A fluorescent gemcitabine prodrug that follows a nucleoside transporter-independent internalization and bears enhanced therapeutic efficacy with respect to gemcitabine.

The multiplexity of cancer has rendered it the second leading cause of mortality worldwide and theragnostic prodrugs have gained popularity in recent years as a means of treatment. Theragnostic prodrugs enable the simultaneous diagnosis and therapy of tumors via high-precision real-time drug release monitoring. Herein, we report the development of the small theragnostic prodrug GF, based on the nucleoside anticancer agent gemcitabine and the fluorescent dye 5(6)-carboxyfluorescein. We have successfully demonstrated its efficient internalization in tumor cells, showing localization throughout both the early and late endocytic pathways. Its mechanism of cell internalization was evaluated, confirming its independence from nucleoside transporters. Its cellular localization via confocal microscopy revealed a clathrin-mediated endocytosis mechanism, distinguishing it from analogous compounds studied previously. Furthermore, GF exhibited stability across various pH values and in human blood plasma. Subsequently, its in vitro cytotoxicity was assessed in three human cancer cell lines (A549, U87 and T98). Additionally, its pharmacokinetic profile in mice was investigated and the consequent drug release was monitored. Finally, its in vivo visualization was accomplished in zebrafish xenotransplantation models and its in vivo efficacy was evaluated in A549 xenografts. The results unveiled an intriguing efficacy profile, positioning GF as a compelling candidate warranting further investigation.

Embryonic stem cells are devoid of macropinocytosis, a trafficking pathway for activin A in differentiated cells.

Ligand-receptor complexes formed at the plasma membrane are internalised via various endocytic pathways that influence the ultimate signalling output by regulating the selection of interaction partners by the complex along the trafficking route. We report that, in differentiated cells, activin A-receptor complexes are internalised via clathrin-mediated endocytosis (CME) and macropinocytosis (MP), whereas in human embryonic stem cells (hESCs) internalisation occurs via CME. We further show that hESCs are devoid of MP, which becomes functional upon differentiation towards endothelial cells through mesoderm mediators. Our results reveal, for the first time, that MP is an internalisation route for activin A in differentiated cells, and that MP is not active in hESCs and is induced as cells differentiate.

Editorial Perspective: Maximising the benefits of intervention research for children and young people with developmental language disorder (DLD) - a call for international consensus on standards of reporting in intervention studies for children with and at risk for DLD.

Current methods for reporting interventions do not allow key questions of importance to practitioners, service providers, policy-makers and people with DLD to be answered, and hence limit the implementation of effective interventions in the real world. To extend the existing EQUATOR guidelines to the context of speech language therapy/pathology for children with language disorder and to provide more specific guidance on participants, interventions and outcomes within the CONSORT checklist (used to improve the reporting of randomised controlled trials) and TIDieR (Template for Intervention Description and Replication) to ensure consistency of reporting. We will develop a core team to include representatives from each of the key groups who will either use or be influenced by the final reporting guidance across different countries. To achieve each set of aims, we will conduct reviews of the literature (which present typologies of intervention characteristics in (D)LD and related disorders); carry out focus groups; and use systematic consensus methods such as the Delphi technique, nominal group technique or consensus development conferences. Through the development and adoption of standard intervention reporting criteria, we anticipate that we will overcome the numerous barriers for practitioners, services and policy-makers in applying intervention evidence to practice. We believe that establishing international consensus on reporting guidelines would significantly accelerate progress in DLD research and the ease with which it can be used in clinical practice, by capitalising on the growth in intervention studies to enable international collaboration and new methodologies of data pooling, meta-analyses and cross-study comparisons.

VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates IRE1α, ATF6, and PERK cascades, leading to a transcriptional/translational response known as unfolded protein response (UPR). Here we show that VEGF activates UPR mediators through a PLCγ-mediated crosstalk with the mTORC1 complex without accumulation of unfolded proteins in the ER. Activation of ATF6 and PERK contributes to the survival effect of VEGF on endothelial cells (ECs) by positively regulating mTORC2-mediated phosphorylation of AKT on Ser473, which is required for full activity of AKT. Low levels of CHOP allow ECs to evade the proapoptotic effect of this UPR product. Depletion of PLCγ, ATF6, or eIF2α dramatically inhibited VEGF-induced vascularization in mouse Matrigel plugs, suggesting that the ER and the UPR machinery constitute components of the VEGF signaling circuit that regulates EC survival and angiogenesis, extending their role beyond adaptation to ER stress.

