Expression of GPR17 receptor in a murine model of perinatal brain neuroinflammation and its possible interaction with Wnt pathway

Oligodendrocyte precursor cells (OPCs) are generated in specific germinal regions and progressively maturate to myelinating cells. Oligodendrocytes (OLs) differentiation is regulated by a complex interplay of intrinsic, epigenetic and extrinsic factors, including Wnt and the G protein-coupled receptor referred to as GPR17 (Mitew et al., 2014). This receptor responds to both extracellular nucleotides (UDP, UDP-glucose) and cysteinyl-leukotrienes (Ciana et al., 2006), endogenous signaling molecules involved in inflammatory response and in the repair of brain lesions. GPR17 is highly expressed in OPCs during the transition to immature OLs, but it is down-regulated in mature cells. Accordingly, GPR17-expressing OPCs are already present in mice at birth, increase over time, reach a peak at P10, before the peak of myelination, and then decline in the adult brain (Boda et al., 2011). Of note, in cultured OPCs, early GPR17 silencing has been shown to profoundly affect their ability to generate mature OLs (Fumagalli et al., 2011, 2015). Myelination defects characterize many brain disorders, including perinatal brain injury caused by systemic inflammation (Favrais et al., 2011), which is a leading cause of preterm birth. It has already been suggested that an imbalance in the Wnt/\u3b2-catenin/TCF4 pathway could be involved in the maturation arrest of OLs that is observed in premature infants (Yuen et al., 2014). No data are currently available on GPR17 in perinatal brain injury and on its possible interaction with Wnt pathway. Based on these premises, the aim of this work was to assess if the maturational blockade of OLs due to mild systemic perinatal inflammation, induced by intraperitoneal injections of interleukin-1\u3b2 (IL- 1\u3b2), is accompanied by defects in GPR17 expression and whether the Wnt pathway is involved in the regulation of GPR17. Data showed that in newborn mice exposed to IL-1\u3b2, which induces a blockade of oligodendrocyte maturation, GPR17 expression is not affected at early time point (P5), but it is downregulated at P10, when its expression should be maximal. Moreover, in vitro studies revealed that the maturation blockade of the oligodendroglial cell line Oli-Neu, after treatment with a Wnt Agonist II, is accompanied by a severe inhibition of GPR17 expression. In conclusion, our data have shown that myelination defects observed in perinatal brain injury are associated with defects in GPR17 expression; further studies are needed to characterize the molecular link between Wnt pathway and GPR17 receptor

Assessing the safety attitudes questionnaire (SAQ), German language version in Swiss university hospitals - A validation study

Background: Improving patient safety has become a major focus of clinical care and research over the past two decades. An institution's patient safety climate represents an essential component of ensuring a safe environment and thereby can be vital to the prevention of adverse events. Covering six patient safety related factors, the Safety Attitudes Questionnaire (SAQ) is a validated and widely used instrument to measure the patient safety climate in clinical areas. The objective of this study was to assess the psychometric properties of the German language version of the SAQ. Methods. A survey was carried out in two University Hospitals in Switzerland in autumn 2009 where the SAQ was distributed to a sample of 406 nurses and physicians in medical and surgical wards. Following the American Educational Research Association guidelines, we tested the questionnaire validity by levels of evidence: content validity, internal structure and relations to other variables. Confirmatory factor analysis was used to examine factor structure. Cronbach's alphas and inter-item correlations were calculated to examine internal consistency reliability. Results: A total of 319 questionnaires were completed representing an overall response rate of 78.6%. For three items, the item content validity index was <0.75. Confirmatory factor analysis showed acceptable model fit (RMSEA = 0.045; CFI = 0.944) for the six-factor model. Additional exploratory factor analysis could not identify a better factor model. SAQ factor scores showed positive correlations with the Safety Organizing Scale (r =.56 -.72). The SAQ German version showed moderate to strong internal consistency reliability indices (Cronbach alpha =.65 -.83). Conclusions: The German language version of the SAQ demonstrated acceptable to good psychometric properties and therefore shows promise to be a sound instrument to measure patient safety climate in Swiss hospital wards. However, the low item content validity and large number of missing responses for several items suggest that improvements and adaptations in translation are required for select items, especially within the perception of management scale. Following these revisions, psychometric properties should reassessed in a randomly selected sample and hospitals and departments prior to use in Swiss hospital settings. © 2013 Zimmermann et al.; licensee BioMed Central Ltd

