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Cell therapy for the ischemic injured heart has been largely investigated in the last two decades, and most of the small cohort and randomized clinical studies, as well as meta-analyses led to the conclusion that cell-based human regenerative therapy is safe and effective in term of reducing adverse clinical outcomes and increasing left ventricular performance. Both the in vitro and in vivo rodent animal models of ischemic heart failure using bone marrow-derived mononuclear cells promised marvelous success in regeneration of the heart suffering from ischemic burden. However, in certain patient groups, stem cell studies failed to reach the primary endpoint, showing no effect of this regenerative therapy. This brief overview addresses the contradictory results between human cardiac regenerative studies and the very positive rodent experiments.

Task batteries mimicking user tasks are of high heuristic value. Supposedly, they measure individual human aptitude regarding the task in question. However, less is often known about the underlying mechanisms or functions that account for task performance in such complex batteries. This is also true of the Multi-Attribute Task Battery (MATB-II). The MATB-II is a computer display task. It aims to measure human control operations on a flight console. Using the MATB-II and a visual-search task measure of spatial attention, we tested if capture of spatial attention in a bottom-up or top-down way predicted performance in the MATB-II. This is important to understand for questions such as how to implement warning signals on visual displays in human–computer interaction and for what to practice during training of operating with such displays. To measure visuospatial attention, we used both classical task-performance measures (i.e., reaction times and accuracy) as well as novel unobtrusive real-time pupillometry. The latter was done as pupil size covaries with task demands. A large number of analyses showed that: (1) Top-down attention measured before and after the MATB-II was positively correlated. (2) Test-retest reliability was also given for bottom-up attention, but to a smaller degree. As expected, the two spatial attention measures were also negatively correlated with one another. However, (3) neither of the visuospatial attention measures was significantly correlated with overall MATB-II performance, nor with (4) any of the MATB-II subtask performance measures. The latter was true even if the subtask required visuospatial attention (as in the system monitoring task of the MATB-II). (5) Neither did pupillometry predict MATB-II performance, nor performance in any of the MATB-II’s subtasks. Yet, (6) pupil size discriminated between different stages of subtask performance in system monitoring. This finding indicated that temporal segregation of pupil size measures is necessary for their correct interpretation, and that caution is advised regarding average pupil-size measures of task demands across tasks and time points within tasks. Finally, we observed surprising effects of workload (or cognitive load) manipulation on MATB-II performance itself, namely, better performance under high- rather than low-workload conditions. The latter findings imply that the MATB-II itself poses a number of questions about its underlying rationale, besides allowing occasional usage in more applied research.

Small extracellular vesicles (EVs) and their cargo are an important component of cell-to-cell communication in cardiac disease. Allogeneic adipose derived stem cells (ADSCs) are thought to be a potential approach for cardiac regenerative therapy in ischemic heart disease. The SCIENCE study investigated the effect of ADSCs administered via intramyocardial injection on cardiac function in patients with ischemic heart disease. The aim of this substudy, based on samples from 15 patients, was to explore small EV miRNA dynamics after treatment with ADSCs compared to a placebo. Small EVs were isolated at several timepoints after the percutaneous intramyocardial application of ADSCs. No significant effect of ADSC treatment on small EV concentration was detected. After 12 months, the expression of miR-126 decreased significantly in ADSC patients, but not in the placebo-treated group. However, all cardiac miRNAs correlated with plasma cardiac biomarkers. In line with the overall negative results of the SCIENCE study, with the exception of one miR, we did not detect any significant regulation of small EV miRNAs in this patient collective.

Cell-free secretomes represent a promising new therapeutic avenue in regenerative medicine, and γ-irradiation of human peripheral blood mononuclear cells (PBMCs) has been shown to promote the release of paracrine factors with high regenerative potential. Recently, the use of alternative irradiation sources, such as artificially generated β- or electron-irradiation, is encouraged by authorities. Since the effect of the less hazardous electron-radiation on the production and functions of paracrine factors has not been tested so far, we compared the effects of γ- and electron-irradiation on PBMCs and determined the efficacy of both radiation sources for producing regenerative secretomes. Exposure to 60 Gy γ-rays from a radioactive nuclide and 60 Gy electron-irradiation provided by a linear accelerator comparably induced cell death and DNA damage. The transcriptional landscapes of PBMCs exposed to either radiation source shared a high degree of similarity. Secretion patterns of proteins, lipids, and extracellular vesicles displayed similar profiles after γ- and electron-irradiation. Lastly, we detected comparable biological activities in functional assays reflecting the regenerative potential of the secretomes. Taken together, we were able to demonstrate that electron-irradiation is an effective, alternative radiation source for producing therapeutic, cell-free secretomes. Our study paves the way for future clinical trials employing secretomes generated with electron-irradiation in tissue-regenerative medicine.