Why Clinicians Choose Their Language Intervention Approach: An International Perspective on Intervention for Children with Developmental Language Disorder.

PURPOSE: Considerable progress has been made in recent years in generating external evidence underpinning interventions for children with developmental language disorder (DLD), but less is known about the practitioner decision-making process underpinning such interventions and whether such decisions are context specific or are internationally generalizable. METHODS: An online survey about clinical practice was developed by members of COST Action IS1406, an EU-funded research network, which included representation from 39 countries. The participants were 2,408 practitioners who answered questions in relation to their decision making for a specific child of their choosing with DLD. Analysis of open-ended questions was undertaken, and data were converted into codes for the purpose of quantitative analysis. RESULTS: Although a wide range of intervention approaches and rationales were reported, the majority of responses referenced a client-centred approach. Level of functioning was used as a rationale only if a child had severe DLD. Practitioners with university level education or above were less likely to report basing intervention on client-centred factors. A number of differently named interventions with variable theoretical and empirical underpinnings were used in different countries. CONCLUSIONS: Specific client and practitioner characteristics have an impact on the intervention approaches and rationales adopted across countries. A limited number of practitioners reported use of external scientific evidence, which suggests that there should be more initiatives in basic training of practitioners and continuing professional development to encourage the uptake of scientific evidence-based practice.

Integrating primary and secondary care to optimize hepatitis C treatment: development and evaluation of a multidisciplinary educational Masterclass series.

BACKGROUND: It is increasingly being recognized that the elimination of HCV requires a multidisciplinary approach and effective cooperation between primary and secondary care. OBJECTIVES: As part of a project (HepCare Europe) to integrate primary and secondary care for patients at risk of or infected with HCV, we developed a multidisciplinary educational Masterclass series for healthcare professionals (HCPs) working in primary care in Dublin and Bucharest. This article aims to describe and evaluate the series and examine how this model might be implemented into practice. METHODS: GPs and other HCPs working in primary care, addiction treatment services and NGOs were invited to eight 1 day symposia (HCV Masterclass series), examining the burden and management of HCV in key populations. Peer-support sessions were also conducted, to give people affected by HCV and community-based organizations working with those directly affected, an update on the latest developments in HCV treatment. RESULTS: One hundred percent of participants 'strongly agreed' or 'agreed' that the Masterclass helped them to appreciate the role of integrated services in 'the management of patients with HCV'. One hundred percent of participants indicated the importance of a 'designated nurse to liaise with hospital services'. An improvement of knowledge regarding HCV management of patients with high-risk behaviour was registered at the end of the course. CONCLUSIONS: Integrated approaches to healthcare and improving the knowledge of HCPs and patients of the latest developments in HCV treatment are very important strategies that can enhance the HCV care pathway and treatment outcomes.

'HepCheck Dublin': an intensified hepatitis C screening programme in a homeless population demonstrates the need for alternative models of care.

BACKGROUND: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. METHODS: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. RESULTS: Five hundred ninety-seven individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were 'new positives' and 44% were 'known positives'. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. Forty-six subjects were referred to specialised services and two subjects completed HCV treatment. CONCLUSIONS: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV.

The seroprevalence of untreated chronic hepatitis C virus (HCV) infection and associated risk factors in male Irish prisoners: a cross-sectional study, 2017.

IntroductionData on chronic hepatitis C (HCV) infection prevalence in European prisons are incomplete and impact the public health opportunity that incarceration provides.AimsWe aimed to estimate the seroprevalence of untreated chronic HCV infection and to identify associated risk factors in an Irish male prison.MethodsWe conducted a cross-sectional study involving a researcher-administered questionnaire, review of medical records and HCV serology.ResultsOf 422 prisoners (78.0% of the study population) who participated in the study, 298 (70.6%) completed the questionnaire and 403 (95.5%) were tested for HCV antibodies. Of those tested, 92 (22.8%) were HCV antibody-positive, and of those, 53 (57.6%) were HCV RNA-positive, 23 (25.0%) had spontaneous clearance, 16 (17.4%) had a sustained viral response, 10 (11.0%) were co-infected with HIV and six (6.0%) with HBV. The untreated chronic HCV seroprevalence estimate was 13.1% and the seroprevalence of HCV among prisoners with a history of injecting drug use (IDU) was 79.7%. Risk factors significantly associated with past HCV infection were IDU (p < 0.0001), having received a prison tattoo (p < 0.0001) or a non-sterile community tattoo (p < 0.0001), sharing needles and other drug-taking paraphernalia (p < 0.0001). Small numbers of prisoners had a history of sharing razors (n=10; 3.4%) and toothbrushes (n=3; 1.0%) while incarcerated. On multivariable analysis, history of receiving a non-sterile community tattoo was the only significant risk factor associated with HCV acquisition (after IDU was removed from the model) (p = 0.005, ß = 0.468).ConclusionThe level of untreated chronic HCV infection in Irish prisons is high, with IDU the main associated risk.

