Efficacy of a fixed combination of calcipotriol/betamethasone dipropionate topical gel in adult patients with mild to moderate psoriasis: blinded interim analysis of a phase IV, multicenter, randomized, controlled, prospective study

Background: Psoriasis is a common, chronic, inflammatory skin disease with the majority of individuals having limited disease, treated with topical medication. However, special attributes of topical treatments like galenic/cosmetic properties or an inconvenient treatment schedule may result in low preference for topical treatments. Hence, there is strong medical need for a topical medication, which is highly efficacious, easy-to-use and preferred by both physicians and patients. Objective: Blinded interim analysis with the purpose to assess efficacy of (both from the physician's and patient's perspective) and the patients' preference with a highly efficacious and easy-to-use fixed combination of calcipotriol/betamethasone dipropionate topical gel after 8 weeks of once daily treatment in a large patient population. Methods: In this phase IV, international, multicentre, randomized, controlled, prospective, parallel group study, adult patients with active, mild to moderate psoriasis despite previous topical psoriasis treatment, i.e. unsuccessful in the 8 weeks preceding study participation, are followed over 64 weeks. During the first 8 weeks the patients apply their medication once a day followed by a 56-weeks maintenance period according to SmPC. Blinded interim analysis of all patients included demographics, Physician's Global Assessment, the novel Patient's self Global Assessment (PsGA) and Patient Preference Questionnaire (PPQ). Results: 1795 patients were analysed. At week 8, 36.5% of the physicians rated the patients' psoriasis as clear/almost clear. Similarly, based on the patients' self-assessment, 34.2% had a clear/almost clear score of PsGA in week 8. Analysis of the PPQ showed that the vast majority of the patients judged their 8-week treatment to be preferable compared with their previous treatments. Conclusion: Results of this blinded interim analysis indicate that the fixed combination of calcipotriol/betamethasone dipropionate gel is highly efficacious and preferred by the majority of analysed patients

Altered Posterior Midline Activity in Patients with Jerky and Tremulous Functional Movement Disorders

Objective: To explore changes in resting-state networks in patients with jerky and tremulous functional movement disorders (JT-FMD). Methods: Resting-state functional magnetic resonance imaging data from seventeen patients with JT-FMD and seventeen age-, sex-, and education-matched healthy controls (HC) were investigated. Independent component analysis was used to examine the central executive network (CEN), salience network, and default mode network (DMN). Frequency distribution of network signal fluctuations and intra- and internetwork functional connectivity were investigated. Symptom severity was measured using the Clinical Global Impression-Severity scale. Beck Depression Inventory and Beck Anxiety Inventory scores were collected tomeasure depression and anxiety in FMD, respectively. Results: Compared with HC, patients with JT-FMD had significantly decreased power of lower range (0.01-0.10 Hz) frequency fluctuations in a precuneus and posterior cingulate cortex component of the DMN and in the dorsal attention network (DAN) component of the CEN (false discovery rate-corrected p < 0.05). No significant group differences were found for intra- and internetwork functional connectivity. In patients with JT-FMD, symptom severity was not significantly correlated with network measures. Depression scores were weakly correlated with intranetwork functional connectivity in the medial prefrontal cortex, while anxiety was not found to be related to network connectivity. Conclusions: Given the changes in the posterodorsal components of the DMN and DAN, we postulate that the JT-FMD-related functional alterations found in these regions could provide support for the concept that particularly attentional dysregulation is a fundamental disturbance in these patients

The Dutch health insurance reform: switching between insurers, a comparison between the general population and the chronically ill and disabled

Background: On 1 January 2006 a number of far-reaching changes in the Dutch health insurance system came into effect. In the new system of managed competition consumer mobility plays an important role. Consumers are free to change their insurer and insurance plan every year. The idea is that consumers who are not satisfied with the premium or quality of care provided will opt for a different insurer. This would force insurers to strive for good prices and quality of care. Internationally, the Dutch changes are under the attention of both policy makers and researchers. Questions answered in this article relate to switching behaviour, reasons for switching, and differences between population categories. Methods: Postal questionnaires were sent to 1516 members of the Dutch Health Care Consumer Panel and to 3757 members of the National Panel of the Chronically ill and Disabled (NPCD) in April 2006. The questionnaire was returned by 1198 members of the Consumer Panel (response 79%) and by 3211 members of the NPCD (response 86%). Among other things, questions were asked about choices for a health insurer and insurance plan and the reasons for this choice. Results: Young and healthy people switch insurer more often than elderly or people in bad health. The chronically ill and disabled do not switch less often than the general population when both populations are comparable on age, sex and education. For the general population, premium is more important than content, while the chronically ill and disabled value content of the insurance package as well. However, quality of care is not important for either group as a reason for switching. Conclusion: There is increased mobility in the new system for both the general population and the chronically ill and disabled. This however is not based on quality of care. If reasons for switching are unrelated to the quality of care, it is hard to believe that switching influences the quality of care. As yet there are no signs of barriers to switch insurer for the chronically ill and disabled. This however could change in the future and it is therefore important to monitor changes.