Summary: Background: IgE-mediated hypersensitivity is becoming increasingly prevalent and activation of mast cells and basophils represent key events in the pathophysiology of allergy. We have previously reported that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) exerts beneficial anti-inflammatory effects. Yet, its ability to alleviate allergic symptoms has not been investigated so far. Methods: Several experimental in vitro and in vivo models have been used in this basic research study. A murine ear swelling model was used to study the effects of PBMCsec on 48/80-induced mast cell degranulation in vivo. The transcriptional profile of murine mast cells was analysed by single cell RNA sequencing (scRNAseq). Mast cell activation was studied in vitro using primary skin mast cells. Basophils from individuals allergic to birch pollens were used to investigate basophile activation by allergens. Transcriptomic and lipidomic analyses were used to identify mRNA expression and lipid species present in PBMCsec, respectively. Findings: Topical application of PBMCsec on mouse ears (C57BL/6) significantly reduced tissue swelling following intradermal injection of compound 48/80, an inducer of mast cell degranulation. Single cell RNA sequencing of PBMCsec-treated murine dermal mast cells (Balb/c) revealed a downregulation of genes involved in immune cell degranulation and Fc-receptor signalling. In addition, treatment of primary human dermal mast cells with PBMCsec strongly inhibited compound 48/80- and α-IgE-induced mediator release in vitro. Furthermore, PBMCsec remarkably attenuated allergen driven activation of basophils from allergic individuals. Transcriptomic analysis of these basophils showed that PBMCsec downregulated a distinct gene battery involved in immune cell degranulation and Fc-receptor signalling, corroborating results obtained from dermal mast cells. Finally, we identified the lipid fraction of PBMCsec as the major active ingredient involved in effector cell inhibition. Interpretation: Collectively, our data demonstrate that PBMCsec is able to reduce activation of mast cells and basophils, encouraging further studies on the potential use of PBMCsec for treating allergy. Funding: Austrian Research Promotion Agency (852748 and 862068, 2015-2019), Vienna Business Agency (2343727, 2018-2020), Aposcience AG, Austrian Federal Ministry of Education, Science and Research (SPA06/055), Danube Allergy Research Cluster, Austrian Science Fund (I4437 and P32953).

Abstract Background Diabetes and its sequelae such as diabetic foot ulcer are rising health hazards not only in western countries but all over the world. Effective, yet safe treatments are desperately sought for by physicians, healthcare providers, and of course patients. Methods/design APOSEC, a novel, innovative drug, is tested in the phase I/II study MARSYAS II, where its efficacy to promote healing of diabetic foot ulcers will be determined. To this end, the cell-free secretome of peripheral blood mononuclear cells (APOSEC) blended with a hydrogel will be applied topically three times weekly for 4 weeks. APOSEC is predominantly effective in hypoxia-induced tissue damages by modulating the immune system and enhancing angiogenesis, whereby its anti-microbial ability and neuro-regenerative capacity will exert further positive effects. In total, 132 patients will be enrolled in the multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-ranging phase I/II study and treated with APOSEC at three dose levels or placebo for 4 weeks, followed by an 8-week follow-up period to evaluate safety and efficacy of the drug. Wound area reduction after 4 weeks of treatment will serve as the primary endpoint. Conclusion We consider our study protocol to be suitable to test topically administered APOSEC in patients suffering from diabetic foot ulcers in a clinical phase I/II trial. Trial registration EudraCT 2018-001653-27 . Registered on 30 July 2019. ClinicalTrials.gov NCT04277598 . Registered on 20 February 2020. Title: “A randomized, placebo-controlled, double-blind study to evaluate safety and dose-dependent clinical efficacy of APO-2 at three different doses in patients with diabetic foot ulcer (MARSYAS II)”

Abstract Background The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds. Methods We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures. Results We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months. Conclusions We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine.