Consequential differences in perspectives and practices concerning children with developmental language disorders: an integrative review.

BACKGROUND: Inter-professional collaboration (IPC) has been recommended for many years as a means by which the needs of children with developmental language disorders (DLD) can be met at school. However, effective IPC remains difficult to achieve and our knowledge of how to support it is limited. A shared understanding between those involved has been identified as critical to IPC. AIMS: To examine the literature, as one source of data, for evidence of a shared understanding between the fields of speech and language therapy (SLT) and education about children with DLD and how such needs can best be met at school. METHODS & PROCEDURES: An integrative review of the literature was undertaken. A systematic search of the published, peer-reviewed literature (between 2006 and 2016) was conducted for empirical and theoretical papers and a manual search was undertaken to obtain a representative sample of policy/professional guidelines. A total of 81 papers across SLT and education were included in the review. The papers were scrutinized using a qualitative content analysis. MAIN CONTRIBUTION: Although some commonality between perspectives in the literature was identified, differences between the fields dominated. These differences related to how DLD is conceptualized; how children's needs are assessed; which outcomes are prioritized and how best these outcomes can be achieved. We also found differences about what constitutes useful knowledge to guide practice. We suggest that the nature of the differences we identified in the literature may have negative implications for practitioners wishing to collaborate to meet the needs of children with DLD in school. The perspectives of practising SLTs and teachers need to be sought to determine whether the findings from the literature reflect dilemmas in practice. CONCLUSIONS: Effective IPC is essential to meet the needs of children with DLD in school; yet, it remains difficult to achieve. Our review of the literature across SLT and education indicates evidence of a lack of shared understanding about DLD. If these differences are also evident in practice, then a conceptual model to support IPC may be warranted.

Moving Beyond Traditional Understandings of Evidence-Based Practice: A Total Evidence and Knowledge Approach (TEKA) to Treatment Evaluation and Clinical Decision Making in Speech-Language Pathology.

Evidence-based practice (EBP) is a well-established framework for supporting clinical decision making in the discipline of speech-language pathology. The benefits of using evidence to inform clinical practice are acknowledged by clinicians and researchers alike. Even so, after over two decades of EBP advocacy, much clinical uncertainty remains and models supporting the evaluation of interventions require review and reconsideration. The EBP model, while promoting positive principles, can be argued to be conceptually flawed because it suffers from a lack of attention to and explicit valuing of other forms of knowledge crucial to the formation of realistic and judiciously informed decisions. We propose that the evaluation of interventions would be better supported by an explicit knowledge management approach reflecting a range of evidence and knowledge. One worked example is presented to demonstrate what using such an approach can produce in terms of intervention information.

VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis.

Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFA-induced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.

Barriers and facilitators to hepatitis C (HCV) screening and treatment-a description of prisoners' perspective.

BACKGROUND: Hepatitis C virus (HCV) infection is a global epidemic with an estimated 71 million people infected worldwide. People who inject drugs (PWID) are overrepresented in prison populations globally and have higher levels of HCV infection than the general population. Despite increased access to primary health care while in prison, many HCV infected prisoners do not engage with screening or treatment. With recent advances in treatment regimes, HCV in now a curable and preventable disease and prisons provide an ideal opportunity to engage this hard to reach population. AIM: To identify barriers and enablers to HCV screening and treatment in prisons. METHODS: A qualitative study of four prisoner focus groups (n = 46) conducted at two prison settings in Dublin, Ireland. RESULTS: The following barriers to HCV screening and treatment were identified: lack of knowledge, concerns regarding confidentiality and stigma experienced and inconsistent and delayed access to prison health services. Enablers identified included; access to health care, opt-out screening at committal, peer support, and stability of prison life which removed many of the competing priorities associated with life on the outside. Unique blocks and enablers to HCV treatment reported were fear of treatment and having a liver biopsy, the requirement to go to hospital and in-reach hepatology services and fibroscanning. CONCLUSION: The many barriers and enablers to HCV screening and treatment reported by Irish prisoners will inform both national and international public health HCV elimination strategies. Incarceration provides a unique opportunity to upscale HCV treatment and linkage to the community would support effectiveness.