Individuals with Fear of Blushing Explicitly and Automatically Associate Blushing with Social Costs

To explain fear of blushing, it has been proposed that individuals with fear of blushing overestimate the social costs of their blushing. Current information-processing models emphasize the relevance of differentiating between more automatic and more explicit cognitions, as both types of cognitions may independently influence behavior. The present study tested whether individuals with fear of blushing expect blushing to have more negative social consequences than controls, both on an explicit level and on a more automatic level. Automatic associations between blushing and social costs were assessed in a treatment-seeking sample of individuals with fear of blushing who met DSM-IV criteria for social anxiety disorder (n = 49) and a non-anxious control group (n = 27) using a single-target Implicit Association Test (stIAT). In addition, participants’ explicit expectations about the social costs of their blushing were assessed. Individuals with fear of blushing showed stronger associations between blushing and negative outcomes, as indicated by both stIAT and self-report. The findings support the view that automatic and explicit associations between blushing and social costs may both help to enhance our understanding of the cognitive processes that underlie fear of blushing

Representing complex data using localized principal components with application to astronomical data

Often the relation between the variables constituting a multivariate data space might be characterized by one or more of the terms: ``nonlinear'', ``branched'', ``disconnected'', ``bended'', ``curved'', ``heterogeneous'', or, more general, ``complex''. In these cases, simple principal component analysis (PCA) as a tool for dimension reduction can fail badly. Of the many alternative approaches proposed so far, local approximations of PCA are among the most promising. This paper will give a short review of localized versions of PCA, focusing on local principal curves and local partitioning algorithms. Furthermore we discuss projections other than the local principal components. When performing local dimension reduction for regression or classification problems it is important to focus not only on the manifold structure of the covariates, but also on the response variable(s). Local principal components only achieve the former, whereas localized regression approaches concentrate on the latter. Local projection directions derived from the partial least squares (PLS) algorithm offer an interesting trade-off between these two objectives. We apply these methods to several real data sets. In particular, we consider simulated astrophysical data from the future Galactic survey mission Gaia.Comment: 25 pages. In "Principal Manifolds for Data Visualization and Dimension Reduction", A. Gorban, B. Kegl, D. Wunsch, and A. Zinovyev (eds), Lecture Notes in Computational Science and Engineering, Springer, 2007, pp. 180--204, http://www.springer.com/dal/home/generic/search/results?SGWID=1-40109-22-173750210-

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case–control study (VeCosCO)

Introduction: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints. To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. / Methods and analysis: This is a prospective case–control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [18F]DPA-714 PET, and brain functioning and structure using (f)MRI. / Ethics and dissemination: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.

BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials

Stage-specific fluorescence intensity of GFP and mCherry during sporulation In Bacillus Subtilis

<p>Abstract</p> <p>Background</p> <p>Fluorescent proteins are powerful molecular biology tools that have been used to study the subcellular dynamics of proteins within live cells for well over a decade. Two fluorescent proteins commonly used to enable dual protein labelling are GFP (green) and mCherry (red). Sporulation in the Gram positive bacterium <it>Bacillus subtilis </it>has been studied for many years as a paradigm for understanding the molecular basis for differential gene expression. As sporulation initiates, cells undergo an asymmetric division leading to differential gene expression in the small prespore and large mother cell compartments. Use of two fluorescent protein reporters permits time resolved examination of differential gene expression either in the same compartments or between compartments. Due to the spectral properties of GFP and mCherry, they are considered an ideal combination for co-localisation and co-expression experiments. They can also be used in combination with fluorescent DNA stains such as DAPI to correlate protein localisation patterns with the developmental stage of sporulation which can be linked to well characterised changes in DNA staining patterns.</p> <p>Findings</p> <p>While observing the recruitment of the transcription machinery into the forespore of sporulating <it>Bacillus subtilis</it>, we noticed the occurrence of stage-specific fluorescence intensity differences between GFP and mCherry. During vegetative growth and the initial stages of sporulation, fluorescence from both GFP and mCherry fusions behaved similarly. During stage II-III of sporulation we found that mCherry fluorescence was considerably diminished, whilst GFP signals remained clearly visible. This fluorescence pattern reversed during the final stage of sporulation with strong mCherry and low GFP fluorescence. These trends were observed in reciprocal tagging experiments indicating a direct effect of sporulation on fluorescent protein fluorophores.</p> <p>Conclusions</p> <p>Great care should be taken when interpreting the results of protein localisation and quantitative gene expression patterns using fluorescent proteins in experiments involving intracellular physiological change. We believe changes in the subcellular environment of the sporulating cell leads to conditions that differently alter the spectral properties of GFP and mCherry making an accurate interpretation of expression profiles technically challenging.</p