Sensitivity analysis for missing outcomes in time-to-event data with covariate adjustment

Covariate-adjusted sensitivity analyses is proposed for missing time-to-event outcomes. The method invokes multiple imputation (MI) for the missing failure times under a variety of specifications regarding the post-withdrawal tendency for having the event of interest. With a clinical trial example, we compared methods of covariance analyses for time-to-event data, i.e., the multivariable Cox proportional hazards model and non-parametric ANCOVA, and then illustrated how to incorporate these methods into the proposed sensitivity analysis for covariate adjustment. The MI methods considered are Kaplan-Meier Multiple Imputation (KMMI), covariate-adjusted and unadjusted proportional hazards multiple imputation (PHMI). The assumptions, statistical issues, and features for these methods are discussed

<i>In vitro</i> Characterization of Phenylacetate Decarboxylase, a Novel Enzyme Catalyzing Toluene Biosynthesis in an Anaerobic Microbial Community

Anaerobic bacterial biosynthesis of toluene from phenylacetate was reported more than two decades ago, but the biochemistry underlying this novel metabolism has never been elucidated. Here we report results of in vitro characterization studies of a novel phenylacetate decarboxylase from an anaerobic, sewage-derived enrichment culture that quantitatively produces toluene from phenylacetate; complementary metagenomic and metaproteomic analyses are also presented. Among the noteworthy findings is that this enzyme is not the well-characterized clostridial p-hydroxyphenylacetate decarboxylase (CsdBC). However, the toluene synthase under study appears to be able to catalyze both phenylacetate and p-hydroxyphenylacetate decarboxylation. Observations suggesting that phenylacetate and p-hydroxyphenylacetate decarboxylation in complex cell-free extracts were catalyzed by the same enzyme include the following: (i) the specific activity for both substrates was comparable in cell-free extracts, (ii) the two activities displayed identical behavior during chromatographic separation of cell-free extracts, (iii) both activities were irreversibly inactivated upon exposure to O2, and (iv) both activities were similarly inhibited by an amide analog of p-hydroxyphenylacetate. Based upon these and other data, we hypothesize that the toluene synthase reaction involves a glycyl radical decarboxylase. This first-time study of the phenylacetate decarboxylase reaction constitutes an important step in understanding and ultimately harnessing it for making bio-based toluene

A robust method for comparing two treatments in a confirmatory clinical trial via multivariate time-to-event methods that jointly incorporate information from longitudinal and time-to-event data

We consider regulatory clinical trials that required a pre-specified method for the comparison of two treatments for chronic diseases (e.g. Chronic Obstructive Pulmonary Disease) in which patients suffer deterioration in a longitudinal process until death occurs. We define a composite endpoint structure that encompasses both the longitudinal data for deterioration and the time-to-event data for death, and use multivariate time-to-event methods to assess treatment differences on both data structures simultaneously, without a need for parametric assumptions or modeling. Our method is straightforward to implement, and simulations show the method has robust power in situations in which incomplete data could lead to lower than expected power for either the longitudinal or survival data. We illustrate the method on data from a study of chronic lung disease

MANTRA: Improving Knowledge of Maternal Health, Neonatal Health, and Geohazards in Women in Rural Nepal Using a Mobile Serious Game

Serious games, conveying educational knowledge rather than merely entertainment, are a rapidly expanding research domain for cutting-edge educational technology. Digital interventions like serious games are great opportunities to overcome challenges in low-and-middle-income countries that limit access to health information, such as social barriers like low-literacy and gender. MANTRA: Increasing maternal and child health resilience before, during and after disasters using mobile technology in Nepal takes on these challenges with a novel digital health intervention; a serious mobile game aimed at vulnerable low-literacy female audiences in rural Nepal. The serious game teaches 28 learning objectives of danger signs in geohazards, maternal, and neonatal health to improve knowledge and self-assessment of common conditions and risks to inform healthcare-seeking behavior. Evaluations consisted of recruiting 35 end users to participate in a pre-test assessment, playing the game, post-test assessment, and focus groups to elicit qualitative feedback. Assessments analyzed knowledge gain in two ways; by learning objective with McNemar tests for each learning objective, and by participant scores with paired t-tests of overall scores and by module. Results of assessments of knowledge gain by learning objective (McNemar tests) indicate participants had sufficient prior knowledge to correctly interpret and respond to 26% of pictograms (coded AA), which is a desirable result although without the possibility of improvement through the intervention. The geohazard module had greatest impact as 16% of responses showed knowledge gain (coded BA). The two most successful learning objectives showing statistically significant positive change were evidence of rockfalls and small cracks in the ground (p = < 0.05). Assessment of knowledge gain by participant scores (paired t-tests) showed the 35 participants averaged a 7.7 point improvement (p < 0.001) in the assessment (28 learning objectives). Average change in knowledge of subdivided module scores (each module normalized to 100 points for comparison) was greatest in the geohazard module (9.5 points, p < 0.001), then maternal health (7.4 points, p = 0.0067), and neonatal health (6.0 points, p = 0.013). This evaluation demonstrated that carefully designed digital health interventions with pictograms co-authored by experts and users can teach complex health and geohazard situations. Significant knowledge gain was demonstrated for several learning objectives while those with non-significant or negative change will be re-designed to effectively convey information