Proteome Changes during Transition from Human Embryonic to Vascular Progenitor Cells.

Human embryonic stem cells (hESCs) are promising in regenerative medicine (RM) due to their differentiation plasticity and proliferation potential. However, a major challenge in RM is the generation of a vascular system to support nutrient flow to newly synthesized tissues. Here we refined an existing method to generate tight vessels by differentiating hESCs in CD34(+) vascular progenitor cells using chemically defined media and growth conditions. We selectively purified these cells from CD34(-) outgrowth populations also formed. To analyze these differentiation processes, we compared the proteomes of the hESCs with those of the CD34(+) and CD34(-) populations using high resolution mass spectrometry, label-free quantification, and multivariate analysis. Eighteen protein markers validate the differentiated phenotypes in immunological assays; nine of these were also detected by proteomics and show statistically significant differential abundance. Another 225 proteins show differential abundance between the three cell types. Sixty-three of these have known functions in CD34(+) and CD34(-) cells. CD34(+) cells synthesize proteins implicated in endothelial cell differentiation and smooth muscle formation, which support the bipotent phenotype of these progenitor cells. CD34(-) cells are more heterogeneous synthesizing muscular/osteogenic/chondrogenic/adipogenic lineage markers. The remaining >150 differentially abundant proteins in CD34(+) or CD34(-) cells raise testable hypotheses for future studies to probe vascular morphogenesis.

A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD.

Feasible Peer-Mediated Intervention for Autistic Children Using Minimal Speech: A Qualitative Intervention Development Process.

PURPOSE: Qualitative engagement with stakeholders in the development of interventions can provide insight into strategies to maximize feasibility in real-life settings. We engaged stakeholders (autistic adults, early childhood educators, early childhood sector leaders and policy influencers, parents of autistic children, and speech-language pathologists) to inform the development of an educator-led peer-mediated intervention (PMI) for autistic preschoolers who use minimal speech that is feasible to implement in inclusive early childhood education and care (ECEC) settings. METHOD: A qualitative iterative intervention design process was utilized. Stakeholders (N = 15) attended an online workshop and completed a document review exploring the acceptability and feasibility of the proposed embedded PMI. A two-step analysis procedure using the Theoretical Domains Framework and template analysis was conducted to identify the barriers, enablers, and supports to the implementation of embedded PMI in early childhood settings. RESULTS: While embedded PMI was unanimously acceptable to stakeholders, several participants expressed concerns regarding feasibility. Barriers to the successful integration and implementation of PMI in inclusive preschool contexts included access to skills, knowledge, and resources. Participants identified strategies to overcome modifiable barriers and to enhance the existing enablers. These strategies are reflected in the following themes: build on the familiar, build capacity in augmentative and alternative communication, adopt a whole center approach, adapt to meet the needs of the ECEC setting, and engage in proactive implementation. CONCLUSION: To address barriers to the implementation of embedded PMI, action is needed at various levels: macro (national/policy), meso (organization/setting), and micro (individual). SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25155770.

ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN.

SARA, an early endosomal protein, plays a key role in TGFß signalling, as it presents SMAD2 and SMAD3 for phosphorylation by the activated TGFß receptors. Here, we show that ERBIN is a new SARA-interacting protein that can be recruited by SARA to early endosomes. ERBIN was recently shown to bind and segregate phosphorylated SMAD2 and SMAD3 (SMAD2/3) in the cytoplasm, thereby inhibiting SMAD2/3-dependent transcription. SARA binds to ERBIN using a new domain, which we have called the ERBID (ERBIN-binding domain), whereas ERBIN binds to SARA using a domain (amino acids 1208-1265) that also interacts with SMAD2 and SMAD3, which we have called the SSID (SARA- and SMAD-interacting domain). We additionally show that SARA competes with SMAD2/3 for binding to ERBIN. In agreement, overexpression of SARA or the ERBID peptide reverses the inhibitory effect of ERBIN on SMAD2/3-dependent transcription. Taken together, these data suggest that the response of cells to TGFß and activin A can be influenced by the relative concentrations of SARA, ERBIN and SMAD2/3.

