Very Delayed Remote Ischemic Post-conditioning Induces Sustained Neurological Recovery by Mechanisms Involving Enhanced Angioneurogenesis and Peripheral Immunosuppression Reversal

Ischemic conditioning is defined as a transient and subcritical period of ischemia integrated in an experimental paradigm that involves a stimulus of injurious ischemia, activating endogenous tissue repair mechanisms that lead to cellular protection under pathological conditions like stroke. Whereas ischemic pre-conditioning is irrelevant for stroke treatment, ischemic post-conditioning, and especially non-invasive remote ischemic post-conditioning (rPostC) is an innovative and potential strategy for stroke treatment. Although rPostC has been shown to induce neuroprotection in stroke models before, resulting in some clinical trials on the way, fundamental questions with regard to its therapeutic time frame and its underlying mechanisms remain elusive. Hence, we herein used a model of non-invasive rPostC of hind limbs after cerebral ischemia in male C57BL6 mice, studying the optimal timing for the application of rPostC and its underlying mechanisms for up to 3 months. Mice undergoing rPostC underwent three different paradigms, starting with the first cycle of rPostC 12 h, 24 h, or 5 days after stroke induction, which is a very delayed time point of rPostC that has not been studied elsewhere. rPostC as applied within 24 h post-stroke induces reduction of infarct volume on day three. On the contrary, very delayed rPostC does not yield reduction of infarct volume on day seven when first applied on day five, albeit long-term brain injury is significantly reduced. Likewise, very delayed rPostC yields sustained neurological recovery, whereas early rPostC (i.e., <24 h) results in transient neuroprotection only. The latter is mediated via heat shock protein 70 that is a well-known signaling protein involved in the pathophysiological cellular cascade of cerebral ischemia, leading to decreased proteasomal activity and decreased post-stroke inflammation. Very delayed rPostC on day five, however, induces a pleiotropic effect, among which a stimulation of angioneurogenesis, a modulation of the ischemic extracellular milieu, and a reversal of the stroke-induced immunosuppression occur. As such, very delayed rPostC appears to be an attractive tool for future adjuvant stroke treatment that deserves further preclinical attention before large clinical trials are in order, which so far have predominantly focused on early rPostC only

A discrete choice experiment to explore patients’ willingness to risk disease relapse from treatment withdrawal in psoriatic arthritis

The objective of this study is to assess patient preferences for treatment-related benefits and risk of disease relapse in the management of low disease states of psoriatic arthritis (PsA). Focus groups with patients and a literature review were undertaken to determine the characteristics of treatment and symptoms of PsA important to patients. Patient preferences were assessed using a discrete choice experiment which compared hypothetical treatment profiles of the risk and benefits of treatment withdrawal. The risk outcome included increased risk of disease relapse, while benefit outcomes included reduced sickness/nausea from medication and changes in health-related quality of life. Each patient completed 12 choice sets comparing treatment profiles. Preference weights were estimated using a logic regression model, and the maximum acceptable risk in disease relapse for a given improvement in benefit outcomes was elicited. Final sample included 136 patients. Respondents attached the greatest importance to eliminating severe side effects of sickness/nausea and the least importance to a change in risk of relapse. Respondents were willing to accept an increase in the risk of relapse of 32.6 % in order to eliminate the side effects of sickness/nausea. For improvements in health status, the maximum acceptable risk in relapse was comparable to a movement from some to no sickness/nausea. The study suggests that patients in low disease states of PsA are willing to accept greater risks of relapse for improvements in side effects of sickness/nausea and overall health status, with the most important benefit attribute being the elimination of severe sickness or nausea

Differences in social decision-making between proposers and responders during the ultimatum game: an eeg study

The Ultimatum Game (UG) is a typical paradigm to investigate social decision-making. Although the behavior of humans in this task is already well established, the underlying brain processes remain poorly understood. Previous investigations using event-related potentials (ERPs) revealed three major components related to cognitive processes in participants engaged in the responder condition, the early ERP component P2, the feedback-related negativity (FRN) and a late positive wave (late positive component, LPC). However, the comparison of the ERP waveforms between the responder and proposer conditions has never been studied. Therefore, to investigate condition-related electrophysiological changes, we applied the UG paradigm and compared parameters of the P2, LPC and FRN components in twenty healthy participants. For the responder condition, we found a significantly decreased amplitude and delayed latency for the P2 component, whereas the mean amplitudes of the LPC and FRN increased compared to the proposer condition. Additionally, the proposer condition elicited an early component consisting of a negative deflection around 190 ms, in the upward slope of the P2, probably as a result of early conflict-related processing. Using independent component analysis (ICA), we extracted one functional component time-locked to this deflection, and with source reconstruction (LAURA) we found the anterior cingulate cortex (ACC) as one of the underlying sources. Overall, our findings indicate that intensity and time-course of neuronal systems engaged in the decision-making processes diverge between both UG conditions, suggesting differential cognitive processes. Understanding the electrophysiological bases of decision-making and social interactions in controls could be useful to further detect which steps are impaired in psychiatric patients in their ability to attribute mental states (such as beliefs, intents, or desires) to oneself and others. This ability is called mentalizing (also known as theory of mind)