On the Theory of Vibronic Superradiance

The Dicke superradiance on vibronic transitions of impurity crystals is considered. It is shown that parameters of the superradiance (duration and intensity of the superradiance pulse and delay times) on each vibronic transition depend on the strength of coupling of electronic states with the intramolecular impurity vibration (responsible for the vibronic structure of the optical spectrum in the form of vibrational replicas of the pure electronic line) and on the crystal temperature through the Debye-Waller factor of the lattice vibrations. Theoretical estimates of the ratios of the time delays, as well as of the superradiance pulse intensities for different vibronic transitions well agree with the results of experimental observations of two-color superradiance in the polar dielectric KCl:O2-. In addition, the theory describes qualitatively correctly the critical temperature dependence of the superradiance effect.Comment: 8 pages, 1 figur

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia-mediated neuroinflammation is key in numerous brain diseases including encephalopathy of the preterm born infant. Microglia of the still-developing brain have unique properties but little is known of how they regulate their inflammatory activation. This is important information as every year 9 million preterm born infants acquire persisting neurological injuries associated with encephalopathy and we lack strategies to prevent and treat these injuries. Our study of activation state regulators in immature brain microglia found a robust down-regulation of Wnt/β-catenin pathway receptors, ligands and intracellular signalling members in pro-inflammatory microglia. We undertook our studies initially in a mouse model of microglia-mediated encephalopathy including the clinical hallmarks of oligodendrocyte injury and hypomyelination. We purified microglia from this model and applied a genome-wide transcriptomics analysis validated with quantitative profiling. We then verified that down-regulation of the Wnt/β-catenin signalling cascade is sufficient and necessary to drive microglia into an oligodendrocyte-damaging phenotype using multiple pharmacological and genetic approaches in vitro and in vivo in mice and in humans and zebrafish. We also demonstrated that genomic variance in the WNT/β-catenin pathway is associated with the anatomical connectivity phenotype of the human preterm born infant. This integrated analysis of genomics and connectivity, as a surrogate for oligodendrocyte function/myelination, is agnostic to cell type. However, this data indicates that the WNT pathway is relevant to human brain injury and specifically that WNT variants may be useful clinically for injury stratification and prognosis. Finally, we performed a translational experiment using a BBB penetrant microglia-specific targeting 3DNA nanocarrier to deliver a Wnt agonist specifically and directly to microglia in vivo. Increasing the activity of the Wnt/β-catenin pathway specifically in microglia in our model of microglia-mediated encephalopathy was able to reduce microglial pro-inflammatory activation, prevent the typical hypomyelination and also prevent the long-term memory deficit associated with this hypomyelination. In summary, the canonical Wnt/β-catenin pathway regulates microglial activation and up-regulation of this pathway could be a viable neurotherapeutic strategy

Falls and mobility in Parkinson's disease: protocol for a randomised controlled clinical trial

Background Although physical therapy and falls prevention education are argued to reduce falls and disability in people with idiopathic Parkinson\u27s disease, this has not yet been confirmed with a large scale randomised controlled clinical trial. The study will investigate the effects on falls, mobility and quality of life of (i) movement strategy training combined with falls prevention education, (ii) progressive resistance strength training combined with falls prevention education, (iii) a generic life-skills social program (control group). Methods/Design People with idiopathic Parkinson\u27s disease who live at home will be recruited and randomly allocated to one of three groups. Each person shall receive therapy in an out-patient setting in groups of 3-4. Each group shall be scheduled to meet once per week for 2 hours for 8 consecutive weeks. All participants will also have a structured 2 hour home practice program for each week during the 8 week intervention phase. Assessments will occur before therapy, after the 8 week therapy program, and at 3 and 12 months after the intervention. A falls calendar will be kept by each participant for 12 months after outpatient therapy. Consistent with the recommendations of the Prevention of Falls Network Europe group, three falls variables will be used as the primary outcome measures: the number of fallers, the number of multiple fallers and the falls rate. In addition to quantifying falls, we shall measure mobility, activity limitations and quality of life as secondary outcomes. Discussion This study has the potential to determine whether outpatient movement strategy training combined with falls prevention education or progressive resistance strength training combined with falls prevention education are effective for reducing falls and improving mobility and life quality in people with Parkinson\u27s disease who live at home