Stakeholder Perceptions of the Acceptability of Peer-Mediated Intervention for Minimally Speaking Preschoolers on the Autism Spectrum.

Peer mediated intervention (PMI) is an evidence-based approach to supporting social and communication development for children on the autism spectrum. For PMI to be integrated into everyday practice, it needs to be acceptable to stakeholders. This article engaged with autistic individuals, early childhood educators, parents, and speech and language pathologists on the prospective acceptability of implementing PMI with minimally speaking preschoolers in inclusive preschool settings. Focus groups and semi-structured interviews were conducted. The transcriptions were analyzed qualitatively using reflexive thematic analysis. Stakeholders described PMI as an acceptable intervention approach for this population and provided valuable insights to inform the development and implementation of PMIs. Attention needs to be paid to how to support preschools to adopt a PMI-friendly philosophy.

Exploring the acceptability, feasibility, and appropriateness of a communication-friendly classroom tool for use in Irish schools: A qualitative inquiry.

BACKGROUND: Ten percent of the school-aged population have speech, language, and communication needs (SLCN) that impact access to the curriculum. Successful implementation of classroom-based SLCN interventions can reduce barriers to learning, thereby improving educational outcomes for this vulnerable population. The challenges of implementing innovations in educational settings are well-documented, yet limited studies have addressed such considerations when developing, and piloting universal level SLCN interventions for use in Irish schools. METHODS: A qualitative exploratory study was undertaken to establish the acceptability, feasibility, and appropriateness of a universal level SLCN intervention. An advisory panel of teachers (n = 8) and children with SLCN (n = 2) were engaged as co-researchers in the study. The Communication Supporting Classrooms Observation Tool, developed as part of the Better Communication Project in the UK, was trialled across a diverse sample of school settings (n = 5). Semi-structured interviews were conducted with school practitioners and school leaders, and a deductive content analysis was undertaken using the domains of the Consolidation Framework for Implementation Research. DISCUSSION: The observation tool was viewed as acceptable with suggested additions. Integrating use of the tool within existing data-informed, school self-evaluation processes aimed at supporting school improvement was noted as a potential means of supporting implementation. A knowledge gap in relation to school-based models of support for SLCN was identified which may negatively impact implementation. An implementation strategy targeting coherence, cognitive engagement and contextual integration is indicated if the tool is to be normalised into routine practice in Irish classrooms. Implementation needs appeared to vary at the school level. CONCLUSIONS: The importance of early-stage exploration to guide implementation planning with regards to developing and testing universal level interventions for SLCN in schools is highlighted. Engaging an advisory panel provides important insights to guide implementation decisions. Findings suggest an adaptive design is required when planning implementation studies targeting classroom setting.

Implementation Science in School-Based, Universal-Level Intervention Research: A Scoping Review.

PURPOSE: The aim of this study was to map the use of implementation science frameworks, models, and theories in intervention research targeting learning needs in the classroom. METHOD: A scoping review was conducted. Electronic database and manual searches were conducted. Two reviewers independently completed screening, data extraction, and quality appraisal. Qualitative content analysis was undertaken using Nilsen's taxonomy and the domains of the Consolidated Framework for Implementation Research (CFIR). The data were further analyzed using the CFIR valence and strength rating scales. RESULTS: Included papers (n = 22) used a diverse sample of implementation science frameworks and models. Most studies used determinant frameworks to guide data collection and analysis. Few studies used implementation science theory. Most studies were mixed methods (n = 11), published since 2019 (n = 20), and conducted in North America (n = 15). Over half of the interventions targeted social, emotional, and mental health (n = 13). A complex interplay of inner setting factors was identified as having a strong influence on implementation. Teachers' knowledge and beliefs, adaptability, and complexity of interventions were also identified as important considerations when conducting research in this context. CONCLUSIONS: Early engagement with stakeholders in education is recommended when designing universal level speech, language, and communication interventions for use in the ordinary classroom. Adaptive, hybrid designs that test both implementation strategies and effectiveness of interventions may be warranted given the influence of inner setting factors on implementation outcomes.