A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial.

The phase III AZA-001 study established that azacitidine significantly improves overall survival compared with conventional care regimens (hazard ratio 0.58 [95% confidence interval 0.43–0.77], P<0.001). This analysis was conducted to investigate the relationship between treatment response and overall survival. AZA-001 data were analyzed in a multivariate Cox regression analysis with response as a time-varying covariate. Response categories were “Overall Response” (defined as complete remission, partial remission, or any hematologic improvement) and “Stable Disease” (no complete or partial remission, hematologic improvement, or progression) or “Other” (e.g. disease progression). Achieving an Overall Response with azacitidine reduced risk of death by 95% compared with achieving an Overall Response with the conventional care regimens (hazard ratio 0.05 [95%CI: 0.01–0.43], P=0.006). Sensitivity analyses indicated that significantly improved overall survival remained manifest for patients with a hematologic improvement who had never achieved complete or partial remission (hazard ratio 0.19 [95%CI: 0.08–0.46], P<0.001). Stable Disease in both azacitidine-treated and conventional care-treated patients was also associated with a significantly reduced risk of death (hazard ratio 0.09, [95%CI: 0.06–0.15]; P<0.001). These results demonstrate azacitidine benefit on overall survival compared with conventional care regimens in patients with higher-risk myelodysplastic syndromes who achieve hematologic response but never attain complete or partial remission, in addition to the survival advantage conferred by achievement of complete or partial remission. This study was registered with clinicaltrials.gov (NCT00071799)

Against strong pluralism

Strong pluralists hold that not even permanent material coincidence is enough for identity. Strong pluralism entails the possibility of purely material objects -- even if not coincident -- alike in all general respects, categorial and dispositional, relational and non-relational, past, present and future, at the microphysical level, but differing in some general modal, counterfactual or dispositional repscts at the macrophysical level. It is objectionable because it thus deprives us of the explanatory resources to explain why evident absurdities are absurd. A second objection is to the suggestion that cases involving artefacts can illustrate strong pluralism. This offends against the principle that gien a complex intrinsic microphysical property instantiated in some regiion, the number of material things possessing it in that region cannot depend on the existence and nature of intentional activity taking place outside it

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

Cognitive function is associated with risk aversion in community-based older persons

<p>Abstract</p> <p>Background</p> <p>Emerging data from younger and middle-aged persons suggest that cognitive ability is negatively associated with risk aversion, but this association has not been studied among older persons who are at high risk of experiencing loss of cognitive function.</p> <p>Methods</p> <p>Using data from 369 community-dwelling older persons without dementia from the Rush Memory and Aging Project, an ongoing longitudinal epidemiologic study of aging, we examined the correlates of risk aversion and tested the hypothesis that cognition is negatively associated with risk aversion. Global cognition and five specific cognitive abilities were measured via detailed cognitive testing, and risk aversion was measured using standard behavioral economics questions in which participants were asked to choose between a certain monetary payment ($15) versus a gamble in which they could gain more than$15 or gain nothing; potential gamble gains ranged from $21.79 to$151.19 with the gain amounts varied randomly over questions. We first examined the bivariate associations of age, education, sex, income and cognition with risk aversion. Next, we examined the associations between cognition and risk aversion via mixed models adjusted for age, sex, education, and income. Finally, we conducted sensitivity analyses to ensure that our results were not driven by persons with preclinical cognitive impairment.</p> <p>Results</p> <p>In bivariate analyses, sex, education, income and global cognition were associated with risk aversion. However, in a mixed effect model, only sex (estimate = -1.49, standard error (SE) = 0.39, p < 0.001) and global cognitive function (estimate = -1.05, standard error (SE) = 0.34, p < 0.003) were significantly inversely associated with risk aversion. Thus, a lower level of global cognitive function and female sex were associated with greater risk aversion. Moreover, performance on four out of the five cognitive domains was negatively related to risk aversion (<it>i.e</it>., semantic memory, episodic memory, working memory, and perceptual speed); performance on visuospatial abilities was not.</p> <p>Conclusion</p> <p>A lower level of cognitive ability and female sex are associated with greater risk aversion in advanced age.</p

On Finding Quantum Multi-collisions

A $k$-collision for a compressing hash function $H$ is a set of $k$ distinct inputs that all map to the same output. In this work, we show that for any constant $k$, $\Theta\left(N^{\frac{1}{2}(1-\frac{1}{2^k-1})}\right)$ quantum queries are both necessary and sufficient to achieve a $k$-collision with constant probability. This improves on both the best prior upper bound (Hosoyamada et al., ASIACRYPT 2017) and provides the first non-trivial lower bound, completely resolving the problem

Multiway modeling and analysis in stem cell systems biology

<p>Abstract</p> <p>Background</p> <p>Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. Stem cells are an attractive target for this analysis, due to their broad therapeutic potential. A central theme of systems biology is the use of computational modeling to reconstruct complex systems from a wealth of reductionist, molecular data (e.g., gene/protein expression, signal transduction activity, metabolic activity, etc.). A number of deterministic, probabilistic, and statistical learning models are used to understand sophisticated cellular behaviors such as protein expression during cellular differentiation and the activity of signaling networks. However, many of these models are bimodal i.e., they only consider row-column relationships. In contrast, multiway modeling techniques (also known as tensor models) can analyze multimodal data, which capture much more information about complex behaviors such as cell differentiation. In particular, tensors can be very powerful tools for modeling the dynamic activity of biological networks over time. Here, we review the application of systems biology to stem cells and illustrate application of tensor analysis to model collagen-induced osteogenic differentiation of human mesenchymal stem cells.</p> <p>Results</p> <p>We applied Tucker1, Tucker3, and Parallel Factor Analysis (PARAFAC) models to identify protein/gene expression patterns during extracellular matrix-induced osteogenic differentiation of human mesenchymal stem cells. In one case, we organized our data into a tensor of type protein/gene locus link × gene ontology category × osteogenic stimulant, and found that our cells expressed two distinct, stimulus-dependent sets of functionally related genes as they underwent osteogenic differentiation. In a second case, we organized DNA microarray data in a three-way tensor of gene IDs × osteogenic stimulus × replicates, and found that application of tensile strain to a collagen I substrate accelerated the osteogenic differentiation induced by a static collagen I substrate.</p> <p>Conclusion</p> <p>Our results suggest gene- and protein-level models whereby stem cells undergo transdifferentiation to osteoblasts, and lay the foundation for mechanistic, hypothesis-driven studies. Our analysis methods are applicable to a wide range of stem cell differentiation models.</p

Measurement of the Negative Muon Anomalous Magnetic Moment to 0.7 ppm

The anomalous magnetic moment of the negative muon has been measured to a precision of 0.7 parts per million (ppm) at the Brookhaven Alternating Gradient Synchrotron. This result is based on data collected in 2001, and is over an order of magnitude more precise than the previous measurement of the negative muon. The result a_mu= 11 659 214(8)(3) \times 10^{-10} (0.7 ppm), where the first uncertainty is statistical and the second is sytematic, is consistend with previous measurements of the anomaly for the positive and negative muon. The average for the muon anomaly a_{mu}(exp) = 11 659 208(6) \times 10^{-10} (0.5ppm).Comment: 4 pages, 4 figures, submitted to Physical Review Letters, revised to reflect referee comments. Text further revised to reflect additional referee comments and a corrected Fig. 3 replaces the older versio