Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can reduce inflammation, promote healing, and improve organ function, thereby providing a potential “cell-free” therapy. Prior to clinical translation, it is critical to synthesize existing evidence on preclinical methods and efficacy. To address these issues, we used gold standard systematic review methodology to consolidate information from all published animal studies investigating MSC-EVs as an intervention. A systematic search of MEDLINE and Embase identified 206 studies. Data were extracted in duplicate for methodology, experimental design, interventional traits, modifications, and outcomes. MSC-EVs were used to treat a variety of diseases and demonstrated benefits in 97% of studies. Adverse effects were reported in only three studies, two demonstrating tumor growth. A quarter of articles modified EVs to enhance efficacy, with 72% leading to markedly improved outcomes as compared to unmodified EVs. However, several key methodological concerns were evident. Only 60% of studies used nomenclature consistent with the size definitions of EVs. Ultracentrifugation (70%) and isolation kits (23%) were the most common isolation techniques with noted differences in yield and purity. EVs were inconsistently dosed by protein (68%) or particle concentration (16%). Two-thirds of studies administered xenogeneic EVs, suggesting immunocompatibility. Less than 25% of studies assessed EV biodistribution. Approaches for determining size, protein markers, and morphology were highly heterogeneous, with only 12 and 4 studies meeting the MISEV 2014 and 2018 recommendations, respectively. Knowledge gaps identified from this systematic review highlight important opportunities to improve preclinical design and methodology in the rapidly growing field of EV therapeutics.

Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC‐EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta‐research methods, we determined the effectiveness of MSC‐EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta‐analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC‐EVs markedly reduced lung injury (SMD ‐4.33, CI ‐5.73 to ‐2.92), vascular permeability (SMD ‐2.43, CI ‐3.05 to ‐1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC‐EVs (SMD ‐1.45, CI ‐2.08 to ‐0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD ‐4.16, CI ‐5.68 to ‐2.64) and hypertrophy (SMD ‐2.80, CI ‐3.68 to ‐1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC‐EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration : PROSPERO CRD42020145334

Background: Over the last 31 years, there have been several institutional efforts to better recognize and reward clinician teachers. However, the perception of inadequate recognition and rewards by clinician teachers for their clinical teaching performance and achievements remains. The objective of this narrative review is two-fold: deepen understanding of the attributes of excellent clinician teachers considered for recognition and reward decisions and identify the barriers clinician teachers face in receiving recognition and rewards. Methods: We searched OVID Medline, Embase, Education Source and Web of Science to identify relevant papers published between 1990 and 2020. After screening for eligibility, we conducted a content analysis of the findings from 43 relevant papers to identify key trends and issues in the literature. Results: We found the majority of relevant papers from the US context, a paucity of relevant papers from the Canadian context, and a declining international focus on the attributes of excellent clinician teachers and barriers to the recognition and rewarding of clinician teachers since 2010. ‘Provides feedback’, ‘excellent communication skills’, ‘good supervision’, and ‘organizational skills’ were common cognitive attributes considered for recognition and rewards. ‘Stimulates’, ‘passionate and enthusiastic’, and ‘creates supportive environment’, were common non-cognitive attributes considered for recognition and rewards. The devaluation of teaching, unclear criteria, and unreliable metrics were the main barriers to the recognition and rewarding of clinician teachers. Conclusions: The findings of our narrative review highlight a need for local empirical research on recognition and reward issues to better inform local, context-specific reforms to policies and practices.

There have been many initiatives to improve the conditions of clinical teachers to enable them to achieve clinical teaching excellence in Academic Medical Centres (AMC). However, the success of such efforts has been limited due to unsupportive institutional cultures and the low value assigned to clinical teaching in comparison to clinical service and research. This forum article characterizes the low value and support for clinical teaching excellence as an expression of a hidden curriculum that is central to the cultural and structural etiology of the inequities clinical teachers experience in their pursuit of clinical teaching excellence. These elements include inequity in relation to time for participation in faculty development and recognition for clinical teaching excellence that exist within AMCs. To further compound these issues, AMCs often engage in the deployment of poor criteria and communication strategies concerning local standards of teaching excellence. Such inequities and poor governance can threaten the clinical teaching workforce's engagement, satisfaction and retention, and ultimately, can create negative downstream effects on the quality of patient care. While there are no clear normative solutions, we suggest that the examination of local policy documents, generation of stakeholder buy-in, and a culturally sensitive, localized needs assessment and integrated knowledge translation approach can develop a deeper understanding of the localized nature of this problem. The findings from local interrogations of structural, cultural and process problems can help to inform more tailored efforts to reform and improve the epistemic value of clinical teaching excellence. In conclusion, we outline a local needs assessment plan and research study that may serve as a conceptually generalizable foundation that could be applied to multiple institutional contexts.

In stem cell research, DNA-binding dyes offer the ability to purify live stem cells using flow cytometry as they form a low-fluorescence side population due to the activity of ABC transporters. Adult neural stem cells exist within the lateral ventricle and dentate gyrus of the adult brain yet the ability of DNA-binding dyes to identify these adult stem cells as side populations remain untested. The following experiments utilize the efflux of a DNA-binding dye, Vyrbant DyeCycle Violet (DCV), to isolate bona fide side populations in the adult mouse dentate gyrus and SVZ and test their sensitivity to ABC transporter inhibitors. A distinct side population was found in both the adult lateral ventricle and dentate gyrus using DCV fluorescence and forward scatter instead of the conventional dual fluorescence approach. These side populations responded strongly to inhibition with the ABC transporter antagonists, verapamil and fumitremorgin C. The cells in the side population were identified as cerebrovascular endothelial cells characterized by their expression of CD31. These findings, therefore, suggest that the side population analysis provides an efficient method to purify endothelial cells, but not adult neural stem cells.