A Systematic Review of Approaches for Continuous Quality Improvement Capacity-Building.

CONTEXT: Continuous quality improvement (CQI) has become prominent in public health settings; yet, little consolidated guidance exists for building CQI capacity of community-based organizations. OBJECTIVE: To synthesize relevant literature to identify guiding principles and core components critical to building the capacity of organizations to adopt and use CQI. DESIGN: We employed a systematic review approach to assess guiding principles and core components for CQI capacity-building as outlined in the literature. ELIGIBILITY CRITERIA: Studies meeting the following criteria were eligible for review: (1) empirical, peer-reviewed journal article, evaluation study, review, or systematic review; (2) published in 2010 or later; and (3) capacity-building activities were described in enough detail to be replicable. Studies not including human subjects, published in a language other than English, or for which full text was not available were excluded. STUDY SELECTION: The initial return of records included 6557 articles, of which 1455 were duplicates. The research team single-screened titles and abstracts of 5102 studies, resulting in the exclusion of 4842 studies. Two hundred sixty-two studies were double-screened during full-text review, yielding a final sample of 61 studies from which data were extracted. MAIN OUTCOME MEASURES: Outcome measures of interest were operationalized descriptions of guiding principles and core components of the CQI capacity-building approach. RESULTS: Results yielded articles from medical education, health care, and public health settings. Findings included guiding principles and core components of CQI capacity-building identified in current practice, as well as infrastructural and contextual elements needed to build CQI capacity. CONCLUSIONS: This consolidation of guiding principles and core components for CQI capacity-building is valuable for public health and related workforces. Despite the uneven distribution of articles from health care, medical education, and public health settings, our findings can be used to guide public health organizations in building CQI capacity in a well-informed, systematic manner.

Implementation support practitioners - a proposal for consolidating a diverse evidence base.

BACKGROUND: Workforce development for implementation practice has been identified as a grand challenge in health services. This is due to the embryonic nature of the existing research in this area, few available training programs and a general shortage of frontline service staff trained and prepared for practicing implementation in the field. The interest in the role of "implementation support" as a way to effectively build the implementation capacities of the human service sector has therefore increased. However, while frequently used, little is known about the skills and competencies required to effectively provide such support. MAIN BODY: To progress the debate and the research agenda on implementation support competencies, we propose the role of the "implementation support practitioner" as a concept unifying the multiple streams of research focused on e.g. consultation, facilitation, or knowledge brokering. Implementation support practitioners are professionals supporting others in implementing evidence-informed practices, policies and programs, and in sustaining and scaling evidence for population impact. They are not involved in direct service delivery or management and work closely with the leadership and staff needed to effectively deliver direct clinical, therapeutic or educational services to individuals, families and communities. They may be specialists or generalists and be located within and/or outside the delivery system they serve. To effectively support the implementation practice of others, implementation support practitioners require an ability to activate implementation-relevant knowledge, skills and attitudes, and to operationalize and apply these in the context of their support activities. In doing so, they aim to trigger both relational and behavioral outcomes. This thinking is reflected in an overarching logic outlined in this article. CONCLUSION: The development of implementation support practitioners as a profession necessitates improved conceptual thinking about their role and work and how they enable the uptake and integration of evidence in real world settings. This article introduces a preliminary logic conceptualizing the role of implementation support practitioners informing research in progress aimed at increasing our knowledge about implementation support and the competencies needed to provide this support.

The ß-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22.

Sensitization to fungi, such as the mold Aspergillus fumigatus, is increasingly becoming linked with asthma severity. We have previously shown that lung responses generated via the ß-glucan receptor Dectin-1 are required for lung defense during acute, invasive A. fumigatus infection. Unexpectedly, in an allergic model of chronic lung exposure to live A. fumigatus conidia, ß-glucan recognition via Dectin-1 led to the induction of multiple proallergic (Muc5ac, Clca3, CCL17, CCL22, and IL-33) and proinflammatory (IL-1ß and CXCL1) mediators that compromised lung function. Attenuated proallergic and proinflammatory responses in the absence of Dectin-1 were not associated with changes in Ido (IDO), Il12p35/Ebi3 (IL-35), IL-10, or TGF-ß levels. Assessment of Th responses demonstrated that purified lung CD4(+) T cells produced IL-4, IL-13, IFN-γ, and IL-17A, but not IL-22, in a Dectin-1-dependent manner. In contrast, we observed robust, Dectin-1-dependent IL-22 production by unfractionated lung digest cells. Intriguingly, the absence of IL-22 alone mimicked the attenuated proallergic and proinflammatory responses observed in the absence of Dectin-1, suggesting that Dectin-1-mediated IL-22 production potentiated responses that led to decrements in lung function. To this end, neutralization of IL-22 improved lung function in normal mice. Collectively, these results indicate that the ß-glucan receptor Dectin-1 contributes to lung inflammation and immunopathology associated with persistent fungal exposure via the production of IL-22.

