Sandbox university: Estimating influence of institutional action

The approach presented in this article represents a generalizable and adaptable methodology for identifying complex interactions in educational systems and for investigating how manipulation of these systems may affect educational outcomes of interest. Multilayer Minimum Spanning Tree and Monte-Carlo methods are used. A virtual Sandbox University is created in order to facilitate effective identification of successful and stable initiatives within higher education, which can affect students' credits and student retention - something that has been lacking up until now. The results highlight the importance of teacher feedback and teacher-student rapport, which is congruent with current educational findings, illustrating the methodology's potential to provide a new basis for further empirical studies of issues in higher education from a complex systems perspective

Requirements and expectations of high-quality biomarkers for atopic dermatitis and psoriasis in 2021-a two-round Delphi survey among international experts

Background Chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO) present major challenges in health care. Thus, biomarkers to identify disease trajectories and response to treatments to improve the lives of affected individuals warrant great research consideration. The requirements that these biomarkers must fulfil for use as practical clinical tools have not yet been adequately investigated. Aim To identify the core elements of high-quality AD and PSO biomarkers to prepare recommendations for current biomarker research. Method A cross-sectional two-round Delphi survey was conducted from August to October 2019 and October to November 2020. All participants were members of the BIOMAP project, an EU-funded consortium of clinicians, researchers, patient organizations and pharmaceutical industry partners. The first round consisted of three open-ended questions. Responses were qualitatively analysed, and 26 closed statements were developed. For the second round, 'agreement' was assumed when the responses of >= 70% of the participants were >= 5 points on a 7-point Likert scale for each statement. Priority classification was based on mean scores (60th percentile = high). Results Twenty-one and twenty-six individuals participated in rounds one and two, respectively. From 26 statements that were included in round 2, 18 achieved agreement (8 concerning the performance, 8 for the purpose and 2 on current obstacles). Seven statements were classified as high priority, e.g. those concerning reliability, clinical validity, a high positive predictive value, prediction of the therapeutic response and disease progression. Another seven statements were assigned medium priority, e.g. those about analytical validity, prediction of comorbidities and therapeutic algorithm. Low priority included four statements, like those concerning cost effectiveness and prediction of disease flares. Conclusion The core requirements that experts agreed on being essential for high-quality AD and PSO biomarkers require rapid validation. Biomarkers can therefore be assessed based on these prioritized requirements.Peer reviewe

The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

Contains fulltext : 220729.pdf (publisher's version ) (Open Access)The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14(+) DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system

Spread of psoriasiform inflammation to remote tissues is restricted by the atypical chemokine receptor ACKR2

Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo, is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis associated atypical chemokine receptor ACKR2 binds, internalises and degrades most pro-inflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion.  Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays and the imiquimod-induced model of psoriasiform skin inflammation. Localised inflammation and IFN together upregulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions, and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases

Validation of separate multi-atlases for auto segmentation of cardiac substructures in CT-scans acquired in deep inspiration breath hold and free breathing

Background and purpose: Developing NTCP-models for cardiac complications after breast cancer (BC) radiotherapy requires cardiac dose-volume parameters for many patients. These can be obtained by using multi-atlas based automatic segmentation (MABAS) of cardiac structures in planning CT scans. We investigated the relevance of separate multi-atlases for deep inspiration breath hold (DIBH) and free breathing (FB) CT scans. Materials and methods: BC patients scanned in DIBH (n = 10) and in FB (n = 20) were selected to create separate multi-atlases consisting of expert panel delineations of the whole heart, atria and ventricles. The accuracy of atlas-generated contours was validated with expert delineations in independent datasets (n = 10 for DIBH and FB) and reported as Dice coefficients, contour distances and dose-volume differences in relation to interobserver variability of manual contours. Dependency of MABAS contouring accuracy on breathing technique was assessed by validation of a FB atlas in DIBH patients and vice versa (cross validation). Results: For all structures the FB and DIBH atlases resulted in Dice coefficients with their respective reference contours > 0.8 and average contour distances < 2 mm smaller than slice thickness of (CTs). No significant differences were found for dose-volume parameters in volumes receiving relevant dose levels (WH, LV and RV). Accuracy of the DIBH atlas was at least similar to, and for the ventricles better than, the interobserver variation in manual delineation. Cross-validation between breathing techniques showed a reduced MABAS performance. Conclusion: Multi-atlas accuracy was at least similar to interobserver delineation variation. Separate atlases for scans made in DIBH and FB could benefit atlas performance because accuracy depends on breathing technique

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH

Vehicles for atopic dermatitis therapies: more than just a placebo

A topical vehicle is a ‘carrier system’ for an active pharmaceutical (or cosmetic) substance, referred to hereafter as the drug, but a vehicle may also be used on its own as an emollient to ameliorate dry skin. It is well established that the vehicle plays an important role in determining the bioavailability of a given drug at its ultimate target within the skin. Yet in the treatment of atopic eczema/dermatitis (AD), wherein the structure and function of the skin's outer barrier play a pivotal role in the development and course of the condition, the interaction of the vehicle with this barrier carries a particular importance. It is now clear that the often-considered inert excipients of a vehicle bring about changes within the skin at the molecular level that promote barrier restoration and enhance innate immune defenses with therapeutic value to AD patients. Moreover, the vehicle control in randomized controlled trials (RCTs) increasingly displays significant efficacy. In light of this, we consider the implications of vehicle design in relation to AD pathophysiology and the role vehicles play as controls in RCTs of new drug treatments for this condition

Sex differences in patients with out-of-hospital cardiac arrest without ST-segment elevation:A COACT trial substudy

Background: Whether sex is associated with outcomes of out-of-hospital cardiac arrest (OHCA) is unclear. Objectives: This study examined sex differences in survival in patients with OHCA without ST-segment elevation myocardial infarction (STEMI). Methods: Using data from the randomized controlled Coronary Angiography after Cardiac Arrest (COACT) trial, the primary point of interest was sex differences in OHCA-related one-year survival. Secondary points of interest included the benefit of immediate coronary angiography compared to delayed angiography until after neurologic recovery, angiographic and clinical outcomes. Results: In total, 522 patients (79.1% men) were included. Overall one-year survival was 59.6% in women and 63.4% in men (HR 1.18; 95% CI: 0.761.81;p = 0.47). No cardiovascular risk factors were found that modified survival. Women less often had significant coronary artery disease (CAD) (37.0% vs. 71.3%; p < 0.001), but when present, they had a worse prognosis than women without CAD (HR 3.06; 95% CI 1.31-7.19; p = 0.01). This was not the case for men (HR 1.05; 95% CI 0.67-1.65; p = 0.83). In both sexes, immediate coronary angiography did not improve one-year survival compared to delayed angiography (women, odds ratio (OR) 0.87; 95% CI 0.58-1.30;p = 0.49; vs. men, OR 0.97; 95% CI 0.45-2.09; p = 0.93). Conclusion: In OHCA patients without STEMI, we found no sex differences in overall one-year survival. Women less often had significant CAD, but when CAD was present they had worse survival than women without CAD. This was not the case for men. Both sexes did not benefit from a strategy of immediate coronary angiography as compared to delayed strategy with respect to one-year survival