Background: Delirium and dementia are two of the most common geriatric syndromes, which requires innovative rehabilitation approaches. Aim: We aimed at determining which occupational therapy and physiotherapy interventions are applied with older people with delirium and dementia in different care settings. We also identified the assessment tools that were used. Materials and methods: We conducted a literature search for scientific articles published from 2012 to 2022 (PubMed, MEDLINE, AMED and CINAHL) with adults aged >65 years including experimental study designs with randomized or non-randomized intervention, exploratory studies, pilot studies, quasi-experimental studies, case series and/or clinical cases. Studies that did not use interventions that could be classified as occupational therapy or physiotherapy were excluded. Results: After applying the exclusion criteria, 9 articles were selected. The most widely used assessment to define dementia was the MMSE (N = 5; 55.5%), whereas the CAM (N = 2; 22.2%), CAM-ICU (N = 2; 22.2%) and RASS (N = 3; 33.3%) were the most widely used to define delirium. The rehabilitation interventions that were most frequently performed were early mobilization, inclusion of the caregiver during treatment, modification of the environment to encourage orientation and autonomy, the interprofessional systemic approach and engaging persons in meaningful activities. Conclusions: Despite the growing evidence on its effectiveness, the role of physiotherapy and occupational therapy interventions in the prevention and treatment of people with dementia and delirium is still emerging. More research is needed to investigate if effective occupational therapy programs known to reduce the behavioral and psychological symptoms in people with dementia are also useful for treating delirium and specifically delirium superimposed on dementia. Regarding physiotherapy, it is crucial to know about the amount and timing of intervention required. Further studies are needed including older adults with delirium superimposed on dementia to define the role of the interprofessional geriatric rehabilitation team.

Closure and revitalisation are essential steps in the life cycle of a mineral extraction site. Proper planning and execution can counteract potential negative impacts caused by extraction activities and allow a positive impact to be left on the post-closure region. Decisions on these steps are not made solely by the extraction company; legislators and the public also exert influence. Different opinions and expectations on closure and revitalisation can lead to tensions between actors. Thus, knowing diverse opinions and expectations and considering them in planning contributes to a successful implementation of measures. Using Q-methodology in a study focused on selected EIT RIS countries, we identified five viewpoints on the closure and revitalisation of an extraction site. The statements for this study have been developed based on international and company standards for closure and revitalisation, namely ICMM, IRMA, AngloAmerican and Rio Tinto, which we then also used for comparison in order to see how they relate to the five resulting viewpoints. Across all viewpoints, our results reveal a preference for environmental considerations, followed by social and economic concerns. Even though this paper considers closure and revitalisation separately from mineral extraction, these processes are intertwined. Thus, a sustainable planning and management of the extraction process itself contributes to a successful and sustainable post-closure landscape.

In the current review, we argue that experimental results usually interpreted as evidence for cognitive resource limitations could also reflect functional necessities of human information processing. First, we point out that selective processing of only specific features, objects, or locations at each moment in time allows humans to monitor the success and failure of their own overt actions and covert cognitive procedures. We then proceed to show how certain instances of selectivity are at odds with commonly assumed resource limitations. Next, we discuss examples of seemingly automatic, resource-free processing that challenge the resource view but can be easily understood from the functional perspective of monitoring cognitive procedures. Finally, we suggest that neurophysiological data supporting resource limitations might actually reflect mechanisms of how procedural control is implemented in the brain.

Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far. Methods: We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and T-cell priming. Findings: PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4+ T-cells into TH1 and TH2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects. Interpretation: Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions. Funding: This research project was supported by the Austrian Research Promotion Agency (Vienna, Austria; grant “APOSEC” 862068; 2015–2019) and the Vienna Business Agency (Vienna, Austria; grant “APOSEC to clinic” 2343727).

As games and gamified applications gain prominence in the academic debate on participatory practices, it is worth examining whether the application of such tools in the daily planning practice could be beneficial. This study identifies a research–practice gap in the current state of participatory urban planning practices in three European cities. Planners and policymakers acknowledge the benefits of employing such tools to illustrate complex urban issues, evoke social learning, and make participation more accessible. However, a series of impediments relating to planners’ inexperience with participatory methods, resource constraints, and sceptical adult audiences, limits the broader application of games and gamified applications within participatory urban planning practices. Games and gamified applications could become more widely employed within participatory planning processes when process facilitators become better educated and better able to judge the situations in which such tools could be implemented as part of the planning process, and if such applications are simple and useful, and if their development process is based on co-creation with the participating publics.

Spatial planning projects can be conceived as processes of collective learning. Planners have been looking at games and playful approaches to support these processes. Considering that planning projects are long and complex, we propose to not reason for single, full-fledged and all-encompassing games, but instead work with strings of, so-called, serious mini-games that each addresses a specific learning goal, guided by a collective learning model. This paper conceptualizes a toolbox to support the development and contextualization of such strings of serious mini-games.