Development and psychometric evaluation of the Implementation Support Competencies Assessment.

BACKGROUND: Implementation support practitioners (ISPs) are professionals that support others to implement evidence-informed practices, programs, and policies in various service delivery settings to achieve population outcomes. Measuring the use of competencies by ISPs provides a unique opportunity to assess an understudied facet of implementation science-how knowledge, attitudes, and skills used by ISPs affects sustainable change in complicated and complex service systems. This study describes the development and validation of a measure-the Implementation Support Competencies Assessment (ISCA)-that assesses implementation support competencies, with versatile applications across service contexts. METHODS: Recently developed practice guide materials included operationalizations of core competencies for ISPs across three domains: co-creation and engagement, ongoing improvement, and sustaining change. These operationalizations, in combination with recent empirical and conceptual work, provided an initial item pool and foundation on which to advance measurement development, largely from a confirmatory perspective (as opposed to exploratory). The measure was further refined through modified cognitive interviewing with three highly experienced ISPs and pilot-testing with 39 individuals enrolled in a university-based certificate program in implementation practice. To recruit a sample for validation analyses, we leveraged a listserv of nearly 4,000 individuals who have registered for or expressed interest in various events and trainings focused on implementation practice offered by an implementation science collaborative housed within a research-intensive university in the Southeast region of the United States. Our final analytic sample included 357 participants who self-identified as ISPs. RESULTS: Assessments of internal consistency reliability for each competency-specific item set yielded evidence of strong reliability. Results from confirmatory factor analyses provided evidence for the factorial and construct validity of all three domains and associated competencies in the ISCA. CONCLUSIONS: The findings suggest that one's possession of high levels of competence across each of the three competency domains is strongly associated with theorized outcomes that can promote successful and sustainable implementation efforts among those who receive implementation support from an ISP. The ISCA serves as a foundational tool for workforce development to formally measure and assess improvement in the skills that are required to tailor a package of implementation strategies situated in context.

How the experiences of implementation support recipients contribute to implementation outcomes.

Introduction: There is a growing body of literature on the activities and competencies of implementation support practitioners (ISPs) and the outcomes of engaging ISPs to support implementation efforts. However, there remains limited knowledge about the experiences of implementation support recipients who engage with ISPs and how these experiences shape the trajectory of implementation and contribute to implementation outcomes. This study aimed to extend the research on ISPs by describing the experiences of professionals who received implementation support and inform our understanding of the mechanisms by which ISPs produce behavior change and contribute to implementation outcomes. Methods: Thirteen individuals with roles in supporting implementation efforts at a private foundation participated in semi-structured interviews. Data were analyzed using qualitative narrative analysis and episode profile analysis approaches. Iterative diagramming was used to visualize the pathway of experiences of implementation support recipients evidenced by the interview data. Results: The majority of recipients described how positive experiences and trusting relationships with ISPs increased acceptance of implementation science throughout the foundation and increased the perception of implementation science as both an appropriate and feasible approach for strengthening the impact of foundation strategies. As perceptions of appropriateness and feasibility increased, recipients of implementation support described increasing knowledge and application of implementation science in their funding engagements and internal foundation strategies. Finally, recipients reported that the application of implementation science across the foundation led to sustained implementation capacity and better outcomes. Discussion: The experiences of implementation support recipients described in this paper provide a source for further understanding the mechanisms of change for delivering effective implementation support leading to better implementation quality. Insights from these experiences can enhance our understanding for building implementation capacity and the rationales for evolving approaches that emphasize the dynamic, emotional, and highly relational nature of supporting others to use evidence in practice.

