Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data

Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets

Execution of the SimSET Monte Carlo PET/SPECT Simulator in the Condor Distributed Computing Environment

SimSET is a package for simulation of emission tomography data sets. Condor is a popular distributed computing environment. Simple C/C++ applications and shell scripts are presented which allow the execution of SimSET on the Condor environment. This is accomplished without any modification to SimSET by executing multiple instances and using its combinebin utility. This enables research facilities without dedicated parallel computing systems to utilize the idle cycles of desktop workstations to greatly reduce the run times of their SimSET simulations. The necessary steps to implement this approach in other environments are presented along with sample results

Parkinson disease clinical subtypes: Key features & clinical milestones

OBJECTIVES: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones. METHODS: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality. RESULTS: LCA identified distinct subtypes: motor only (N = 63) characterized by primary motor deficits; psychiatric & motor (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; cognitive & motor (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the cognitive & motor subtype. Surprisingly, mortality risk was similarly elevated for both cognitive & motor and psychiatric & motor subtypes compared to the motor only subtype (relative risk = 3.15, 2.60). INTERPRETATION: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes

A structural and dynamic model for the assembly of Replication Protein A on single-stranded DNA

Replication Protein A (RPA), the major eukaryotic single stranded DNA-binding protein, binds to exposed ssDNA to protect it from nucleases, participates in a myriad of nucleic acid transactions and coordinates the recruitment of other important players. RPA is a heterotrimer and coats long stretches of single-stranded DNA (ssDNA). The precise molecular architecture of the RPA subunits and its DNA binding domains (DBDs) during assembly is poorly understood. Using cryo electron microscopy we obtained a 3D reconstruction of the RPA trimerisation core bound with ssDNA (∼55 kDa) at ∼4.7 Å resolution and a dimeric RPA assembly on ssDNA. FRET-based solution studies reveal dynamic rearrangements of DBDs during coordinated RPA binding and this activity is regulated by phosphorylation at S178 in RPA70. We present a structural model on how dynamic DBDs promote the cooperative assembly of multiple RPAs on long ssDNA

TREC-Rio trial: a randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms [ISRCTN44153243]

Agitated or violent patients constitute 10% of all emergency psychiatric treatment. Management guidelines, the preferred treatment of clinicians and clinical practice all differ. Systematic reviews show that all relevant studies are small and none are likely to have adequate power to show true differences between treatments. Worldwide, current treatment is not based on evidence from randomised trials. In Brazil, the combination haloperidol-promethazine is frequently used, but no studies involving this mix exist. TREC-Rio (Tranquilização Rápida-Ensaio Clínico [Translation: Rapid Tranquillisation-Clinical Trial]) will compare midazolam with haloperidol-promethazine mix for treatment of agitated patients in emergency psychiatric rooms of Rio de Janeiro, Brazil. TREC-Rio is a randomised, controlled, pragmatic and open study. Primary measure of outcome is tranquillisation at 20 minutes but effects on other measures of morbidity will also be assessed. TREC-Rio will involve the collaboration of as many health care professionals based in four psychiatric emergency rooms of Rio as possible. Because the design of this trial does not substantially complicate clinical management, and in several aspects simplifies it, the study can be large, and treatments used in everyday practice can be evaluated

Quantum Gravity in Everyday Life: General Relativity as an Effective Field Theory

This article is meant as a summary and introduction to the ideas of effective field theory as applied to gravitational systems. Contents: 1. Introduction 2. Effective Field Theories 3. Low-Energy Quantum Gravity 4. Explicit Quantum Calculations 5. ConclusionsComment: 56 pages, 2 figures, JHEP style, Invited review to appear in Living Reviews of Relativit