The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA. The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naïve PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids). Methods/design: GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naïve, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index. Reflecting a “step down” therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks. Discussion: The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy. Trial registration: EudraCT 2013–004122-28. 24/09/2013

Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis

BACKGROUND: Conventional tests for tuberculous pleuritis have several limitations. A variety of new, rapid tests such as nucleic acid amplification tests – including polymerase chain reaction – have been evaluated in recent times. We conducted a systematic review to determine the accuracy of nucleic acid amplification (NAA) tests in the diagnosis of tuberculous pleuritis. METHODS: A systematic review and meta-analysis of 38 English and Spanish articles (with 40 studies), identified via searches of six electronic databases, hand searching of selected journals, and contact with authors, experts, and test manufacturers. Sensitivity, specificity, and other measures of accuracy were pooled using random effects models. Summary receiver operating characteristic curves were used to summarize overall test performance. Heterogeneity in study results was formally explored using subgroup analyses. RESULTS: Of the 40 studies included, 26 used in-house ("home-brew") tests, and 14 used commercial tests. Commercial tests had a low overall sensitivity (0.62; 95% confidence interval [CI] 0.43, 0.77), and high specificity (0.98; 95% CI 0.96, 0.98). The positive and negative likelihood ratios for commercial tests were 25.4 (95% CI 16.2, 40.0) and 0.40 (95% CI 0.24, 0.67), respectively. All commercial tests had consistently high specificity estimates; the sensitivity estimates, however, were heterogeneous across studies. With the in-house tests, both sensitivity and specificity estimates were significantly heterogeneous. Clinically meaningful summary estimates could not be determined for in-house tests. CONCLUSIONS: Our results suggest that commercial NAA tests may have a potential role in confirming (ruling in) tuberculous pleuritis. However, these tests have low and variable sensitivity and, therefore, may not be useful in excluding (ruling out) the disease. NAA test results, therefore, cannot replace conventional tests; they need to be interpreted in parallel with clinical findings and results of conventional tests. The accuracy of in-house nucleic acid amplification tests is poorly defined because of heterogeneity in study results. The clinical applicability of in-house NAA tests remains unclear

The Populist politics of Euroscepticism in times of crisis: a framework for analysis

The European Union has been recently exposed to the multiple shocks of the Great Recession, the migrant crisis, and Brexit. Populist parties have been, either directly or indirectly, considered the principal beneficiaries of these crises in light of their Eurosceptic profiles. In this introductory article, we lay out the conceptual and analytical tools necessary to identify populist Eurosceptic actors, and systematically tackle the under-explored link between populist Eurosceptic framing and the unfolding of the different European crises. While we provide a framework to assess (alleged) changes in the framing of these parties, we also contend that these parties may have released effects in the political process by conditioning shifts in the positions on Europe of their mainstream competitors. In doing so, we define a set of possible interactive scenarios

#EEGManyLabs: Investigating the Replicability of Influential EEG Experiments

There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations. © 2021 The Authors

Cognitive Effects of Mindfulness Training: Results of a Pilot Study Based on a Theory Driven Approach

The present paper reports a pilot study which tested cognitive effects of mindfulness practice in a theory-driven approach. Thirty-four fifth graders received either a mindfulness training which was based on the mindfulness-based stress reduction approach (experimental group), a concentration training (active control group), or no treatment (passive control group). Based on the operational definition of mindfulness by Bishop et al. (2004), effects on sustained attention, cognitive flexibility, cognitive inhibition, and data-driven as opposed to schema-based information processing were predicted. These abilities were assessed in a pre-post design by means of a vigilance test, a reversible figures test, the Wisconsin Card Sorting Test, a Stroop test, a visual search task, and a recognition task of prototypical faces. Results suggest that the mindfulness training specifically improved cognitive inhibition and data-driven information processing

#EEGManyLabs: Investigating the replicability of influential EEG experiments

There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations