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"Harrison, John"
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Drug Development
Many tests have been used to study memory in Alzheimer's disease (AD) and related dementias. At the turn of the century, these assessments included the CANTAB system, MMSE, Cognitive Drug Research (CDR), RBANS, and Cogstate, along with a large set of established paper and pencil tests. Several additional assessments have been developed and used in observational studies and clinical trials since 2000, including the mini-cog (2000) and MOCA (2005) as well as the NIH toolbox (2004). However, since the registration of the first AD drugs, the preferred cognitive assessment has been the ADAS-cog. This is despite several substantial criticisms levelled at this test and despite expanding options in cognitive assessments. The ADAS-cog has issues with ceiling effects, lack of parallel forms of the praxis and language tests and generally poor content validity, and the attempt to add items to the ADAS-cog to solve these issues has not been successful. The persistent use of the ADAS-cog seems unaffected, despite the fact that better tests of some missing domains, such as verbal fluency, coding, attention and working memory have all demonstrated assay sensitivity in early AD. The lack of assay sensitivity of the ADAS-cog in mild AD (MMSE 21 to 26) in the phase 2 AN1792 study, presented side-by-side with the newly proposed NTB showing comparable mild and moderate sensitivity, inspired development of several optimized cognitive composites for early AD stages from 2010-2020. These included the PACC to separate amyloid positive and negative individuals, and the APCC, API-LOAD and PACC-5 for measuring progression in the pre-MCI stage. Also in the late 2010s, additional composite outcomes were proposed that included both cognition and global or functional scale items, and were intended primarily for the early AD stage of disease (ADCOMS, iADRS). While the ADAS-Cog has aided in the search for effective AD treatments, a reflection on the past 25 years of the development of cognitive assessments reveals that much effort has been spent to overcome its deficiencies and the AD world would experience more rapid advancement if we make better use of the tools we have and continue to address deficiencies.
Journal Article
Reservoir CO2 and CH4 emissions and their climate impact over the period 1900–2060
Reservoirs are essential for human populations, but their global carbon footprint is substantial (0.73–2.41 PgCO
2
-equivalent yr
−1
). Yet the temporal evolution of reservoir carbon emissions and their contribution to anthropogenic radiative forcing remains unresolved. Here we quantify the long-term historical and future evolution (1900–2060) of cumulative global reservoir area, carbon dioxide and methane emissions and the resulting radiative forcing. We show that global reservoir carbon emissions peaked in 1987 (4.4 TmolC yr
−1
) and have been declining since, due largely to decreasing carbon dioxide emissions as reservoirs age. However, reservoir-induced radiative forcing continues to rise due to ongoing increases in reservoir methane emissions, which accounted for 5.2% of global anthropogenic methane emissions in 2020. We estimate that, in the future, methane ebullition and degassing flux will make up >75% of the reservoir-induced radiative forcing, making these flux pathways key targets for improved understanding and mitigation.
Reservoir-induced radiative forcing is increasing globally due to rising methane emissions outweighing declining carbon dioxide emissions, according to modelling based on reservoir surface area observations.
Journal Article
Evaluation of Speech-Based Digital Biomarkers: Review and Recommendations
Speech represents a promising novel biomarker by providing a window into brain health, as shown by its disruption in various neurological and psychiatric diseases. As with many novel digital biomarkers, however, rigorous evaluation is currently lacking and is required for these measures to be used effectively and safely. This paper outlines and provides examples from the literature of evaluation steps for speech-based digital biomarkers, based on the recent V3 framework (Goldsack et al., 2020). The V3 framework describes 3 components of evaluation for digital biomarkers: verification, analytical validation, and clinical validation. Verification includes assessing the quality of speech recordings and comparing the effects of hardware and recording conditions on the integrity of the recordings. Analytical validation includes checking the accuracy and reliability of data processing and computed measures, including understanding test-retest reliability, demographic variability, and comparing measures to reference standards. Clinical validity involves verifying the correspondence of a measure to clinical outcomes which can include diagnosis, disease progression, or response to treatment. For each of these sections, we provide recommendations for the types of evaluation necessary for speech-based biomarkers and review published examples. The examples in this paper focus on speech-based biomarkers, but they can be used as a template for digital biomarker development more generally.
Journal Article
Greenhouse Gas Emissions from Reservoir Water Surfaces
Collectively, reservoirs created by dams are thought to be an important source of greenhouse gases (GHGs) to the atmosphere. So far, efforts to quantify, model, and manage these emissions have been limited by data availability and inconsistencies in methodological approach. Here, we synthesize reservoir CH4, CO2, and N2O emission data with three main objectives: (1) to generate a global estimate of GHG emissions from reservoirs, (2) to identify the best predictors of these emissions, and (3) to consider the effect of methodology on emission estimates. We estimate that GHG emissions from reservoir water surfaces account for 0.8 (0.5–1.2) Pg CO2 equivalents per year, with the majority of this forcing due to CH4. We then discuss the potential for several alternative pathways such as dam degassing and downstream emissions to contribute significantly to overall emissions. Although prior studies have linked reservoir GHG emissions to reservoir age and latitude, we find that factors related to reservoir productivity are better predictors of emission.
Journal Article
Exocomets from a Solar System Perspective
Exocomets are small bodies releasing gas and dust which orbit stars other than the Sun. Their existence was first inferred from the detection of variable absorption features in stellar spectra in the late 1980s using spectroscopy. More recently, they have been detected through photometric transits from space, and through far-IR/mm gas emission within debris disks. As (exo)comets are considered to contain the most pristine material accessible in stellar systems, they hold the potential to give us information about early stage formation and evolution conditions of extra solar systems. In the solar system, comets carry the physical and chemical memory of the protoplanetary disk environment where they formed, providing relevant information on processes in the primordial solar nebula. The aim of this paper is to compare essential compositional properties between solar system comets and exocomets to allow for the development of new observational methods and techniques. The paper aims to highlight commonalities and to discuss differences which may aid the communication between the involved research communities and perhaps also avoid misconceptions. The compositional properties of solar system comets and exocomets are summarized before providing an observational comparison between them. Exocomets likely vary in their composition depending on their formation environment like solar system comets do, and since exocomets are not resolved spatially, they pose a challenge when comparing them to high fidelity observations of solar system comets. Observations of gas around main sequence stars, spectroscopic observations of \"polluted\" white dwarf atmospheres and spectroscopic observations of transiting exocomets suggest that exocomets may show compositional similarities with solar system comets. The recent interstellar visitor 2I/Borisov showed gas, dust and nuclear properties similar to that of solar system comets. This raises the tantalising prospect that observations of interstellar comets may help bridge the fields of exocomet and solar system comets.
Journal Article