An approach to trial design and analysis in the era of non-proportional hazards of the treatment effect

Background: Most randomized controlled trials with a time-to-event outcome are designed and analysed under the proportional hazards assumption, with a target hazard ratio for the treatment effect in mind. However, the hazards may be non-proportional. We address how to design a trial under such conditions, and how to analyse the results. Methods: We propose to extend the usual approach, a logrank test, to also include the Grambsch-Therneau test of proportional hazards. We test the resulting composite null hypothesis using a joint test for the hazard ratio and for time-dependent behaviour of the hazard ratio. We compute the power and sample size for the logrank test under proportional hazards, and from that we compute the power of the joint test. For the estimation of relevant quantities from the trial data, various models could be used; we advocate adopting a pre-specified flexible parametric survival model that supports time-dependent behaviour of the hazard ratio. Results: We present the mathematics for calculating the power and sample size for the joint test. We illustrate the methodology in real data from two randomized trials, one in ovarian cancer and the other in treating cellulitis. We show selected estimates and their uncertainty derived from the advocated flexible parametric model. We demonstrate in a small simulation study that when a treatment effect either increases or decreases over time, the joint test can outperform the logrank test in the presence of both patterns of non-proportional hazards. Conclusions: Those designing and analysing trials in the era of non-proportional hazards need to acknowledge that a more complex type of treatment effect is becoming more common. Our method for the design of the trial retains the tools familiar in the standard methodology based on the logrank test, and extends it to incorporate a joint test of the null hypothesis with power against non-proportional hazards. For the analysis of trial data, we propose the use of a pre-specified flexible parametric model that can represent a time-dependent hazard ratio if one is present

The signer and the sign: Cortical correlates of person identity and language processing from point-light displays

In this study, the first to explore the cortical correlates of signed language (SL) processing under point-light display conditions, the observer identified either a signer or a lexical sign from a display in which different signers were seen producing a number of different individual signs. many of the regions activated by point-light under these conditions replicated those previously reported for full-image displays, including regions within the inferior temporal cortex that are specialised for face and body-part identification, although such body parts were invisible in the display. Right frontal regions were also recruited - a pattern not usually seen in full-image SL processing. This activation may reflect the recruitment of information about person identity from the reduced display. A direct comparison of identify-signer and identify-sign conditions showed these tasks relied to a different extent on the posterior inferior regions. Signer identification elicited greater activation than sign identification in (bilateral) inferior temporal gyri (BA 37/19), fusiform gyri (BA 37), middle and posterior portions of the middle temporal gyri (BAs 37 and 19), and superior temporal gyri (BA 22 and 42). Right inferior frontal cortex was a further focus of differential activation (signer > sign).These findings suggest that the neural systems supporting point-light displays for the processing of SL rely on a cortical network including areas of the inferior temporal cortex specialized for face and body identification. While this might be predicted from other studies of whole body point-light actions (Vaina, Solomon, Chowdhury, Sinha, & Belliveau, 2001) it is not predicted from the perspective of spoken language processing, where voice characteristics and speech content recruit distinct cortical regions (Stevens, 2004) in addition to a common network. In this respect, our findings contrast with studies of voice/speech recognition (Von Kriegstein, Kleinschmidt, Sterzer, & Giraud, 2005). Inferior temporal regions associated with the visual recognition of a person appear to be required during SL processing, for both carrier and content information. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Specific requirement of NMDA receptors for long-term memory consolidation in Drosophila ellipsoid body

In humans and many other animals, memory consolidation occurs through multiple temporal phases and usually involves more than one neuroanatomical brain system. Genetic dissection of Pavlovian olfactory learning in Drosophila melanogaster has revealed multiple memory phases, but the predominant view holds that all memory phases occur in mushroom body neurons. Here, we demonstrate an acute requirement for NMDA receptors (NMDARs) outside of the mushroom body during long-term memory (LTM) consolidation. Targeted dsRNA-mediated silencing of Nmdar1 and Nmdar2 (also known as dNR1 or dNR2, respectively) in cholinergic R4m-subtype large-field neurons of the ellipsoid body specifically disrupted LTM consolidation, but not retrieval. Similar silencing of functional NMDARs in the mushroom body disrupted an earlier memory phase, leaving LTM intact. Our results clearly establish an anatomical site outside of the mushroom body involved with LTM consolidation, thus revealing both a distributed brain system subserving olfactory memory formation and the existence of a system-level memory consolidation in Drosophila

