D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Reverse-engineering biological networks from large data sets

Much of contemporary systems biology owes its success to the abstraction of a network, the idea that diverse kinds of molecular, cellular, and organismal species and interactions can be modeled as relational nodes and edges in a graph of dependencies. Since the advent of high-throughput data-acquisition technologies in fields such as genomics, metabolomics, and neuroscience, the automated inference and reconstruction of such interaction networks directly from large sets of activation data, commonly known as reverse-engineering, has become a routine procedure. Whereas early attempts at network reverse-engineering focused predominantly on producing maps of system architectures with minimal predictive modeling, reconstructions now play instrumental roles in answering questions about the statistics and dynamics of the underlying systems they represent. Many of these predictions have clinical relevance, suggesting novel paradigms for drug discovery and disease treatment. While other reviews focus predominantly on the details and effectiveness of individual network inference algorithms, here we examine the emerging field as a whole. We first summarize several key application areas in which inferred networks have made successful predictions. We then outline the two major classes of reverse-engineering methodologies, emphasizing that the type of prediction that one aims to make dictates the algorithms one should employ. We conclude by discussing whether recent breakthroughs justify the computational costs of large-scale reverse-engineering sufficiently to admit it as a mainstay in the quantitative analysis of living systems.Fil: Natale, Joseph J.. University of Emory; Estados UnidosFil: Hofmann, David. University of Emory; Estados UnidosFil: Hernández Lahme, Damián Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); Argentina. University of Emory; Estados UnidosFil: Nemenman, Ilya. University of Emory; Estados Unido

R & D for collider beauty physics at the LHC

We propose an R&D program for the development of a Beauty trigger and innovative elements of the associated spectrometer. A series of short test runs is proposed at the SPS p-pbar Collider with the minimal spectrometer which will allow a credible B signal to be obtained in an invariant mass spectrum of reconstructed B mesons. The program builds on the success of the recent collider run of the P238 Collaboration, in which clean signals from beam-beam interactions were observed in a large silicon strip microvertex detector running 1.5 mm from the circulating beams. A continuing successful R&D program of the type proposed could ultimately lead to a collider experiment at the LHC to study CP Violation and rare B decays

The US Southern Ocean Global Ocean Ecosystems Dynamics Program

The article presents information on the U.S. Southern Ocean Global Ocean Ecosystem Dynamics program (US SO GLOBEC). It was aimed at understanding the environmental and biological factors that contribute to enhanced Antarctic krill growth, reproduction, recruitment and survivorship, as well as the interactions between Antarctic krill and its predators and competitors. The highlights of US SO GLOBEC research are also discussed

The Higgs as a Portal to Plasmon-like Unparticle Excitations

12 LaTeX pages, 2 figures.-- Published in: JHEP04(2008)028.-- Final full-text version available at: http://dx.doi.org/10.1088/1126-6708/2008/04/028.A renormalizable coupling between the Higgs and a scalar unparticle operator O_U of non-integer dimension d_U<2 triggers, after electroweak symmetry breaking, an infrared divergent vacuum expectation value for O_U. Such IR divergence should be tamed before any phenomenological implications of the Higgs-unparticle interplay can be drawn. In this paper we present a novel mechanism to cure that IR divergence through (scale-invariant) unparticle self-interactions, which has properties qualitatively different from the mechanism considered previously. Besides finding a mass gap in the unparticle continuum we also find an unparticle pole reminiscent of a plasmon resonance. Such unparticle features could be explored experimentally through their mixing with the Higgs boson.Work supported in part by the European Commission under the European Union through the Marie Curie Research and Training Networks “Quest for Unification” (MRTN-CT- 2004-503369) and “UniverseNet” (MRTN-CT-2006-035863); by the Spanish Consolider- Ingenio 2010 Programme CPAN (CSD2007-0042); by a Comunidad de Madrid project (P-ESP-00346) and by CICYT, Spain, under contracts FPA 2007-60252 and FPA 2005-02211

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments

Comparison of Illumina and 454 Deep Sequencing in Participants Failing Raltegravir-Based Antiretroviral Therapy

Background: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. Methods: A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. Results: Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. Conclusions: In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls

Reactive community-based self-administered treatment against residual malaria transmission: study protocol for a randomized controlled trial

Background: Systematic treatment of all individuals living in the same compound of a clinical malaria case may clear asymptomatic infections and possibly reduce malaria transmission, where this is focal. High and sustained coverage is extremely important and requires active community engagement. This study explores a communitybased approach to treating malaria case contacts. Methods/design: This is a cluster-randomized trial to determine whether, in low-transmission areas, treating individuals living in the same compound of a clinical malaria case with dihydroartemisinin-piperaquine can reduce parasite carriage and thus residual malaria transmission. Treatment will be administered through the local health system with the approach of encouraging community participation designed and monitored through formative research. The trial goal is to show that this approach can reduce in intervention villages the prevalence of Plasmodium falciparum infection toward the end of the malaria transmission season. Discussion: Adherence and cooperation of the local communities are critical for the success of mass treatment campaigns aimed at reducing malaria transmission. By exploring community perceptions of the changing trends in malaria burden, existing health systems, and reaction to self-administered treatment, this study will develop and adapt a model for community engagement toward malaria elimination that is cost-effective and fits within the existing health system. Trial registration: Clinical trials.gov, NCT02878200. Registered on 25 August 2016

Integrating Positive and Clinical Psychology: Viewing Human Functioning as Continua from Positive to Negative Can Benefit Clinical Assessment, Interventions and Understandings of Resilience

In this review we argue in favour of further integration between the disciplines of positive and clinical psychology. We argue that most of the constructs studied by both positive and clinical psychology exist on continua ranging from positive to negative (e.g., gratitude to ingratitude, anxiety to calmness) and so it is meaningless to speak of one or other field studying the “positive” or the “negative”. However, we highlight historical and cultural factors which have led positive and clinical psychologies to focus on different constructs; thus the difference between the fields is more due to the constructs of study rather than their being inherently “positive” or “negative”. We argue that there is much benefit to clinical psychology of considering positive psychology constructs because; (a) constructs studied by positive psychology researchers can independently predict wellbeing when accounting for traditional clinical factors, both cross-sectionally and prospectively, (2) the constructs studied by positive psychologists can interact with risk factors to predict outcomes, thereby conferring resilience, (3) interventions that aim to increase movement towards the positive pole of well-being can be used encourage movement away from the negative pole, either in isolation or alongside traditional clinical interventions, and (4) research from positive psychology can support clinical psychology as it seeks to adapt therapies developed in Western nations to other cultures