CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders.

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1-42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2-4 years). There was an overall reduction in Aβ42 from a mean concentration of 211-195 pg ml(-1) after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques

Structural and magnetic properties of Co-V nanoparticles

We have investigated the structural and magnetic properties of Co1-xVx nanoparticles (NPs) with composition x = 0.25 (stoichiometric) and 0.29 (under-stoichiometric) prepared by the cluster-beam deposition (CBD) technique. Our data shows that the as-made Co1-xVx NPs are a mixture of the high-temperature phase (HTP) and the low-temperature phase (LTP) of Co3V and the particles are superparamagnetic at room temperature (RT) with blocking temperatures (TB) of 90 and 137 K for x = 0.25 and 0.29, respectively. This behavior contrasts with the bulk which are paramagnetic down to 4.2 K. When the Co75V25 NPs are annealed at 573 K, they undergo a phase separation into a mixture of phases and become ferromagnetic at room temperature with Curie temperature (Tc) of 515 K

Proportionate and disproportionate policy responses to climate change: core concepts and empirical applications

A fresh perspective on policy-making and planning has emerged which views disproportionate policy as an intentional policy response. A disproportionate policy response is understood to be a lack of‘fit’or balance between the costs of a public policy and the benefits that are derived from this policy, and between policy ends and means. This paper applies this new perspective on the proportionality of policy-making to the area of climate change. The first part of the paper discusses the underlying causes of disproportionate policy responses in broad terms and then applies the theoretical reasoning to understand the conditions in which they are likely to appear in relation to climate change. These conditions are hypothesized to relate to four main factors: economic considerations; levels of public demand; focusing events; and strategic considerations. It concludes with the suggestion that societal actors may be able to manipulate these four factors to encourage politicians to adopt policies that mitigate climate change more rapidly than is currently the case in most countries

Towards an operationalization of test-driven development skills: An industrial empirical study

Abstract Context: The majority of the empirical studies on Test-driven development (TDD) are concerned with verifying or refuting the effectiveness of the technique over a traditional approach, and they tend to neglect whether the subjects possess the necessary skills to apply TDD, though they argue such skills are necessary. Objective: We evaluate a set of minimal, a priori and in process skills necessary to apply TDD. We determine whether variations in external quality (i.e., number of defects) and productivity (i.e., number of features implemented) can be associated with different clusters of the TDD skills? set. Method: We executed a quasi-experiment involving 30 practitioners from industry. We first grouped the participants according to their TDD skills? set (consisting of a priori experience on programming and testing as well as in-process TDD conformance) into three levels (Low-Medium-High) using k-means clustering. We then applied ANOVA to compare the clusters in terms of external quality and productivity, and conducted post-hoc pairwise analysis. Results: We did not observe a statistically significant difference between the clusters either for external software quality ( F ( 2 , 27 = 1.44 , p = . 260 ), or productivity ( F ( 2 , 27 ) = 3.02 , p = . 065 ). However, the analysis of the effect sizes and their confidence intervals shows that the TDD skills? set is a factor that could account for up to 28% of the external quality, and 38% for productivity. Conclusion: We have reason to conclude that focusing on the improvement of TDD skills? set investigated in this study could benefit software developers in improving their baseline productivity and the external quality of the code they produce. However, replications are needed to overcome the issues related with the statistical power of this study. We suggest practical insights for future work to investigate the phenomenon further.hisresearchispartiallysupportedbytheAcademyofFinlandwithdecisionno.:278354,andbyFinnishDistinguishedProfessor(Fi.Di.Pro.) programme, ESEIL

Options to Reform the European Union Legislation on GMOs: Scope and Definitions

We discuss options to reform the EU genetically modified organisms (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. The first in a three-part series, this article focuses on reform options related to the scope of the legislation and the GMO definition

Towards good practice guidelines for the contour method of residual stress measurement

Accurate measurement of residual stress in metallic components using the contour method relies on the achievement of a good quality cut, on the appropriate measurement of the deformed cut surface and on the robust analysis of the measured data. There is currently no published standard or code of practice for the contour method. As a first step towards such a standard, this study draws on research investigations addressing the three main steps in the method: how best to cut the specimens; how to measure the deformation contour of the cut surface; and how to analyse the data. Good practice guidance is provided throughout the text accompanied by more detailed observations and advice tabulated in Appendi

Accelerated swell testing of artificial sulfate bearing lime stabilised cohesive soils

This paper reports on the physico-chemical response of two lime stabilised sulfate bearing artificial soils subject to the European Accelerated Volumetric Swell Test (EN13286-49). At various intervals during the test, a specimen was removed and subject to compositional and microstructural analysis. Ettringite was formed by both soils types, but with significant differences in crystal morphology. Ettringite crystals formed from kaolin based soils were very small, colloidal in size and tended to form on the surface of other particles. Conversely, those formed from montmorillonite were relatively large and typically formed away from the surface in the pore solution. It was concluded that the mechanism by which ettringite forms is determined by the hydroxide ion concentration in the pore solution and the fundamental structure of the bulk clay. In the kaolin soil, ettringite forms by a topochemical mechanism and expands by crystal swelling. In the montmorillonite soil, it forms by a through-solution mechanism and crystal growth

Characterizing Heterogeneity in Neuroimaging, Cognition, Clinical Symptoms, and Genetics Among Patients With Late-Life Depression

Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine. Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles. Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35 000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021. Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics. Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×10⁸) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant–based heritability of 18% to 27% within the general population (N = 12 518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen ƒ² = 0.03; P = .02) and were more likely to progress to Alzheimer disease (Cohen ƒ² = 0.03; P = .03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer’s Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets). Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions

Detecting the translocation of DNA through a nanopore using graphene nanoribbons

Solid-state nanopores can act as single-molecule sensors and could potentially be used to rapidly sequence DNA molecules. However, nanopores are typically fabricated in insulating membranes that are as thick as 15 bases, which makes it difficult for the devices to read individual bases. Graphene is only 0.335 nm thick (equivalent to the spacing between two bases in a DNA chain) and could therefore provide a suitable membrane for sequencing applications. Here, we show that a solid-state nanopore can be integrated with a graphene nanoribbon transistor to create a sensor for DNA translocation. As DNA molecules move through the pore, the device can simultaneously measure drops in ionic current and changes in local voltage in the transistor, which can both be used to detect the molecules. We examine the correlation between these two signals and use the ionic current measurements as a real-time control of the graphene-based sensing device

The management of tetanus in adults in an intensive care unit in Southern Vietnam

Background: Tetanus remains common in many low- and middle-income countries (LMICs) yet the evidence base guiding management of this disease is extremely limited, particularly with respect to contemporary management options. Sharing knowledge about practice may facilitate improvement in outcomes elsewhere. Methods: We describe clinical interventions and outcomes of 180 adult patients ≥16 years-old with tetanus enrolled in prospective observational studies at a specialist infectious diseases hospital in Southern Vietnam. Patients were treated according to a holistic management protocol encompassing wound-care, antitoxin, antibiotics, symptom control, airway management, nutrition and de-escalation criteria. Results: Mortality rate in our cohort was 2.8%, with 90 (50%) patients requiring mechanical ventilation for a median 16 [IQR 12-24] days. Median [IQR] duration of ICU stay was 15 [8-23] days. Autonomic nervous system dysfunction occurred in 45 (25%) patients. Hospital acquired infections occurred in 77 (43%) of patients. Conclusion: We report favourable outcomes for patients with tetanus in a single centre LMIC ICU, treated according to a holistic protocol. Nevertheless, many patients required prolonged intensive care support and hospital acquired infections were common