A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ⩾30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) – placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD

Grounding Hypnosis in Science: The 'New' APA Division 30 definition of hypnosis as a step backwards.

Every decade or so, the Division 30 of the American Psychological Association (APA) has seen fit to redefine hypnosis (Elkins, Barabasz, Council, & Spiegel, 2015; Green, Barabasz, Barrett, & Montgomery, 2005; Kirsch, 1994). In the latest attempt, the Hypnosis Definition Committee (HDC) defined hypnosis as a 'state of consciousness involving focused attention and reduced peripheral awareness characterized by an enhanced capacity for response to suggestion' (Elkins et al., 2015, p. 6). One might justifiably wonder whether important discoveries or scientific breakthroughs or novel theoretical insights motivated the impetus to update the previous definition. In fact, the recently adopted definition is neither based on any apparent empirical foundation, noris it 'new.' Moreover, it has the potential to sow the seeds of conceptual and pragmatic confusion to an area sorely in need of greater clarification

Transfer Learning on Structural Brain Age Models to Decode Cognition in MS: A Federated Learning Approach.

Introduction. Classical deep learning research requires lots of centralised data. However, data sets are often stored at different clinical centers, and sharing sensitive patient data such as brain images is difficult. In this manuscript, we investigated the feasibility of federated learning, sending models to the data instead of the other way round, for research on brain magnetic resonant images of people with multiple sclerosis (MS). Methods. Using transfer learning on a previously published brain age model, we trained a model to decode performance on the symbol digit modalities test (SDMT) of patients with MS from structural T1 weighted MRI. Three international centers in Brussels, Greifswald and Prague participated in the project. In Brussels, one computer served as the server coordinating the FL project, while the other served as client for model training on local data (n=97). The other two clients were Greifswald (n=104) and Prague (n=100). Each FL round, the server sent a global model to the clients, where its fully connected layer was updated on the local data. After collecting the local models, the server applied a weighted average of two randomly picked clients, yielding a new global model. Results. After 22 federated learning rounds, the average validation loss across clients reached a minimum. The model appeared to have learned to assign SDMT values close to the mean with a mean absolute error of 9.04, 10.59 and 10.71 points between true and predicted SDMT on the test data sets of Brussels, Greifswald and Prague respectively. The overall test MAE across all clients was 10.13 points. Conclusion. Federated learning is feasible for machine learning research on brain MRI of persons with MS, setting the stage for larger transfer learning studies to investigate the utility of brain age latent representations in cognitive decoding tasks

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Reconfiguration, contestation, and decline: conceptualizing mature large technical systems

Large technical systems (LTS) are integral to modern lifestyles but arduous to analyze. In this paper, we advance a conceptualization of LTS using the notion of mature “phases,” drawing from insights into innovation studies, science and technology studies, political science, the sociology of infra- structure, history of technology, and governance. We begin by defining LTS as a unit of analysis and explaining its conceptual utility and novelty, situating it among other prominent sociotechnical theories. Next, we argue that after LTS have moved through the (overlapping) phases proposed by Thomas Hughes of invention, expansion, growth, momentum, and style,mature LTS undergo the additional (overlapping) phases of reconfiguration, contestation (subject to pressures such as drift and crisis), and eventually stagnation and decline. We illustrate these analytical phases with historical case studies and the conceptual literature, and close by suggesting future research to refine and develop the LTS framework, particularly related to more refined typologies, temporal dimensions, and a broadening of system users. We aim to contribute to theoretical debates about the coevolution of LTS as well as empirical discussions about system-related use, socio- technical change, and policy-making

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway

10.1371/journal.pone.0068283PLoS ONE87-POLN

Clinical and cost-effectiveness of computerised cognitive behavioural therapy for depression in primary care: Design of a randomised trial

<p>Abstract</p> <p>Background</p> <p>Major depression is a common mental health problem in the general population, associated with a substantial impact on quality of life and societal costs. However, many depressed patients in primary care do not receive the care they need. Reason for this is that pharmacotherapy is only effective in severely depressed patients and psychological treatments in primary care are scarce and costly. A more feasible treatment in primary care might be computerised cognitive behavioural therapy. This can be a self-help computer program based on the principles of cognitive behavioural therapy. Although previous studies suggest that computerised cognitive behavioural therapy is effective, more research is necessary. Therefore, the objective of the current study is to evaluate the (cost-) effectiveness of online computerised cognitive behavioural therapy for depression in primary care.</p> <p>Methods/Design</p> <p>In a randomised trial we will compare (a) computerised cognitive behavioural therapy with (b) treatment as usual by a GP, and (c) computerised cognitive behavioural therapy in combination with usual GP care. Three hundred mild to moderately depressed patients (aged 18–65) will be recruited in the general population by means of a large-scale Internet-based screening (<it>N </it>= 200,000). Patients will be randomly allocated to one of the three treatment groups. Primary outcome measure of the clinical evaluation is the severity of depression. Other outcomes include psychological distress, social functioning, and dysfunctional beliefs. The economic evaluation will be performed from a societal perspective, in which all costs will be related to clinical effectiveness and health-related quality of life. All outcome assessments will take place on the Internet at baseline, two, three, six, nine, and twelve months. Costs are measured on a monthly basis. A time horizon of one year will be used without long-term extrapolation of either costs or quality of life.</p> <p>Discussion</p> <p>Although computerised cognitive behavioural therapy is a promising treatment for depression in primary care, more research is needed. The effectiveness of online computerised cognitive behavioural therapy without support remains to be evaluated as well as the effects of computerised cognitive behavioural therapy in combination with usual GP care. Economic evaluation is also needed. Methodological strengths and weaknesses are discussed.</p> <p>Trial registration</p> <p>The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (ISRCTN47481236).</p

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Light-front holographic QCD and emerging confinement

In this report we explore the remarkable connections between light-front dynamics, its holographic mapping to gravity in a higher-dimensional anti-de Sitter (AdS) space, and conformal quantum mechanics. This approach provides new insights into the origin of a fundamental mass scale and the physics underlying confinement dynamics in QCD in the limit of massless quarks. The result is a relativistic light-front wave equation for arbitrary spin with an effective confinement potential derived from a conformal action and its embedding in AdS space. This equation allows for the computation of essential features of hadron spectra in terms of a single scale. The light-front holographic methods described here give a precise interpretation of holographic variables and quantities in AdS space in terms of light-front variables and quantum numbers. This leads to a relation between the AdS wave functions and the boost-invariant light-front wave functions describing the internal structure of hadronic bound-states in physical space-time. The pion is massless in the chiral limit and the excitation spectra of relativistic light-quark meson and baryon bound states lie on linear Regge trajectories with identical slopes in the radial and orbital quantum numbers. In the light-front holographic approach described here currents are expressed as an infinite sum of poles, and form factors as a product of poles. At large q(2) the form factor incorporates the correct power-law fall-off for hard scattering independent of the specific dynamics and is dictated by the twist. At low q2 the form factor leads to vector dominance. The approach is also extended to include small quark masses. We briefly review in this report other holographic approaches to QCD, in particular top-down and bottom-up models based on chiral symmetry breaking. We also include a discussion of open problems and future applications. (C)) 2015 Elsevier B.V. All rights reserved