Awareness Is Not Enough: Pitfalls of Learning Analytics Dashboards in the Educational Practice

Presentation at 12th European Conference on Technology enhanced learning (EC-TEL 2017

Operation and performance of MEG II detector

The MEG II experiment, located at the Paul Scherrer Institut (PSI) in Switzerland, is the successor to the MEG experiment, which completed data taking in 2013. MEG II started fully operational data taking in 2021, with the goal of improving the sensitivity of the mu+ -> e+ gamma decay down to 6e-14 almost an order of magnitude better than the current limit. In this paper, we describe the operation and performance of the experiment and give a new estimate of its sensitivity versus data acquisition time.Comment: 42 pages, 55 figures. Submitted to EPJ

A search for μ+→e+γ\mu^+\to e^+\gamma with the first dataset of the MEG II experiment

The MEG II experiment, based at the Paul Scherrer Institut in Switzerland, reports the result of a search for the decay $\mu^+\to e^+\gamma$ from data taken in the first physics run in 2021. No excess of events over the expected background is observed, yielding an upper limit on the branching ratio of B($\mu^+\to e^+\gamma$) < $7.5 \times 10^{-13}$ (90% C.L.). The combination of this result and the limit obtained by MEG gives B($\mu^+\to e^+\gamma$) < $3.1 \times 10^{-13}$ (90% C.L.), which is the most stringent limit to date. A ten-fold larger sample of data is being collected during the years 2022-2023, and data-taking will continue in the coming years.Comment: 10 pages, 6 figures. To be published in EPJ

High performing hospitals: a qualitative systematic review of associated factors and practical strategies for improvement.

BACKGROUND: High performing hospitals attain excellence across multiple measures of performance and multiple departments. Studying high performing hospitals can be valuable if factors associated with high performance can be identified and applied. Factors leading to high performance are complex and an exclusive quantitative approach may fail to identify richly descriptive or relevant contextual factors. The objective of this study was to undertake a systematic review of qualitative literature to identify methods used to identify high performing hospitals, the factors associated with high performers, and practical strategies for improvement. METHODS: Methods used to collect and summarise the evidence contributing to this review followed the 'enhancing transparency in reporting the synthesis of qualitative research' protocol. Peer reviewed studies were identified through Medline, Embase and Cinahl (Jan 2000-Feb 2014) using specified key words, subject terms, and medical subject headings. Eligible studies required the use of a quantitative method to identify high performing hospitals, and qualitative methods or tools to identify factors associated with high performing hospitals or hospital departments. Title, abstract, and full text screening was undertaken by four reviewers, and inter-rater reliability statistics were calculated for each review phase. Risk of bias was assessed. Following data extraction, thematic syntheses identified contextual factors important for explaining success. Practical strategies for achieving high performance were then mapped against the identified themes. RESULTS: A total of 19 studies from a possible 11,428 were included in the review. A range of process, output, outcome and other indicators were used to identify high performing hospitals. Seven themes representing factors associated with high performance (and 25 sub-themes) emerged from the thematic syntheses: positive organisational culture, senior management support, effective performance monitoring, building and maintaining a proficient workforce, effective leaders across the organisation, expertise-driven practice, and interdisciplinary teamwork. Fifty six practical strategies for achieving high performance were catalogued. CONCLUSIONS: This review provides insights into methods used to identify high performing hospitals, and yields ideas about the factors important for success. It highlights the need to advance approaches for understanding what constitutes high performance and how to harness factors associated with high performance