Dissociating Slow Responses From Slow Responding

Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (tau) shared only little variance with Gaussian mu (mu), thus dissociating slow responses (tau) from response speed or-if given-slow responding (mu). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls

Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD

Objective: Recent discussions of aetiological overlap between ADHD and Autism Spectrum Disorder (ASD) require comparative studying of these disorders. Method: We examined performance of ASD patients with (ASD+) and without (ASD-) comorbid ADHD, ADHD patients, and controls for selected putative endophenotypes of ADHD: Intrasubject Variability (ISV) of reaction times, working memory (WM), inhibition, and temporal processing. Results: We found that patients with ADHD or ASD+, but not ASD-, had elevated ISV across the entire task battery and temporal processing deficits, and that none of the groups were impaired in WM or inhibition. High levels of ISV and generally poor performance in ASD+ patients were only partially due to additive effects of the pure disorders. Conclusion: Overall, we conclude that, within our limited but heterogeneous task battery, ISV and temporal processing deficits are most sensitive to ADHD symptomatology and that controlling for ADHD comorbidity is mandatory when assessing ISV in autism

Enhancement of tunneling from a correlated 2D electron system by a many-electron Mossbauer-type recoil in a magnetic field

We consider the effect of electron correlations on tunneling from a 2D electron layer in a magnetic field parallel to the layer. A tunneling electron can exchange its momentum with other electrons, which leads to an exponential increase of the tunneling rate compared to the single-electron approximation. Explicit results are obtained for a Wigner crystal. They provide a qualitative and quantitative explanation of the data on electrons on helium. We also discuss tunneling in semiconductor heterostructures.Comment: published version, 4 pages, 2 figures, RevTeX 3.

A network approach for managing ecosystem services and improving food and nutrition security on smallholder farms

Smallholder farmers are some of the poorest and most food insecure people on Earth. Their high nutritional and economic reliance on home-grown produce makes them particularly vulnerable to environmental stressors such as pollinator loss or climate change which threaten agricultural productivity. Improving smallholder agriculture in a way that is environmentally sustainable and resilient to climate change is a key challenge of the 21st century. Ecological intensification, whereby ecosystem services are managed to increase agricultural productivity, is a promising solution for smallholders. However, smallholder farms are complex socio-ecological systems with a range of social, ecological and environmental factors interacting to influence ecosystem service provisioning. To truly understand the functioning of a smallholder farm and identify the most effective management options to support household food and nutrition security, a holistic, systems-based understanding is required. In this paper, we propose a network approach to understand, visualise and model the complex interactions occurring among wild species, crops and people on smallholder farms. Specifically, we demonstrate how networks may be used to (a) identify wild species with a key role in supporting, delivering or increasing the resilience of an ecosystem service; (b) quantify the value of an ecosystem service in a way that is relevant to the food and nutrition security of smallholders; and (c) understand the social interactions that influence the management of shared ecosystem services. Using a case study based on data from rural Nepal, we demonstrate how this framework can be used to connect wild plants, pollinators and crops to key nutrients consumed by humans. This allows us to quantify the nutritional value of an ecosystem service and identify the wild plants and pollinators involved in its provision, as well as providing a framework to predict the effects of environmental change on human nutrition. Our framework identifies mechanistic links between ecosystem services and the nutrients consumed by smallholder farmers and highlights social factors that may influence the management of these services. Applying this framework to smallholder farms in a range of socio-ecological contexts may provide new, sustainable and equitable solutions to smallholder food and nutrition security. A free Plain Language Summary can be found within the Supporting Information of this article

Tunneling from a correlated 2D electron system transverse to a magnetic field

We show that, in a magnetic field parallel to the 2D electron layer, strong electron correlations change the rate of tunneling from the layer exponentially. It results in a specific density dependence of the escape rate. The mechanism is a dynamical Mossbauer-type recoil, in which the Hall momentum of the tunneling electron is partly transferred to the whole electron system, depending on the interrelation between the rate of interelectron momentum exchange and the tunneling duration. We also show that, in a certain temperature range, magnetic field can enhance rather than suppress the tunneling rate. The effect is due to the magnetic field induced energy exchange between the in-plane and out-of-plane motion. Magnetic field can also induce switching between intra-well states from which the system tunnels, and a transition from tunneling to thermal activation. Explicit results are obtained for a Wigner crystal. They are in qualitative and quantitative agreement with the relevant experimental data, with no adjustable parameters.Comment: 16 pages, 9 figure

New times, new politics: history and memory during the final years of the CPGB

This article examines the relationship between collective memory, historical interpretation and political identity. It focuses on the dissolution of the Communist Party of Great Britain (CPGB) as constructed through collective narrative memory, and on Marxist interpretations of history. The divisions within the party and the wider Marxist community, stretching from 1956 until 1991, were often framed around questions of historical interpretation. The events of 1989–1991 created an historical and mnemonic crisis for CPGB members who struggled to reconcile their past identities with their present situation. Unlike the outward-facing revisionism of other political parties, this was an intensely personal affair. The solution for many was to emphasise the need to find new ways to progress socialist aims, without relying on a discredited grand narrative. In contrast, other Communist parties, such as the Communist Party of Britain, which had been established (or ‘re-established’) in 1988, fared rather better. By adhering to the international party line of renewal and continued struggle, the party was able to hold its narrative together, condemning the excesses of totalitarian regimes, while reaffirming the need for international class struggle