A comparison of methods to adjust for continuous covariates in the analysis of randomised trials

BACKGROUND: Although covariate adjustment in the analysis of randomised trials can be beneficial, adjustment for continuous covariates is complicated by the fact that the association between covariate and outcome must be specified. Misspecification of this association can lead to reduced power, and potentially incorrect conclusions regarding treatment efficacy. METHODS: We compared several methods of adjustment to determine which is best when the association between covariate and outcome is unknown. We assessed (a) dichotomisation or categorisation; (b) assuming a linear association with outcome; (c) using fractional polynomials with one (FP1) or two (FP2) polynomial terms; and (d) using restricted cubic splines with 3 or 5 knots. We evaluated each method using simulation and through a re-analysis of trial datasets. RESULTS: Methods which kept covariates as continuous typically had higher power than methods which used categorisation. Dichotomisation, categorisation, and assuming a linear association all led to large reductions in power when the true association was non-linear. FP2 models and restricted cubic splines with 3 or 5 knots performed best overall. CONCLUSIONS: For the analysis of randomised trials we recommend (1) adjusting for continuous covariates even if their association with outcome is unknown; (2) keeping covariates as continuous; and (3) using fractional polynomials with two polynomial terms or restricted cubic splines with 3 to 5 knots when a linear association is in doubt

Genetic analysis of male reproductive success in relation to density in the zebrafish, Danio rerio

BACKGROUND: We used behavioural and genetic data to investigate the effects of density on male reproductive success in the zebrafish, Danio rerio. Based on previous measurements of aggression and courtship behaviour by territorial males, we predicted that they would sire more offspring than non-territorial males. RESULTS: Microsatellite analysis of paternity showed that at low densities territorial males had higher reproductive success than non-territorial males. However, at high density territorial males were no more successful than non-territorials and the sex difference in the opportunity for sexual selection, based on the parameter I(mates), was low. CONCLUSION: Male zebrafish exhibit two distinct mating tactics; territoriality and active pursuit of females. Male reproductive success is density dependent and the opportunity for sexual selection appears to be weak in this species

Towards a Holographic Model of Color-Flavor Locking Phase

We demonstrate a holographic realization of color-flavor locking phase, using N=4 SU(Nc) SYM coupled to N=2 Nf fundamental hypermultiplets as an example. The gravity dual consists of Nc D3-branes and Nf D7-branes with world volume gauge field representing the baryon density. Treating a small number \tilde{N}c << Nc of D3-branes as Yang-Mills instantons on the D7-branes, we consider possible potential(s) on their moduli space or equivalently the Higgs branch. We show that a non-trivial potential can be generated by including the backreaction of the baryonic density on the D7-branes, this dynamically drives the instantons (= D3-branes) into dissolution. We interpret this as a color-flavor locking since the size of the instanton is the squark vev, and study the symmetry breaking patterns. Extending to finite temperature setup, we demonstrate that color-flavor locking persists, and the thermal effect provides additional structures in the phase diagram.Comment: 1+38 pages, 6 eps figures; typos corrected, acknowledgment and references added, discussions in sections 3.1 and 4.3 improve

On Stability and Transport of Cold Holographic Matter

We use gauge-gravity duality to study the stability of zero-temperature, finite baryon density states of N=4 supersymmetric SU(Nc) Yang-Mills theory coupled to a single massive fundamental-representation N=2 hypermultiplet in the large-Nc and large-coupling limits. In particular, we study the spectrum of mesons. The dual description is a probe D7-brane in anti-de Sitter space with a particular configuration of worldvolume fields. The meson spectrum is dual to the spectrum of fluctuations of worldvolume fields about that configuration. We use a combination of analytical and numerical techniques to compute the spectrum, including a special numerical technique designed to deal with singular points in the fluctuations' equations of motion. Despite circumstantial evidence that the system might be unstable, such as a finite entropy density at zero temperature and the existence of instabilities in similar theories, we find no evidence of any instabilities, at least for the ranges of frequency and momenta that we consider. We discover a pole on the imaginary frequency axis in a scalar meson two-point function, similar to the diffusive mode in the two-point function of a conserved charge.Comment: 40 pages, 7 figure

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction

Should Attractive Males Sneak: The Trade-Off between Current and Future Offspring

Peer reviewe

Electro-acupuncture for treatment of knee pain from osteoarthritis and the possible endocrinology changes: a study protocol for a randomized controlled trial

BACKGROUND: Osteoarthritis of the knee is a major cause of disability among adults. Electro-acupuncture is considered a potentially useful treatment for osteoarthritis. The purpose of this study is to assess the efficacy of electro-acupuncture on pain control, pain perception, plasma cortisol and beta-endorphin levels, patient-perceived quality of life, and pain medication use in patients with chronic knee pain. METHODS/DESIGN: This study is a placebo-controlled, randomized, double-blind, parallel design trial. One hundred sixty out-patients who are more than 50 years old and who have osteoarthritis of the knee will be recruited from the island of Mallorca, Spain. Each participant will be randomly placed into one of two groups: (sham) electro-acupuncture non-insertion technique and real electro-acupuncture. Acupuncture treatments will be the Traditional Chinese Medicine type. The patients will be evaluated after a period of 1 month (with two weekly sessions), 3 months (with one monthly session), 6 months (with one session every 45 days), and 1 year later with follow-up sessions at the end of the study (with one session every 2 months). The primary outcomes will be based on the observed changes from the baseline of the visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain measured at 12 weeks after the end of treatment. Also to be included in the study are the possible changes in the secondary efficacy variables from baseline as assessed by the Short Form 36 version 2 health survey (patient-perceived quality of life), patient plasma cortisol and beta-endorphin levels at the different treatment stages, the Goldberg Anxiety and Depression Scale, pain medication use, functional capacity and stiffness (WOMAC subscales), and a VAS. These variables will be assessed at 1 month, 3 months, 6 months, and 1 year after study commencement. DISCUSSION: The findings from this study will help to determine whether electro-acupuncture is effective for chronic knee pain management in older people and whether electro-acupuncture can deliver results for the improvement of pain relief, stiffness, and disability. The study will therefore be a major step toward understanding the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system in the effectiveness of electro-acupuncture for chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02299713 (11 Nov. 2014)