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury.

Macrophage G2A and CD36 lipid receptors are thought to mediate efferocytosis following tissue injury and thereby prevent excessive inflammation that could compromise tissue repair. To test this, we subjected mice lacking G2A or CD36 receptor to bleomycin-induced lung injury and measured efferocytosis, inflammation, and fibrosis. Loss of CD36 (but not G2A) delayed clearance of apoptotic alveolar cells (mean 78% increase in apoptotic cells 7 days postinjury), potentiated inflammation (mean 56% increase in lung neutrophils and 75% increase in lung KC levels 7 days postinjury, 51% increase in lung macrophages 14 days postinjury), and reduced lung fibrosis (mean 41% and 29% reduction 14 and 21 days postinjury, respectively). Reduced fibrosis in CD36(-/-) mice was associated with lower levels of profibrotic TH2 cytokines (IL-9, IL-13, IL-4), decreased expression of the M2 macrophage marker Arginase-1, and reduced interstitial myofibroblasts. G2A, on the other hand, was required for optimal clearance of apoptotic neutrophils during zymosan-induced peritoneal inflammation (50.3% increase in apoptotic neutrophils and 30.6% increase in total neutrophils 24 h following zymosan administration in G2A(-/-) mice). Thus, CD36 is required for timely removal of apoptotic cells in the context of lung injury and modulates subsequent inflammatory and fibrotic processes relevant to fibrotic lung disease.

IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina.

We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis.

Developing a practice-driven research agenda in implementation science: Perspectives from experienced implementation support practitioners.

Background: Attention is being placed on the "ironic gap" or "secondary" research-to-practice gap in the field of implementation science. Among several challenges posited to exacerbate this research-to-practice gap, we call attention to one challenge in particular-the relative dearth of implementation research that is tethered intimately to the lived experiences of implementation support practitioners (ISPs). The purpose of this study is to feature a qualitative approach to engaging with highly experienced ISPs to inform the development of a practice-driven research agenda in implementation science. In general, we aim to encourage ongoing empirical inquiry that foregrounds practice-driven implementation research questions. Method: Our analytic sample was comprised of 17 professionals in different child and family service systems, each with long-term experience using implementation science frameworks to support change efforts. Data were collected via in-depth, semi-structured interviews. Our analysis followed a qualitative content analysis approach. Our focal conceptual category centered on the desired areas of future research highlighted by respondents, with subcategories reflecting subsets of related research question ideas. Results: Interviews yielded varying responses that could help shape a practice-driven research agenda for the field of implementation science. The following subcategories regarding desired areas for future research were identified in respondents' answers: (a) stakeholder engagement and developing trusting relationships, (b) evidence use, (c) workforce development, and (d) cost-effective implementation. Conclusions: There is significant promise in bringing implementation research and implementation practice together more closely and building a practice-informed research agenda to shape implementation science. Our findings point not only to valuable practice-informed gaps in the literature that could be filled by implementation researchers, but also topics for which dissemination and translation efforts may not have yielded optimal reach. We also highlight the value in ISPs bolstering their own capacity for engaging with the implementation science literature to the fullest extent possible.

In the field of implementation science, increasing attention is being placed on the "ironic gap" or "secondary" research-to-practice gap. This gap reflects a general lag or disconnect between implementation research and implementation practice, often stemming from knowledge generated by implementation research not being accessible to or applied by professionals who support implementation efforts in various service-delivery systems. Several explanations for the research-to-practice gap in implementation science have been offered in recent years; the authors highlight one notable challenge that may be exacerbating the research-to-practice gap in this field, namely that implementation research often remains disconnected from the lived experiences of implementation support practitioners. In this paper, the authors demonstrate the promise of developing a practice-drive research agenda in implementation science, with specific research question ideas offered by highly experienced implementation support practitioners. The paper concludes by expressing enthusiasm for future efforts to bring implementation research and implementation practice together more closely, empirically foreground practice-driven implementation research questions, translate and disseminate existing implementation research findings more widely, and build the capacity of implementation support practitioners to fully engage with the implementation science literature.

Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus.

We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility to Aspergillus fumigatus lung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense against A. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early after A. fumigatus challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1ß, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice. In vivo neutralization of IL-22 in the lungs of WT mice resulted in impaired A. fumigatus lung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1ß production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from both A. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impaired A. fumigatus clearance. Moreover, lung S100a8, S100a9, and Reg3g mRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production.

What implementation strategies are relational? Using Relational Theory to explore the ERIC implementation strategies.

The identification and use of implementation strategies in implementation research and practice have strengthened our understanding of the implementation process as well as the causal pathways between mechanisms, strategies, and implementation outcomes. Although these contributions have advanced the application of strategies, there is still a need to learn more about how strategies might integrate relational exchanges and interactions. The inclusion of critical perspectives has been limited in implementation science, and theories such as Relational Theory can expand our understanding of the relational nature of implementation and enhance rigor through alternative theoretical applications. This study applied Relational Theory through a qualitative directed content analysis of the 73 Expert Recommendations for Implementation Change (ERIC) implementation strategies and examine relational components in strategy descriptions. Three reviewers used the structured approach to review and categorize the implementation strategies based on the Relational and Transactional Strategy Continuum measure, which operationalizes types of interactions, exchanges and alliances. Relational alliance strategies are those in which there is mutual growth and accountability, frequent interaction, shared power, and potential vulnerability. Operational alliances include forms of working exchanges between parties with balanced transactional and relational features. Operational alliances can be somewhat interactive in nature, with minor exchanges and limited accountability. Transactional alliance strategies are mostly uni-directional, influenced by power differentials, and do not require mutual growth, commitment, or exchange; thus, the power of growth is inherently one-sided. Results from the review suggest more implementation strategies with relational alliance features (highly relational, n = 17, semi-relational, n = 19) compared to transactional (highly transactional, n = 9, semi-transactional, n = 10) and 18 strategies coded as operational alliances. The qualitative review revealed opportunities to further expand how relational exchanges are considered within the implementation strategies descriptions, as well as the role of actors and power dynamics within strategy exchanges. The Relational and Transactional Strategy Continuum measure can help practitioners and researchers consider the sequencing, pairing, and impact on outcomes of different types and combinations of strategies in implementation practice and research. Additionally, the measure can support reflection on strategies that promote positive alliances, frequent connections, bi-directional communication, and power sharing.

Intervening for sustainable change: Tailoring strategies to align with values and principles of communities.

This paper presents a rationale for tailoring implementation strategies within a values-driven implementation approach. Values-driven implementation seeks to organize implementers around clarifying statements of their shared values in ways that harmonize implementation dynamics related to individual and group mental models, relationships among implementers, and the implementation climate. The proposed approach to tailoring strategies is informed by systems theory and emphasizes the need to focus on both tangible events and behaviors, as well deeper patterns, structures, relationships, and mental models, in order to increase the likelihood of sustaining implementation efforts and improving outcomes for people and communities. We offer for consideration three specific sets of context determinants that are under-represented in the implementation literature and that emerge as especially relevant within a systems approach to identifying and successfully tailoring implementation strategies in the implementation setting including relationships, mental models, and implementation climate.

Is implementation research out of step with implementation practice? Pathways to effective implementation support over the last decade.

Background: There is growing interest in the lived experience of professionals who provide implementation support (i.e., implementation support practitioners). However, there remains limited knowledge about their experiences and how those experiences can contribute to the knowledge base on what constitutes successful and sustainable implementation support models. This study aimed to examine pathways of implementation support practice, as described by experienced professionals actively supporting systems' uptake and sustainment of evidence to benefit children and families. Methods: Seventeen individuals with extensive experience providing implementation support in various settings participated in semi-structured interviews. Data were analyzed using qualitative content analysis and episode profile analysis approaches. Iterative diagramming was used to visualize the various pathways of implementation support practitioners' role reflection and transformation evidenced by the interview data. Results: Findings highlighted rich pathways of implementation support practitioners' role reflection and transformation. Participants described their roots in providing implementation support as it relates to implementing and expanding the use of evidence-based programs and practices in child and family services. Almost all participants reflected on the early stages of their careers providing implementation support and described a trajectory starting with the use of "push models," which evolved into "pull models" and eventually "co-creation or exchange models" of implementation support involving both technical and relational skills. Conclusions: Developing an implementation support workforce will require a deeper understanding of this lived experience to prevent repeated use of strategies observed to be unsuccessful by those most proximal to the work. The pathways for implementation practice in this study highlight impressive leaps forward in the field of implementation over the last 15 years and speaks to the importance of the professionals leading change efforts in this growth. Plain Language Summary: Over the past few years, professionals in the field of implementation science have identified a growing gap between implementation research and implementation practice. While this issue has been highlighted informally, the field is lacking a shared understanding and clear way forward to reconcile this gap. In this paper, the authors describe how professionals providing implementation support have shifted their implementation practice over time through systematic observations of what works (and what does not work) for supporting and sustaining evidence use in service systems to improve population outcomes. The authors share the impressive leaps forward made in the field of implementation practice - from didactic training to responsive and tailored implementation strategies to co-created and relationship-based implementation solutions. The paper concludes with a call to action to the field for the creation of a virtuous learning cycle between professionals conducting implementation research and professionals providing implementation support to change practice as a way to produce a more robust and relevant science of implementation.

Building trusting relationships to support implementation: A proposed theoretical model.

This paper presents a theory of change that articulates (a) proposed strategies for building trust among implementation stakeholders and (b) the theoretical linkages between trusting relationships and implementation outcomes. The theory of change describes how trusting relationships cultivate increases in motivation, capability, and opportunity for supporting implementation among implementation stakeholders, with implications for commitment and resilience for sustained implementation, and ultimately, positive implementation outcomes. Recommendations related to the measurement of key constructs in the theory of change are provided. The paper highlights how the development of a testable causal model on trusting relationships and implementation outcomes can provide a bridge between implementation research and implementation practice.

Knowledge and attitudes of Implementation Support Practitioners-Findings from a systematic integrative review.

BACKGROUND: It requires thoughtful planning and work to successfully apply and sustain research-supported interventions like healthcare treatments, social support, or preventive programs in practice. Implementation support practitioners (ISPs) such as facilitators, technical assistance providers, knowledge brokers, coaches or consultants may be involved to actively support the implementation process. This article presents knowledge and attitudes ISPs bring to their work. METHODS: Building on a previously developed program logic, a systematic integrative review was conducted. Literature was sourced by searching nine electronic data bases, organizational websites, and by launching a call for publications among selected experts and social media. Article screening was performed independently by two researchers, and data from included studies were extracted by members of the research team and quality-assured by the lead researcher. The quality of included RCTs was assessed based on a framework by Hodder and colleagues. Thematic Analysis was used to capture information on knowledge and attitudes of ISPs across the included studies. Euler diagrams and heatmaps were used to present the results. RESULTS: Results are based on 79 included studies. ISPs reportedly displayed knowledge about the clinical practice they work with, implementation / improvement practice, the local context, supporting change processes, and facilitating evidence-based practice in general. In particular, knowledge about the intervention to be implemented and its target population, specific improvement / implementation methods and approaches, organizational structures and sensitivities, training, and characteristics of (good) research was described in the literature. Seven themes describing ISPs' attitudes were identified: 1) professional, 2) motivated / motivating / encouraging / empowering, 3) empathetic / respectful / sensitive, 4) collaborative / inclusive, 5) authentic, 6) creative / flexible / innovative / adaptive, and 7) frank / direct / honest. Pertaining to a professional attitude, being responsive and focused were the most prevalent indicators across included publications. CONCLUSION: The wide range and complexity of knowledge and attitudes found in the literature calls for a comprehensive and systematic approach to collaboratively develop a professional role for ISPs across disciplines. Embedding the ISP role in different health and social welfare settings will enhance implementation capacities considerably.

Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection.

