Underdiagnosis of mild cognitive impairment: A consequence of ignoring practice effects

INTRODUCTION: Longitudinal testing is necessary to accurately measure cognitive change. However, repeated testing is susceptible to practice effects, which may obscure true cognitive decline and delay detection of mild cognitive impairment (MCI). METHODS: We retested 995 late-middle-aged men in a ∼6-year follow-up of the Vietnam Era Twin Study of Aging. In addition, 170 age-matched replacements were tested for the first time at study wave 2. Group differences were used to calculate practice effects after controlling for attrition effects. MCI diagnoses were generated from practice-adjusted scores. RESULTS: There were significant practice effects on most cognitive domains. Conversion to MCI doubled after correcting for practice effects, from 4.5% to 9%. Importantly, practice effects were present although there were declines in uncorrected scores. DISCUSSION: Accounting for practice effects is critical to early detection of MCI. Declines, when lower than expected, can still indicate practice effects. Replacement participants are needed for accurately assessing disease progression.Published versio

The NN scattering 3S1-3D1 mixing angle at NNLO

The 3S1-3D1 mixing angle for nucleon-nucleon scattering, epsilon_1, is calculated to next-to-next-to-leading order in an effective field theory with perturbative pions. Without pions, the low energy theory fits the observed epsilon_1 well for momenta less than $\sim 50$ MeV. Including pions perturbatively significantly improves the agreement with data for momenta up to $\sim 150$ MeV with one less parameter. Furthermore, for these momenta the accuracy of our calculation is similar to an effective field theory calculation in which the pion is treated non-perturbatively. This gives phenomenological support for a perturbative treatment of pions in low energy two-nucleon processes. We explain why it is necessary to perform spin and isospin traces in d dimensions when regulating divergences with dimensional regularization in higher partial wave amplitudes.Comment: 17 pages, journal versio

Multi-matrix models and emergent geometry

Encouraged by the AdS/CFT correspondence, we study emergent local geometry in large N multi-matrix models from the perspective of a strong coupling expansion. By considering various solvable interacting models we show how the emergence or non-emergence of local geometry at strong coupling is captured by observables that effectively measure the mass of off-diagonal excitations about a semiclassical eigenvalue background. We find emergent geometry at strong coupling in models where a mass term regulates an infrared divergence. We also show that our notion of emergent geometry can be usefully applied to fuzzy spheres. Although most of our results are analytic, we have found numerical input valuable in guiding and checking our results.Comment: 1+34 pages, 4 figures. References adde

Characterizing Circumgalactic Gas around Massive Ellipticals at z ~ 0.4 I. Initial Results

We present a new Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) absorption-line survey to study halo gas around 16 luminous red galaxies (LRGs) at z=0.21-0.55. The LRGs are selected uniformly with stellar mass Mstar>1e11 Msun and no prior knowledge of the presence/absence of any absorption features. Based on observations of the full Lyman series, we obtain accurate measurements of neutral hydrogen column density N(HI) and find that high-N(HI) gas is common in these massive quiescent halos with a median of <log N(HI)> = 16.6 at projected distances d<~160 kpc. We measure a mean covering fraction of optically-thick gas with log N(HI)>~17.2 of LLS=0.44^{+0.12}_{-0.11} at d<~160 kpc and LLS=0.71^{+0.11}_{-0.20} at d<~100 kpc. The line-of-sight velocity separations between the HI absorbing gas and LRGs are characterized by a mean and dispersion of =29 km/s and \sigma_v_{gas-gal}=171 km/s. Combining COS FUV and ground-based echelle spectra provides an expanded spectral coverage for multiple ionic transitions, from low-ionization MgII and SiII, to intermediate ionization SiIII and CIII, and to high-ionization OVI absorption lines. We find that intermediate ions probed by CIII and SiIII are the most prominent UV metal lines in LRG halos with a mean covering fraction of _{0.1}=0.75^{+0.08}_{-0.13} for W(977)>=0.1 Ang at d<160 kpc, comparable to what is seen for CIII in L* and sub-L* star-forming and red galaxies but exceeding MgII or OVI in quiescent halos. The COS-LRG survey shows that massive quiescent halos contain widespread chemically-enriched cool gas and that little distinction between LRG and star-forming halos is found in their HI and CIII content.Comment: 19 pages, 6 figures, accepted by MNRA

The Cosmic Ultraviolet Baryon Survey (CUBS) I. Overview and the diverse environments of Lyman limit systems at z<1

