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Abstract Background Many respiratory viruses attack the airway epithelium and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. As a result, most of the drug screening assays for respiratory viruses are performed on commercial cell line-based 2D cultures that provide limited translational ability. Methods We optimized a primary human stem cell-based mucociliary airway epithelium model of SARS-CoV-2 infection, in 96-well air–liquid-interface (ALI) format, which is amenable to moderate throughput drug screening. We tested the model against SARS-CoV-2 parental strain (Wuhan) and variants Beta, Delta, and Omicron. We applied this model to screen 2100 compounds from targeted drug libraries using a high throughput-high content image-based quantification method. Results The model recapitulated the heterogeneity of infection among patients with SARS-CoV-2 parental strain and variants. While there were heterogeneous responses across variants for host factor targeting compounds, the two direct-acting antivirals we tested, Remdesivir and Paxlovid, showed consistent efficacy in reducing infection across all variants and donors. Using the model, we characterized a new antiviral drug effective against both the parental strain and the Omicron variant. Conclusion This study demonstrates that the 96-well ALI model of primary human mucociliary epithelium can recapitulate the heterogeneity of infection among different donors and SARS-CoV-2 variants and can be used for moderate throughput screening. Compounds that target host factors showed variability among patients in response to SARS-CoV-2, while direct-acting antivirals were effective against SARS-CoV-2 despite the heterogeneity of patients tested.

Objective Automated machine learning (autoML) platforms allow health care professionals to play an active role in the development of machine learning (ML) algorithms according to scientific or clinical needs. The aim of this study was to develop and evaluate such a model for automated detection and grading of distal hand osteoarthritis (OA). Methods A total of 13,690 hand radiographs from 2,863 patients within the Swiss Cohort of Quality Management (SCQM) and an external control data set of 346 non‐SCQM patients were collected and scored for distal interphalangeal OA (DIP‐OA) using the modified Kellgren/Lawrence (K/L) score. Giotto (Learn to Forecast [L2F]) was used as an autoML platform for training two convolutional neural networks for DIP joint extraction and subsequent classification according to the K/L scores. A total of 48,892 DIP joints were extracted and then used to train the classification model. Heatmaps were generated independently of the platform. User experience of a web application as a provisional user interface was investigated by rheumatologists and radiologists. Results The sensitivity and specificity of this model for detecting DIP‐OA were 79% and 86%, respectively. The accuracy for grading the correct K/L score was 75%, with a κ score of 0.76. The accuracy per DIP‐OA class differed, with 86% for no OA (defined as K/L scores 0 and 1), 71% for a K/L score of 2, 46% for a K/L score of 3, and 67% for a K/L score of 4. Similar values were obtained in an independent external test set. Qualitative and quantitative user experience testing of the web application revealed a moderate to high demand for automated DIP‐OA scoring among rheumatologists. Conversely, radiologists expressed a low demand, except for the use of heatmaps. Conclusion AutoML platforms are an opportunity to develop clinical end‐to‐end ML algorithms. Here, automated radiographic DIP‐OA detection is both feasible and usable, whereas grading among individual K/L scores (eg, for clinical trials) remains challenging.

Abstract Assessment of lung function is an important clinical tool for the diagnosis and monitoring of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In mice, lung function maneuvers use algorithm-based ventilation strategies including forced oscillation technique (FOT), negative pressure-driven forced expiratory (NPFE) and pressure–volume (PV) maneuvers via the FlexiVent system. This lung function test (LFT) is usually performed as end-point measurement only, requiring several mice for each time point to be analyzed. Repetitive lung function maneuvers would allow monitoring of a disease process within the same individual while reducing the numbers of laboratory animals. However, its feasibility in mice and impact on developing lung fibrosis has not been studied so far. Using orotracheal cannulation without surgical exposure of the trachea, we examined the tolerability to repetitive lung function maneuvers (up to four times) in one and the same mouse, both under healthy conditions and in a model of AdTGF-β1 induced lung fibrosis. In essence, we found that repetitive invasive lung function maneuvers were well tolerated and did not accentuate experimental lung fibrosis in mice. This study contributes to the 3R principle aiming to reduce the numbers of experimental animals used in biomedical research.

Abstract Objectives Neutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making. Methods This single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR). Results One hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x108 copies/mL) compared to HC (median 5.4 x106 copies/mL, p

Abstract Pre-injured lungs are prone to injury progression in response to mechanical ventilation. Heterogeneous ventilation due to (micro)atelectases imparts injurious strains on open alveoli (known as volutrauma). Hence, recruitment of (micro)atelectases by positive end-expiratory pressure (PEEP) is necessary to interrupt this vicious circle of injury but needs to be balanced against acinar overdistension. In this study, the lung-protective potential of alveolar recruitment was investigated and balanced against overdistension in pre-injured lungs. Mice, treated with empty vector (AdCl) or adenoviral active TGF-β1 (AdTGF-β1) were subjected to lung mechanical measurements during descending PEEP ventilation from 12 to 0 cmH2O. At each PEEP level, recruitability tests consisting of two recruitment maneuvers followed by repetitive forced oscillation perturbations to determine tissue elastance (H) and damping (G) were performed. Finally, lungs were fixed by vascular perfusion at end-expiratory airway opening pressures (Pao) of 20, 10, 5 and 2 cmH2O after a recruitment maneuver, and processed for design-based stereology to quantify derecruitment and distension. H and G were significantly elevated in AdTGF-β1 compared to AdCl across PEEP levels. H was minimized at PEEP = 5–8 cmH2O and increased at lower and higher PEEP in both groups. These findings correlated with increasing septal wall folding (= derecruitment) and reduced density of alveolar number and surface area (= distension), respectively. In AdTGF-β1 exposed mice, 27% of alveoli remained derecruited at Pao = 20 cmH2O. A further decrease in Pao down to 2 cmH2O showed derecruitment of an additional 1.1 million alveoli (48%), which was linked with an increase in alveolar size heterogeneity at Pao = 2–5 cmH2O. In AdCl, decreased Pao resulted in septal folding with virtually no alveolar collapse. In essence, in healthy mice alveoli do not derecruit at low PEEP ventilation. The potential of alveolar recruitability in AdTGF-β1 exposed mice is high. H is optimized at PEEP 5–8 cmH2O. Lower PEEP folds and larger PEEP stretches septa which results in higher H and is more pronounced in AdTGF-β1 than in AdCl. The increased alveolar size heterogeneity at Pao = 5 cmH2O argues for the use of PEEP = 8 cmH2O for lung protective mechanical ventilation in this animal model.

Abstract Background Mesenchymal stromal cells (MSCs) are excessively investigated in the context of inflammation-driven diseases, but the clinical results are often moderate. MSCs are naturally activated by inflammatory signals, which lead to the secretion of immune inhibitory factors in inflamed tissues. Many work groups try to improve the therapeutic outcome of MSCs by genetic modification and the constitutive overexpression of immune modulatory transgenes. However, the ectopic secretion of immune inhibitory transgenes increases the chances of infections, and constitutive transgene expression is not necessary for chronic diseases undergoing different inflammatory stages. Methods We designed and tested inflammation-induced promoters to control transgene expression from integrating lentiviral vectors in human umbilical cord MSCs. Therefore, we investigated different combinations of general transcription factor elements to achieve a minimal promoter with low basal activity. The best candidates were combined with interferon-induced GAS or ISRE DNA motifs. The constructs with the highest transgene expression upon addition of pro-inflammatory cytokines were compared to vectorized promoters from inflammation-induced genes (CD317, CXCL9, CXCL10, CXCL11 and IDO1). Finally, we investigated IL10 as a potential immune inhibitory transgene by transcriptome analyses, ELISA and in an acute lung injury mouse model. Results The synthetic promoters achieved a high and specific transgene expression upon IFN-γ addition. However, the CXCL11 promoter showed synergistic activity upon IFN-γ, TNF-α and IL1-β treatment and surpassed the transgene expression height of all tested promoters in the study. We observed in transcriptome analyses that IL10 has no effect on MSCs and in ELISA that IL10 is only secreted by our genetically modified and activated CXCL11-IL10-MSCs. Finally, transplanted CXCL11-IL10-MSCs increased CD19+ and CD4+ lymphoid cells, and decreased CD11b+ Ly6g myeloid cells in an ALI mouse model. Conclusion These results provide new insights into MSC inflammatory activation and the subsequent translation into a tool for a tailored expression of transgenes in inflammatory microenvironments. The newly developed promoter elements are potentially interesting for other inflamed tissues, and can be combined with other elements or used in other cell types.

Abstract Background The Chronic Care Model (CCM) is a longstanding and widely adopted model guiding chronic illness management. Little is known about how CCM elements are implemented in rare disease care or how patients’ care experiences relate to health-related quality of life (HRQoL). We engaged patients living with systemic sclerosis (SSc) to assess current care according to the CCM from the patient perspective and their HRQoL. Methods We employed an explanatory sequential mixed methods design. First, we conducted a cross-sectional quantitative survey (n = 101) using the Patient Assessment of Chronic Illness Care (PACIC) and Systemic Sclerosis Quality of Life (SScQoL) questionnaires. Next, we used data from individual patient interviews (n = 4) and one patient focus group (n = 4) to further explore care experiences of people living with SSc with a focus on the PACIC dimensions. Results The mean overall PACIC score was 3.0/5.0 (95% CI 2.8–3.2, n = 100), indicating care was ‘never’ to ‘generally not’ aligned with the CCM. Lowest PACIC subscale scores related to ‘goal setting/tailoring’ (mean = 2.5, 95% CI 2.2–2.7) and ‘problem solving/contextual counselling’ (mean = 2.9, 95% CI 2.7–3.2). No significant correlations were identified between the mean PACIC and SScQoL scores. Interviews revealed patients frequently encounter major shortcomings in care including ‘experiencing organized care with limited participation’, ‘not knowing which strategies are effective or harmful’ and ‘feeling left alone with disease and psychosocial consequences’. Patients often responded to challenges by ‘dealing with the illness in tailored measure’, ‘taking over complex coordination of care’ and ‘relying on an accessible and trustworthy team’. Conclusions The low PACIC mean overall score is comparable to findings in patients with common chronic diseases. Key elements of the CCM have yet to be systematically implemented in Swiss SSc management. Identified gaps in care related to lack of shared decision-making, goal-setting and individual counselling-aspects that are essential for supporting patient self-management skills. Furthermore, there appears to be a lack of complex care coordination tailored to individual patient needs.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease characterized by exuberant deposition of extracellular matrix (ECM) proteins in the lung interstitium, which contributes to substantial morbidity and mortality in IPF patients. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, many of which have been implicated in the regulation of ECM degradation in lung fibrosis. However, the roles of MMP-2 and -9 (also termed gelatinases A and B) have not yet been explored in lung fibrosis in detail. Methods AdTGF-β1 was applied via orotracheal routes to the lungs of WT, MMP-2 KO, MMP-9 KO and MMP-2/-9 dKO mice on day 0 to induce lung fibrosis. Using hydroxyproline assay, FlexiVent based lung function measurement, histopathology, western blot and ELISA techniques, we analyzed MMP-2 and MMP-9 levels in BAL fluid and lung, collagen contents in lung and lung function in mice on day 14 and 21 post-treatment. Result IPF lung homogenates exhibited significantly increased levels of MMP-2 and MMP-9, relative to disease controls. Enzymatically active MMP-2 and MMP-9 was increased in lungs of mice exposed to adenoviral TGF-β1, suggesting a role for these metalloproteinases in lung fibrogenesis. However, we found that neither MMP-2 or MMP-9 nor combined MMP-2/-9 deletion had any effect on experimental lung fibrosis in mice. Conclusion Together, our data strongly suggest that both gelatinases MMP-2 and MMP-9 play only a subordinate role in experimental lung fibrosis in mice.

An innovative strategy to address recent challenges in the oral administration of poorly soluble drugs is the formulation of amorphous solid dispersions (ASDs), where the drug is dissolved in a highly soluble carrier polymer. Therefore, special knowledge of the drug–polymer phase behavior is essential for an effective product and process design, accelerating the introduction of novel efficacious ASD products. Flory–Huggins theory can be applied to model solubility temperatures of crystalline drugs in carrier polymers over the drug fraction. However, predicted solubility temperatures lack accuracy in cases of strong drug/polymer interactions that are not represented in the Flory–Huggins lattice model. Within this study, a modeling strategy is proposed to improve the predictive power through an extension of the Flory–Huggins interaction parameter by a correlation with the drug fraction. Therefore, the composition dependency of the Flory–Huggins interaction parameter was evaluated experimentally for various drug–polymer formulations that cover a wide variety of drug and polymer characteristics regarding molecular weights, glass transition temperatures and melting temperatures, as well as drug–polymer interactions of different strengths and effects. The extended model was successfully approved for nine exemplary ASD formulations containing the drugs acetaminophen, itraconazole, and griseofulvine, as well as the following polymers: basic butylated methacrylate copolymer, Soluplus®, and vinylpyrrolidone/vinyl acetate copolymer. A high correlation between the predicted solubility temperatures and experimental and literature data was found, particularly at low drug fractions, since the model accounts for composition dependent drug–polymer interactions.

Background: Age-related hyperkyphosis is multifactorial and involves alterations of vertebral bone, intervertebral discs (IVD) and paraspinal muscles. The relative contribution of these tissues remains unclear. Here, we compared differences in vertebral bone microarchitecture and IVD thickness between prematurely aging mice with spinal hyperkyphosis and wild type littermates. Methods: Thoracolumbar vertebral columns were dissected from homozygous PolgD257A and age-matched wild type littermates. Micro-computed tomography was performed to quantify cortical and trabecular bone parameters at anterior and posterior portions of T8-L4 vertebrae. In addition, vertebral shape, transaxial facet joint orientation and IVD thickness were quantified. Differences in anterior/posterior ratios between genotypes were compared by Student's t-test and association between vertebral bone and IVD parameters was investigated using Pearson correlation analysis. Results: Hyperkyphotic homozygous mice displayed generalized osteopenia that was more pronounced at the posterior compared with anterior portion of thoracolumbar vertebrae. An increase in the anterior/posterior ratio of trabecular bone parameters was revealed at the thoracolumbar junction (T13-L1). PolgD257A displayed diffuse loss of cortical bone thickness, yet anterior/posterior ratios were unchanged. Despite generalized and regional bone loss, vertebral shape was unaffected. PolGD257A mice showed a 10–20 % reduction of IVD thickness at both thoracic and lumbar levels, with only minimal histopathological changes. IVD thickness was negatively correlated with anterior/posterior ratios of trabecular bone parameters, as well as with more coronally oriented facet joints, but negatively correlated with the anterior/posterior ratio of cortical bone thickness. Conclusions: Aging-induced regional changes of vertebral trabecular and cortical bone did not lead to altered vertebral shape in PolgD257A mice but may indirectly cause hyperkyphosis through reduction of IVD thickness. These findings suggest a limited role for aging-induced bone loss in spinal hyperkyphosis and warrants further research on the involvement of paraspinal muscle degeneration.

Abstract Background Rare disease patient-reported outcome measures (PROMs) require linguistic adaptation to overcome the challenge of geographically dispersed patient populations. Importantly, PROMs such as health-related quality of life (HRQoL) should accurately capture responses to patient-identified concerns. The Systemic Sclerosis Quality of Life Questionnaire (SScQoL) is a 29-item tool validated in six languages. Previous evaluation of the German version revealed problems with dichotomous responses. This study aimed to revise the German SScQoL, extend the response structure, and evaluate content and construct validity, reliability and unidimensionality. Methods The instrument validation study involved revising the German SScQoL response structure, cognitive debriefing with patients and validation using Rasch analysis. The revised SScQoL was completed by Swiss-German-speaking patients with SSc within the Swiss MANagement Of Systemic Sclerosis (MANOSS) study. Rasch analysis was employed to test the validity, reliability and unidimensionality of the revised instrument. Results Based on cognitive debriefing with patients (n = 6) dichotomous items were extended to a polytomous 4-point response structure. A total of 78 patients completed the revised SScQoL. Initial analysis of the 29 items suggested the scale lacked fit to the model (χ2 = 51.224, df = 29, p = 0.007). Grouping items into five domains resulted in an adequate fit to the Rasch model (χ2 = 5.343, df = 5, p = 0.376) and unidimensionality (proportion of significant independent t tests: 0.045, 95% CI 0.016–0.114). Overall, the scale was well targeted, had high internal consistency (Person Separation Index, PSI = 0.931) and worked consistently in patients with different demographic and clinical characteristics. Conclusions The revised German SScQoL has a 4-point response structure and is a valid, reliable measure. Rasch analysis is useful for validating continuous response structure of quality of life measures. Further evaluation of measurement equivalence with other German-speaking cultures is required for multinational comparisons and data pooling.

Abstract Aims The aim of this study was to compare individuals with type 1 diabetes with continuous subcutaneous insulin infusion (CSII) and intensified insulin therapy (ICT) in routine care regarding metabolic control and treatment satisfaction. Methods Individuals with type 1 diabetes (CSII n = 74; ICT n = 163) were analysed regarding metabolic control, frequency of hypoglycaemia and treatment satisfaction (DTSQs range 0–36). Results Individuals with CSII (duration of CSII: 14.1 ± 7.2 years) were younger (51.1 ± 15.8 vs. 56.2 ± 16.2 years, p = 0.023), had longer diabetes duration (28.7 ± 12.4 vs. 24.6 ± 14.3 years, p = 0.033), lower insulin dosage (0.6 ± 0.2 vs. 0.7 ± 0.4 IU/kg, p = 0.004), used more frequently short-acting analogue insulin (90.5% vs. 48.5%, p

Abstract Objective The aim of the present study was to assess diabetes-related distress in inpatients and its association with metabolic control in people with diabetes type 1 (DM1) and type 2 (DM2). Research design and methods In a cross-sectional study, 107 inpatients with DM1 (age 45.9 years, diabetes duration 18.7 years, HbA1c 8.4%/67.8 mmol/mol) and 109 with DM2 (age 62.0 years, diabetes duration 16.2 years, HbA1c 8.9%/74.3 mmol/mol) from a University department for endocrinology and metabolic diseases (Germany) were included over 2 years. Diabetes-related distress was assessed with the PAID questionnaire (range 0–100, higher scores imply higher diabetes-related distress, cut-off ≥ 40). The PAID questionnaire was completed by 214 of 216 participants. Results Fifty-one of 214 individuals (23.8%) showed high distress (PAID score ≥ 40). The mean PAID score was 28.1 ± 17.5 in all participants with no difference between DM1 and DM2 (28.1 ± 17.4 vs. 26.2 ± 16.9, p = 0.532). Individuals with DM2 on insulin scored higher than patients without insulin (27.8 ± 17.6 vs. 18.7 ± 8.5, p = 0.004). Additionally, people with DM1 treated with a system for continuous glucose monitoring (n = 50, 33.1 ± 18.8) scored higher than participants without such system (n = 32, 20.6 ± 13.3, p = 0.001). HbA1c was not correlated with the PAID score in both, DM1 (r = 0.040, p = 0.684) and DM2 (r = − 0.024, p = 0.804). Participants with DM2 and severe hypoglycaemia/last 12 months scored higher than people without (PAID score 43.0 ± 20.4 vs. 25.1 ± 16.5, p = 0.026). Frequency of non-severe hypoglycaemia was not associated with the PAID score in DM1 and DM2. Conclusions Patients with diabetes treated in hospital for problems with diabetes suffer frequently from diabetes-related distress (~ 24%) regardless of diabetes type.

Research on the big-fish-little-pond effect demonstrates that class-average achievement negatively affects students' academic self-concept via social comparison processes. The neighborhood-effects literature reports positive effects of advantageous socioeconomic neighborhood conditions on students' academic development via collective socialization mechanisms. To investigate how socioeconomic neighborhood conditions affect academic self-concept, we separately and simultaneously analyzed classroom- and neighborhood-level composition effects on students' academic self-concept, using two samples drawn from two grade levels (N[subscript Grade5] = 3,906, N[subscript Grade9] = 3,277). Analyses of the neighborhood level only indicate that socioeconomic neighborhood conditions negatively predict general, math, and German self-concept in Grade 5. In Grade 9, this holds only for math self-concept. In simultaneous analyses including classrooms and neighborhoods, socioeconomically advantageous neighborhood conditions negatively predicted general and math self-concept in Grade 5.