The Cosmology of Composite Inelastic Dark Matter

Composite dark matter is a natural setting for implementing inelastic dark matter - the O(100 keV) mass splitting arises from spin-spin interactions of constituent fermions. In models where the constituents are charged under an axial U(1) gauge symmetry that also couples to the Standard Model quarks, dark matter scatters inelastically off Standard Model nuclei and can explain the DAMA/LIBRA annual modulation signal. This article describes the early Universe cosmology of a minimal implementation of a composite inelastic dark matter model where the dark matter is a meson composed of a light and a heavy quark. The synthesis of the constituent quarks into dark mesons and baryons results in several qualitatively different configurations of the resulting dark matter hadrons depending on the relative mass scales in the system.Comment: 31 pages, 4 figures; references added, typos correcte

Bullying girls - Changes after brief strategic family therapy: A randomized, prospective, controlled trial with one-year follow-up

Background: Many girls bully others. They are conspicuous because of their risk-taking behavior, increased anger, problematic interpersonal relationships and poor quality of life. Our aim was to determine the efficacy of brief strategic family therapy (BSFT) for bullying-related behavior, anger reduction, improvement of interpersonal relationships, and improvement of health-related quality of life in girls who bully, and to find out whether their expressive aggression correlates with their distinctive psychological features. Methods: 40 bullying girls were recruited from the general population: 20 were randomly selected for 3 months of BSFT. Follow-up took place 12 months after the therapy had ended. The results of treatment were examined using the Adolescents' Risk-taking Behavior Scale (ARBS), the State-Trait Anger Expression Inventory (STAXI), the Inventory of Interpersonal Problems (IIP-D), and the SF-36 Health Survey (SF-36). Results: In comparison with the control group (CG) (according to the intent-to-treat principle), bullying behavior in the BSFT group was reduced (BSFT-G from n = 20 to n = 6; CG from n = 20 to n = 18, p = 0.05) and statistically significant changes in all risk-taking behaviors (ARBS), on most STAXI, IIP-D, and SF-36 scales were observed after BSFT. The reduction in expressive aggression (Anger-Out scale of the STAXI) correlated with the reduction on several scales of the ARBS, IIP-D, and SF-36. Follow-up a year later showed relatively stable events. Conclusions: Our findings suggest that bullying girls suffer from psychological and social problems which may be reduced by the use of BSFT. Expressive aggression in girls appears to correlate with several types of risk-taking behavior and interpersonal problems, as well as with health-related quality of life. Copyright (c) 2006 S. Karger AG, Basel

Progression and Forecast of a Curated Web-of-Trust: A Study on the Debian Project's Cryptographic Keyring

The Debian project is one of the largest free software undertakings worldwide. It is geographically distributed, and participation in the project is done on a voluntary basis, without a single formal employee or directly funded person. As we will explain, due to the nature of the project, its authentication needs are very strict — User/password schemes are way surpassed, and centralized trust management schemes such as PKI are not compatible with its distributed and flat organization; fully decentralized schemes such as the PGP Web of Trust are insuficient by themselves. The Debian project has solved this need by using what we termed a ``curated Web of Trust''. We will explain some lessons learned from a massive key migration process that was triggered in 2014. We will present the social insight we have found from examining the relationships expressed as signatures in this curated Web of Trust, some recommendations on personal key-signing policies, and a statistical study and forecast on aging, refreshment and survival of project participants stemming from an analysis on their key-handling

T Cell Integrin Overexpression as a Model of Murine Autoimmunity

Integrin adhesion molecules have important adhesion and signaling functions. They also play a central role in the pathogenesis of many autoimmune diseases. Over the past few years we have described a T cell adoptive transfer model to investigate the role of T cell integrin adhesion molecules in the development of autoimmunity. This report summarizes the methods we used in establishing this murine model. By treating murine CD4+ T cells with DNA hypomethylating agents and by transfection we were able to test the in vitro effects of integrin overexpression on T cell autoreactive proliferation, cytotoxicity, adhesion and trafficking. Furthermore, we showed that the ability to induce in vivo autoimmunity may be unique to the integrin lymphocyte function associated antigen-1 (LFA-1)