traditionally played an important role. Whilst such data remain vital, new insights are now possible thanks to freely accessible aerial and satellite imagery, the widespread availability and affordability of Uncrewed Aerial Vehicles, and accessibility to 3D rendering software. In this paper, we showcase examples of glaciated landscapes from the Cryogenian, Ediacaran, Late Ordovician and Late Carboniferous where this approach is revolutionizing our understanding of deep time glaciation. Although some problems cannot be overcome (erosion or dissolution of the evidence), robust interpretations in terms of the evolving subglacial environment can be made. Citing examples from Australia (Cryogenian), China (Ediacaran), North and South Africa (Late Ordovician, Late Carboniferous), and Namibia (Late Carboniferous), we illustrate how the power of glacial geomorphology can be harnessed to interpret Earth's ancient glacial record

Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles

In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma. The PPMO pre-treatment allowed efficient maintenance of AAV genomes in mdx muscles and enhanced the AAV-U7 therapy effect with a ten-fold increase of the protein level after 6 months. PPMO pre-treatment was also beneficial to AAV-mediated gene therapy with transfer of micro-dystrophin cDNA into muscles. Therefore, avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients

Bedforms and sedimentary structures related to supercritical flows in glacigenic settings

Upper-flow-regime bedforms, including upper-stage-plane beds, antidunes, chutes-and-pools and cyclic steps, are ubiquitous in glacigenic depositional environments characterized by abundant meltwater discharge and sediment supply. In this study, the depositional record of Froude near-critical and supercritical flows in glacigenic settings is reviewed, and similarities and differences between different depositional environments are discussed. Upper-flow-regime bedforms may occur in subglacial, subaerial and subaqueous environments, recording deposition by free-surface flows and submerged density flows. Although individual bedform types are generally not indicative of any specific depositional environment, some observed trends are similar to those documented in non-glacigenic settings. Important parameters for bedform evolution that differ between depositional environments include flow confinement, bed slope, aggradation rate and grain size. Cyclic-step deposits are more common in confined settings, like channels or incised valleys, or steep slopes of coarse-grained deltas. Antidune deposits prevail in unconfined settings and on more gentle slopes, like glacifluvial fans, sand-rich delta slopes or subaqueous (ice-contact) fans. At low aggradation rates, only the basal portions of bedforms are preserved, such as scour fills related to the hydraulic-jump zone of cyclic steps or antidune-wave breaking, which are common in glacifluvial systems and during glacial lake-outburst floods and (related) lake-level falls. Higher aggradation rates result in increased preservation potential, possibly leading to the preservation of complete bedforms. Such conditions are met in sediment-laden jökulhlaups and subaqueous proglacial environments characterized by expanding density flows. Coarser-grained sediment leads to steeper bedform profiles and highly scoured facies architectures, while finer-grained deposits display less steep bedform architectures. Such differences are in part related to stronger flows, faster settling of coarse clasts, and more rapid breaking of antidune waves or hydraulic-jump formation over hydraulically rough beds. © 2020 The Authors. Sedimentology published by John Wiley & Sons Ltd on behalf of International Association of Sedimentologist

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study).

It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants