Healthcare professionals' longitudinal perceptions of group phenomena as determinants of self-assessed learning in organizational communities of practice.

BACKGROUND: Given the importance of continuous learning as a response to the increasing complexity of health care practice, there is a need to better understand what makes communities of practice in health effective at fostering learning. Despite the conceptual stance that communities of practice facilitate individual learning, the scientific literature does not offer much evidence for this. Known factors associated with the effectiveness of communities of practice - such as collaboration, psychological safety within the community, and commitment to the community - have been studied in cross-sectional qualitative designs. However, no studies to date have used a quantitative predictive design. The objective of this study is to assess how members of a community of practice perceive interactions among themselves and determine the extent to which these interactions predict self-assessed learning over time. METHODS: Data was collected using validated questionnaires from six communities of practice (N = 83) in four waves of measures over the course of 36 months and was analysed by means of General Estimating Equations. This allowed to build a longitudinal model of the associations between perceptions of collaboration, psychological safety within the community, commitment to the community and self-assessed learning over time. RESULTS: Perception of collaboration in the community of practice, a personal sense of psychological safety and a commitment to the community of practice are predictors longitudinally associated with self-assessed learning. CONCLUSIONS: In terms of theory, conceptual links can be made between intensity of collaboration and learning over time in the context of a community of practice. Recent work on psychological safety suggests that it is still unclear whether psychological safety acts as a direct enhancer of learning or as a remover of barriers to learning. This study's longitudinal results suggest that psychological safety may enhance how and to what extent professionals feel they learn over time. Commitment towards the community of practice is a strong predictor of learning over time, which hints at differential effects of affective, normative and continuance commitment. Communities of practice can therefore apply these findings by making collaboration, psychological safety, commitment and learning regular reflexive topics of discussion.

Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives.

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid ß-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

[Organizational learning and health promotion: a Quebec project] / Apprentissage organisationnel en promotion de la santé : une expérience québécoise.

OBJECTIVE: This article focuses on health promotion laboratories, a Quebec professional development program offered by the Public Health Department of the Montréal Region to teams of professionals and managers working in health promotion within local public health organizations. The objective is to examine the process of translating the knowledge gained by participants as a result of the program over the longer term within the organization. METHOD: This was a qualitative descriptive study. The work was guided by Nonaka's Organizational Knowledge Creation Model. Data were collected from participants at several types of discussion and development events held in the three months following the end of the pilot project. A thematic content analysis was performed using a grid derived from Nonaka's model. RESULTS: The analysis revealed the presence of both externalization and internalization in two of the sites, as well as a considerable volume of combinations in the four sites studied. In the latter case, the learnings reused over the longer term were similar to those that had been transferred in the short term (e.g. ideas and methods relating to partnership, planning, etc.). CONCLUSION: These results are important, in that they confirm the laboratories' potential to propagate the learnings throughout the organization, beyond the short-term gains made by participants during the laboratories. These learnings could potentially pave the way for new practices.

Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome.

Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients.

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

APVO210: A Bispecific Anti-CD86-IL-10 Fusion Protein (ADAPTIR™) to Induce Antigen-Specific T Regulatory Type 1 Cells.

IL-10 is a potent immunosuppressive cytokine that promotes the differentiation of tolerogenic dendritic cells (DC-10), and the subsequent induction of antigen-specific T regulatory type 1 (Tr1) cells, which suppress immune responses. However, IL-10 acts on multiple cell types and its effects are not solely inhibitory, therefore, limiting its use as immunomodulant. APVO210 is a bispecific fusion protein composed of an anti-CD86 antibody fused with monomeric IL-10 (ADAPTIR™ from Aptevo Therapeutics). APVO210 specifically induces IL-10R signaling in CD86+ antigen-presenting cells, but not in T and B cells. In this study, we tested whether APVO210 promotes the differentiation of tolerogenic DC-10 and the differentiation of antigen-specific CD4+ Tr1 cells in vitro. We compared the effect of APVO210 with that of recombinant human (rh) IL-10 on the in vitro differentiation of DC-10, induction of alloantigen-specific anergic CD4+ T cells, enrichment in CD49b+LAG3+ Tr1 cells mediating antigen-specific suppression, and stability upon exposure to inflammatory cytokines. APVO210 induced the differentiation of tolerogenic DC (DC-A210) that produced high levels of IL-10, expressed CD86, HLA-G, and intermediate levels of CD14 and CD16. These DC-A210 induced alloantigen-specific anergic T-cell cultures (T-alloA210) that were enriched in CD49b+ LAG3+ Tr1 cells, produced high levels of IL-10, and had suppressive properties. The phenotype and high IL-10 production by DC-A210, and the alloantigen-specific anergy of T-alloA210 were preserved upon exposure to the inflammatory cytokines IL-1ß, IL-6, and TNF-α. The effects of APVO210 were comparable to that of dimeric rh IL-10. In conclusion, our data demonstrate that APVO210 drives the differentiation of tolerogenic DC and functional alloantigen-specific Tr1 cells in vitro. Since APVO210 specifically targets CD86+ cells, we hypothesize that it will specifically target CD86+ DC to induce Tr1 cells in vivo, and mediate antigen-specific immunological tolerance by induction of tolerogenic DC and Tr1 cells.

Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired.

BACKGROUND: Peanut allergy (PA) is a life-threatening condition that lacks regulator-approved treatment. Regulatory T type 1 (TR1) cells are potent suppressors of immune responses and can be induced in vivo upon repeated antigen exposure or in vitro by using tolerogenic dendritic cells. Whether oral immunotherapy (OIT) leads to antigen-specific TR1 cell induction has not been established. OBJECTIVES: We sought to determine whether peanut-specific TR1 cells can be generated in vitro from peripheral blood of patients with PA at baseline or during OIT and whether they are functional compared with peanut-specific TR1 cells induced from healthy control (HC) subjects. METHODS: Tolerogenic dendritic cells were differentiated in the presence of IL-10 from PBMCs of patients with PA and HC subjects pulsed with the main peanut allergens of Arachis hypogaea, Ara h 1 and 2, and used as antigen-presenting cells for autologous CD4+ T cells (CD4+ T cells coincubated with tolerogenic dendritic cells pulsed with the main peanut allergens [pea-T10 cells]). Pea-T10 cells were characterized by the presence of CD49b+ lymphocyte-activation gene 3 (LAG3)+ TR1 cells, antigen-specific proliferative responses, and cytokine production. RESULTS: CD49b+LAG3+ TR1 cells were induced in pea-T10 cells at comparable percentages from HC subjects and patients with PA. Despite their antigen specificity, pea-T10 cells of patients with PA with or without OIT, as compared with those of HC subjects, were not anergic and had high TH2 cytokine production upon peanut-specific restimulation. CONCLUSIONS: Peanut-specific TR1 cells can be induced from HC subjects and patients with PA, but those from patients with PA are functionally defective independent of OIT. The unfavorable TR1/TH2 ratio is discussed as a possible cause of PA TR1 cell impairment.

An analysis of the adaptability of a professional development program in public health: results from the ALPS Study.

BACKGROUND: Professional development is a key component of effective public health infrastructures. To be successful, professional development programs in public health and health promotion must adapt to practitioners' complex real-world practice settings while preserving the core components of those programs' models and theoretical bases. An appropriate balance must be struck between implementation fidelity, defined as respecting the core nature of the program that underlies its effects, and adaptability to context to maximize benefit in specific situations. This article presents a professional development pilot program, the Health Promotion Laboratory (HPL), and analyzes how it was adapted to three different settings while preserving its core components. An exploratory analysis was also conducted to identify team and contextual factors that might have been at play in the emergence of implementation profiles in each site. METHODS: This paper describes the program, its core components and adaptive features, along with three implementation experiences in local public health teams in Quebec, Canada. For each setting, documentary sources were analyzed to trace the implementation of activities, including temporal patterns throughout the project for each program component. Information about teams and their contexts/settings was obtained through documentary analysis and semi-structured interviews with HPL participants, colleagues and managers from each organization. RESULTS: While each team developed a unique pattern of implementing the activities, all the program's core components were implemented. Differences of implementation were observed in terms of numbers and percentages of activities related to different components of the program as well as in the patterns of activities across time. It is plausible that organizational characteristics influencing, for example, work schedule flexibility or learning culture might have played a role in the HPL implementation process. CONCLUSIONS: This paper shows how a professional development program model can be adapted to different contexts while preserving its core components. Capturing the heterogeneity of the intervention's exposure, as was done here, will make possible in-depth impact analyses involving, for example, the testing of program-context interactions to identify program outcomes predictors. Such work is essential to advance knowledge on the action mechanisms of professional development programs.

Defects of corneocyte structural proteins and epidermal barrier in atopic dermatitis.

The main function of the epidermis is to establish a vital multifunctional barrier between the body and its external environment. A defective epidermal barrier is one of the key features of atopic dermatitis (AD), a chronic and relapsing inflammatory skin disorder that affects up to 20% of children and 2-3% of adults and often precedes the development of allergic rhinitis and asthma. This review summarizes recent discoveries on the origin of the skin barrier alterations in AD at the structural protein level, including hereditary and acquired components. The consequences of the epidermal barrier alteration on our current understanding of the pathogenesis of AD, and its possible implications on the treatment of patients, are discussed here.

Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation.

Atopic dermatitis is a chronic inflammatory skin disorder characterized by defects in the epidermal barrier and keratinocyte differentiation. The expression of filaggrin, a protein thought to have a major role in the function of the epidermis, is downregulated. However, the impact of this deficiency on keratinocytes is not really known. This was investigated using lentivirus-mediated small-hairpin RNA interference in a three-dimensional reconstructed human epidermis (RHE) model, in the absence of other cell types than keratinocytes. Similar to what is known for atopic skin, the experimental filaggrin downregulation resulted in hypogranulosis, a disturbed corneocyte intracellular matrix, reduced amounts of natural moisturizing factor components, increased permeability and UV-B sensitivity of the RHE, and impaired keratinocyte differentiation at the messenger RNA and protein levels. In particular, the amounts of two filaggrin-related proteins and one protease involved in the degradation of filaggrin, bleomycin hydrolase, were lower. In addition, caspase-14 activation was reduced. These results demonstrate the importance of filaggrin for the stratum corneum properties/functions. They indicate that filaggrin downregulation in the epidermis of atopic patients, either acquired or innate, may be directly responsible for some of the disease-related alterations in the epidermal differentiation program and epidermal barrier function.

Regulatory T cells and their roles in immune dysregulation and allergy.

The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3(+) (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3(+) Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs.

Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a disturbed epidermal barrier. In a subset of patients, this is explained by nonsense mutations in the gene encoding filaggrin (FLG). OBJECTIVES: We sought to evaluate the respective role of FLG mutations and proinflammatory cytokines and to assess the expression of FLG, hornerin (HRNR), and FLG2, 2 FLG-like proteins, which are involved in epidermal barrier functions, in normal skin and both lesional and nonlesional skin of patients with AD. METHODS: An FLG-genotyped cohort of 73 adults with AD and 73 aged-matched control subjects was analyzed by using immunohistochemistry and immunoblotting. Normal primary human keratinocytes were differentiated in either the absence or presence of IL-4, IL-13, and IL-25. RESULTS: Compared with control subjects, FLG, HRNR, and FLG2 were detected at significantly lower levels in the skin of patients with AD, irrespective of their FLG genotype. The reduction was greater in lesional compared with nonlesional skin. In addition, the proFLG/FLG ratio was found to be higher in the skin of wild-type patients than in control subjects. Cytokine treatment of keratinocytes induced a dramatic reduction in FLG, FLG2, and HRNR expression both at the mRNA and protein levels. CONCLUSION: The stratum corneum of lesional but also clinically unaffected skin of adults with AD is abnormal, with reduced expression of FLG and FLG-like proteins. In addition to nonsense mutations, proinflammatory cytokines and some defects in the proFLG processing can contribute to the FLG downregulation. Our study suggests that skin inflammation reduces the expression of FLG-like proteins, contributing to the AD-related epidermal barrier dysfunction.

Update on the epidermal differentiation complex.

On human chromosome 1q21, a 2-Mb region called the epidermal differentiation complex comprises many genes encoding structural and regulatory proteins that are of crucial importance for keratinocyte differentiation and stratum corneum properties. Apart from those for involucrin and loricrin, most of the genes are organized in four families: the genes encoding EF-hand calcium-binding proteins of the S100A family, the genes encoding the small proline rich proteins (SPRRs) and the late cornified envelope (LCE) proteins, two families of cornified cell envelope components, and the genes encoding the S100-fused type proteins (SFTPs). This review focuses on the SPRRs, LCE proteins and SFTPs. It describes their structures, their specific functions and, when known, the mechanisms involved in the regulation of their expression. It also highlights their possible involvement in skin diseases.

[Social representation of pregnancy in adolescence: appraisal of dominant attitudes and others of negative impact]. / Les représentations sociales de la grossesse à l'adolescence: des prises de position dominantes et d'autres...déstabilisantes.

This study was undertaken to gather information on the social representations of teenage pregnancy among adolescents, aged between 15 and 17. Eighteen focus groups were conducted among 150 boys and girls. The data were subjected to a qualitative content analysis. Results show that youths did not form homogeneous groups. The points of view expressed gave rise to 4 dimensions (emotive, reflexive, psychobiological, economic-social) and 4 positions (negative, positive, ambivalent and dynamic). From these dimensions and positions, 4 representations of teenage pregnancy were identified: pregnancy as a problem, pregnancy as a project, pregnancy as a source of tension, and pregnancy as a source of power. This study illustrates the importance of educative strategies such as going beyond alarmist preventive messages, opening dialogue with and between youngsters, and promoting social support and mutual aid.