The macroecology of phylogenetically structured hummingbird-plant networks

Aim To investigate the association between species richness, species' phylogenetic signal, insularity and historical and current climate with hummingbird-plant network structure. Location 54 communities along a c. 10,000 kilometer latitudinal gradient across the Americas (39ºN - 32ºS), ranging from sea level to c. 3700 m asl, located on the mainland and on islands, and covering a wide range of climate regimes. Methods We measured null-modeled corrected complementary specialization and bipartite modularity (compartmentalization) in networks of quantitative interactions between hummingbird and plant species. Using an ordinary least squares multi-model approach, we examined the influence of species richness, phylogenetic signal, insularity, and current and historical climate conditions on network structure. Results Phylogenetically-related species, especially plants, showed a tendency to interact with a similar array of partners. The spatial variation in network structure exhibited a constant association with species' phylogeny (R2=0.18-0.19). Species richness and environmental factors showed the strongest associations with network structure (R2=0.20-0.44; R2138 =0.32-0.45, respectively). Specifically, higher levels of complementary specialization and modularity were associated to species-rich communities and communities in which closely-related hummingbirds visited distinct sets of flowering species. On the mainland, warmer temperatures and higher historical temperature stability associated to higher levels of complementary specialization. Main conclusions Previous macroecological studies of interaction networks have highlighted the importance of environment and species richness in determining network structure. Here, for the first time, we report an association between species phylogenetic signal and network structure at macroecological scale. Specifically, null model corrected complementary specialization and modularity exhibited a positive association with species richness and a negative association with hummingbird phylogenetic signal, indicating that both high richness and high inter-specific competition among closely-related 150 hummingbirds exhibit important relationships with specialization in hummingbird-plant networks. Our results document how species richness, phylogenetic signal and climate associate with network structure in complex ways at macroecological scale

Narcissism and prosocial behavior

There are many motivations for prosocial behavior, some more altruistic and some more egoistic. We posit that more narcissistic people may perform prosocial acts strategically, for example, to improve their reputations or to receive something in return

Deciphering the contribution of biofilm to the pathogenesis of peritoneal dialysis infections: characterization and microbial behaviour on dialysis fluids

Infections are major complications in peritoneal dialysis (PD) with a multifactorial etiology that comprises patient, microbial and dialytic factors. This study aimed at investigating the contribution of microbial biofilms on PD catheters to recalcitrant infections and their interplay with PD related-factors. A prospective observational study was performed on 47 patients attending Centro Hospitalar of Porto and Vila Nova de Gaia/Espinho to whom the catheter was removed due to infectious (n = 16) and non-infectious causes (n = 31). Microbial density on the catheter was assessed by culture methods and the isolated microorganisms identified by matrix-assisted laser desorption/ionization time-of-flight intact cell mass spectrometry. The effect of conventional and three biocompatible PD solutions on 16 Coagulase Negative Staphylococci (CNS) and 10 Pseudomonas aeruginosa strains planktonic growth and biofilm formation was evaluated. Cultures were positive in 87.5% of the catheters removed due infectious and 90.3% removed due to non-infectious causes. However, microbial yields were higher on the cuffs of catheters removed due to infection vs. non-infection. Staphylococci (CNS and Staphylococcus aureus) and P. aeruginosa were the predominant species: 32% and 20% in the infection and 43.3% and 22.7% in the non-infection group, respectively. In general, PD solutions had a detrimental effect on planktonic CNS and P. aeruginosa strains growth. All strains formed biofilms in the presence of PD solutions. The solutions had a more detrimental effect on P. aeruginosa than CNS strains. No major differences were observed between conventional and biocompatible solutions, although in icodextrin solution biofilm biomass was lower than in bicarbonate/lactate solution. Overall, we show that microbial biofilm is universal in PD catheters with the subclinical menace of Staphylococci and P. aeruginosa. Cuffs colonization may significantly contribute to infection. PD solutions differentially impact microbial species. This knowledge is important for the development of infection diagnosis, treatment and preventive strategies.This work received support from a Sociedade Portuguesa de Nefrologia (http://www.spnefro.pt) research grant to AR and a Fundação para a Ciência e Tecnologia (http://www.fct.pt) post doc grant (SFRH/BPD/73663/2010) to MM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Inner Speech during Silent Reading Reflects the Reader's Regional Accent

While reading silently, we often have the subjective experience of inner speech. However, there is currently little evidence regarding whether this inner voice resembles our own voice while we are speaking out loud. To investigate this issue, we compared reading behaviour of Northern and Southern English participants who have differing pronunciations for words like ‘glass’, in which the vowel duration is short in a Northern accent and long in a Southern accent. Participants' eye movements were monitored while they silently read limericks in which the end words of the first two lines (e.g., glass/class) would be pronounced differently by Northern and Southern participants. The final word of the limerick (e.g., mass/sparse) then either did or did not rhyme, depending on the reader's accent. Results showed disruption to eye movement behaviour when the final word did not rhyme, determined by the reader's accent, suggesting that inner speech resembles our own voice