We have previously reported that compromised interleukin 17A (IL-17A) production in the lungs increased susceptibility to infection with the invasive fungal pathogen Aspergillus fumigatus. Here we have shown that culturing lung cells from A. fumigatus-challenged mice ex vivo demonstrated Dectin-1-dependent IL-17A production. In this system, neutralization of IL-23 but not IL-6, IL-1ß, or IL-18 resulted in attenuated IL-17A production. Il23 mRNA expression was found to be lower in lung cells from A. fumigatus-challenged Dectin-1-deficient mice, whereas bone marrow-derived dendritic cells from Dectin-1-deficient mice failed to produce IL-23 in response to A. fumigatus in vitro. Addition of recombinant IL-23 augmented IL-17A production by wild-type (WT) and Dectin-1-deficient lung cells, although the addition of IL-6 or IL-1ß did not augment the effect of IL-23. Intracellular cytokine staining of lung cells revealed lower levels of CD11b(+) IL-17A(+) and Ly-6G(+) IL-17A(+) cells in A. fumigatus-challenged Dectin-1-deficient mice. Ly-6G(+) neutrophils purified from the lungs of A. fumigatus-challenged Dectin-1-deficient mice displayed lower Il17a mRNA expression but surprisingly had intact Rorc and Rora mRNA expression. We further demonstrated that Ly-6G(+) neutrophils required the presence of myeloid cells for IL-17A production. Finally, upon in vitro stimulation with A. fumigatus, thioglycolate-elicited peritoneal neutrophils were positive for intracellular IL-17A expression and produced IL-17A in a Dectin-1- and IL-23-dependent manner. In summary, Dectin-1-dependent IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b(+) Ly-6G(+) neutrophils in an IL-23-dependent manner.

Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus.

Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.

The absence of Hck, Fgr, and Lyn tyrosine kinases augments lung innate immune responses to Pneumocystis murina.

Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1beta (IL-1beta), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn(-/-) mice 3 days postchallenge, although the level was less than that observed in Hck(-/-) Fgr(-/-) Lyn(-/-) mice. A correlate to augmented clearance of P. murina in Hck(-/-) Fgr(-/-) Lyn(-/-) mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.

What does it take? How federal initiatives can support the implementation of evidence-based programs to improve outcomes for adolescents.

Over the last 20 years, there has been a growing emphasis on developing and identifying evidence-based programs and practices for children and families and within the last decade an increasing number of federally funded initiatives have been dedicated to replicating and scaling evidence-based programs with the hope of achieving socially meaningful impact. However, only recently have efforts to promote high-fidelity implementation been given the attention needed to ensure evidence-based practices are used as intended and generate the outcomes they were designed to produce. In this article, we propose that the wide-scale implementation of evidence-based practices requires: (1) careful assessment and selection of the "what"; (2) a stage-based approach that provides adequate time and resources for planning and installation activities; (3) the co-creation of a visible infrastructure by a triad of key stakeholders including funders and policymakers, program developers, and implementing sites; and (4) the use of data to guide decision-making and foster curiosity into continuous improvement among grantees. Each of these strategies is explored in greater detail through the lens of the Teen Pregnancy Prevention (TPP) Program, a $100 million initiative overseen by the Office of Adolescent Health (OAH) in the U.S. Department of Health and Human Services.

Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice.

In type 1 diabetes (T1D), reactive oxygen species (ROS) and proinflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic ß cells while promoting autoreactive T cell maturation. Superoxide-deficient nonobese diabetic mice (NOD.Ncf1(m1J)) are resistant to spontaneous diabetes, revealing the integral role of ROS signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-Mϕ) from NOD and NOD.Ncf1(m1J) mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-κB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1(m1J) BM-Mϕ exhibited a 2- and 10-fold decrease in TNF-α and IFN-ß proinflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mϕ. Optimal expression of IFN-α/ß is not solely dependent on superoxide synthesis, but requires p47(phox) to function in a NOX-independent manner to mediate type I interferon synthesis. Interestingly, MHC-II I-A(g7) expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-A(g7) downregulation. These findings suggest that defective innate immune-pattern-recognition receptor activation and subsequent decrease in TNF-α and IFN-ß proinflammatory cytokine synthesis necessary for autoreactive T cell maturation may contribute to the T1D protection observed in NOD.Ncf1(m1J) mice.

Dectin-1 Fc targeting of aspergillus fumigatus beta-glucans augments innate defense against invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) has significantly increased over the last decade. Here, a fusion protein consisting of the Dectin-1 extracellular domain linked to the Fc portion of murine immunoglobulin G1 augmented alveolar macrophage killing of Aspergillus fumigatus and shifted mortality associated with IPA via attenuation of A. fumigatus growth in the lung.