We present initial results from the Cosmic Ultraviolet Baryon Survey (CUBS). CUBS is designed to map diffuse baryonic structures at redshift z<~1 using absorption-line spectroscopy of 15 UV-bright QSOs with matching deep galaxy survey data. CUBS QSOs are selected based on their NUV brightness to avoid biases against the presence of intervening Lyman Limit Systems (LLSs) at zabs~ 17.2 over a total redshift survey pathlength of dz=9.3, and a number density of n(z)=0.43 (-0.18, +0.26). Considering all absorbers with log N(HI)/cm^-2 > 16.5 leads to n(z)=1.08 (-0.25, +0.31) at z<1. All LLSs exhibit a multi-component structure and associated metal transitions from multiple ionization states such as CII, CIII, MgII, SiII, SiIII, and OVI absorption. Differential chemical enrichment levels as well as ionization states are directly observed across individual components in three LLSs. We present deep galaxy survey data obtained using the VLT-MUSE integral field spectrograph and the Magellan Telescopes, reaching sensitivities necessary for detecting galaxies fainter than 0.1L* at d<~300 physical kpc (pkpc) in all five fields. A diverse range of galaxy properties is seen around these LLSs, from a low-mass dwarf galaxy pair, a co-rotating gaseous halo/disk, a star-forming galaxy, a massive quiescent galaxy, to a galaxy group. The closest galaxies have projected distances ranging from d=15 to 72 pkpc and intrinsic luminosities from ~0.01L* to ~3L*. Our study shows that LLSs originate in a variety of galaxy environments and trace gaseous structures with a broad range of metallicities.Comment: 26 pages, 14 figures, MNRAS in pres

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Kinome and Transcriptome Profiling Reveal Broad and Distinct Activities of Erlotinib, Sunitinib, and Sorafenib in the Mouse Heart and Suggest Cardiotoxicity From Combined Signal Transducer and Activator of Transcription and Epidermal Growth Factor Receptor Inhibition

BACKGROUND: Most novel cancer therapeutics target kinases that are essential to tumor survival. Some of these kinase inhibitors are associated with cardiotoxicity, whereas others appear to be cardiosafe. The basis for this distinction is unclear, as are the molecular effects of kinase inhibitors in the heart. METHODS AND RESULTS: We administered clinically relevant doses of sorafenib, sunitinib (cardiotoxic multitargeted kinase inhibitors), or erlotinib (a cardiosafe epidermal growth factor receptor inhibitor) to mice daily for 2 weeks. We then compared the effects of these 3 kinase inhibitors on the cardiac transcriptome using RNAseq and the cardiac kinome using multiplexed inhibitor beads coupled with mass spectrometry. We found unexpectedly broad molecular effects of all 3 kinase inhibitors, suggesting that target kinase selectivity does not define either the molecular response or the potential for cardiotoxicity. Using in vivo drug administration and primary cardiomyocyte culture, we also show that the cardiosafety of erlotinib treatment may result from upregulation of the cardioprotective signal transducer and activator of transcription 3 pathway, as co-treatment with erlotinib and a signal transducer and activator of transcription inhibitor decreases cardiac contractile function and cardiomyocyte fatty acid oxidation. CONCLUSIONS: Collectively our findings indicate that preclinical kinome and transcriptome profiling may predict the cardiotoxicity of novel kinase inhibitors, and suggest caution for the proposed therapeutic strategy of combined signal transducer and activator of transcription/epidermal growth factor receptor inhibition for cancer treatment

Hamilton-Jacobi Tunneling Method for Dynamical Horizons in Different Coordinate Gauges

Previous work on dynamical black hole instability is further elucidated within the Hamilton-Jacobi method for horizon tunneling and the reconstruction of the classical action by means of the null-expansion method. Everything is based on two natural requirements, namely that the tunneling rate is an observable and therefore it must be based on invariantly defined quantities, and that coordinate systems which do not cover the horizon should not be admitted. These simple observations can help to clarify some ambiguities, like the doubling of the temperature occurring in the static case when using singular coordinates, and the role, if any, of the temporal contribution of the action to the emission rate. The formalism is also applied to FRW cosmological models, where it is observed that it predicts the positivity of the temperature naturally, without further assumptions on the sign of the energy.Comment: Standard Latex document, typos corrected, refined discussion of tunneling picture, subsection 5.1 remove