BackgroundChronic heart failure and hospital admissions are well-known risk factors for acute gouty arthritis. However, in-depth analyses of patients admitted for decompensated heart failure (DHF) who subsequently developed a gout attack are sparse. This study aims to characterize DHF patients who developed a gout attack during their inpatient treatment and describe potential risk factors, its consequences, and its management in the setting of heart failure exacerbation.MethodsRetrospective chart review of 50 patients with an admission diagnosis of DHF who subsequently experienced a gout attack during admission at a Swiss tertiary care hospital between 2018 and 2020. Patients with a refusal of the general research consent were excluded (n = 10).ResultsA gout attack developed in 66/1,832 (3.6%) DHF admissions of whom 50 individual patients were analyzed. Patients were predominately male (76%), of advanced age (median 80.5 years), with several comorbidities including chronic kidney disease (74%), comorbid gout (70%, only 43% on urate lowering therapy) and hyperuricemia (median 547 μmol/l, IQR 434–667 μmol/l). Diuretics were intensified in all patients. Acute gout presented as polyarticular arthritis (62%) and was often accompanied by fever (30%). Joint aspiration was performed in 32%, and intra-articular steroid injections administered in 20% of patients. Median length of stay and 6-month mortality were 16 days (IQR 12–25) and 32%, respectively, compared to 9 days (IQR 6–14) and 16% for DHF patients without a gout attack.ConclusionOur study highlights features of gout attacks in the context of DHF including the absence of comorbid gout in a significant proportion of patients, the presence of polyarticular disease during the flare, and a poor prognosis. The present study identifies the necessity to better address gout as a comorbidity in DHF patients and may assist clinicians in identifying DHF patients at risk for a gout attack.

The glass transition of amorphous polymers determines the mobility of polymer chains and the time scale of relaxation processes. The glass transition temperature is reduced by the presence of low molecular weight molecules, e.g., dissolved gases or organic solvents. The quantitative knowledge of reduction of the glass transition temperature caused by the addition of carbon dioxide in a polymer melt is highly relevant for foam extrusion. However, measurement of the reduction of glass transition temperature caused by gas loading has to be performed under elevated pressure which implies high experimental efforts. In this work, we discuss and compare three methods for determination of the influence of carbon dioxide on thermal properties of amorphous polymers, i.e., calorimetric measurements, creep tests, and rheological experiments. The advantages and disadvantages of these methods are elucidated. Furthermore, the influence of molecular structure of the styrenic and vinylpyridine polymers on the glass transition temperature is discussed. Polystyrene generally shows the highest reduction of glass transition temperature. Poly(2-vinylpyridine) and poly(4-vinylpyridine) show a slightly less pronounced behaviour in comparison to polystyrene because of the lower polarity of polystyrene. Poly(α-methyl styrene) is associated with a different dependence of glass transition temperature on gas loading in calorimetric and rheological experiments.

This article originated from a working group on "Learning beyond formal schooling through human--computer--human interaction (HCHI)" convened at the UNESCO EDUSummIT 2023 in Kyoto (Japan). A polylogue approach was adopted by engaging eight co-authors whose diverse perspectives culminated in propositions that addressed the pivotal question: How should the connections between formal, non-formal, and informal learning be considered in a digitally mediated world? Formal learning is typically structured, organized and chronologically arranged institutional learning, whereas informal learning is associated with everyday learning across contexts throughout one's life, and non-formal learning is a hybrid of these forms of learning. Considering the growing prominence of informal and non-formal learning in a digitally mediated world, the evolving learning ecosystem calls for a recalibration of the emphasis on formal learning. In this regard, HCHI has the potential to mediate human--human interactions, thereby bridging formal and informal learning. Our articulated position is to preserve the distinct boundaries and inherent complexities of each type of learning while creating opportunities or 'bridges' to authentically draw on the processes of each through meaningful actions. The polylogue yielded three propositions to bridge the connections between formal, non-formal and informal learning spaces in a digitally mediated world: (a) formal education institutions can establish strategic alliances and collaborations with learning organizations beyond the formal educational system, (b) the creation of digital learning communities within formal and non-formal spaces exemplify a paradigm of operation in an unregulated, student-centric cohesive space where the educator is a co-participant, (c) the recognition of the value of informal learning experiences by formal education institutions is critical, with emphasis on the learning process rather than the product.