Presentation design and delivery to improve knowledge translation in a remote world.

The practical dissemination of new knowledge is not given adequate attention despite large investment in undertaking high-quality research and the desire for evidence-based practice. It is important that those involved in knowledge translation and continuing medical education understand the fundamental principles of effective presentations, whether at scientific conferences, workshops or group teaching sessions. The switch to remote presentations has made this a more challenging endeavour. We describe established presentation techniques that improve knowledge translation and how to use them in both face-to-face and remote settings.

Assessing Healthcare Professionals' Identification of Paediatric Dermatological Conditions in Darker Skin Tones.

The impacts of the lack of skin tone diversity in medical education images on healthcare professionals (HCPs) and patients are not well studied. The aim of this study was to assess the diagnostic knowledge of HCPs and correlate this with confidence and training resources used. An online multiple choice quiz was developed. The participants' demographics, training resources and self-confidence in diagnosing skin conditions were collected. The differences in the results between the subgroups and the correlations between the respondents' experience, self-reported confidence and quiz results were assessed. The mean score of 432 international participants was 5.37 (SD 1.75) out of a maximum of 10 (highest score). Eleven percent (n = 47) reached the 80% pass mark. Subanalysis showed no difference by the continent (p = 0.270), ethnicity (p = 0.397), profession (p = 0.599), training resources (p = 0.198) or confidence (p = 0.400). A significance was observed in the specialty (p = 0.01). A weak correlation between experience and confidence (Spearman's ρ = 0.286), but no correlation between scores and confidence or experience (ρ = 0.087 and 0.076), was observed. Of diagnoses, eczema was recognised in 40% and meningococcal rash in 61%. This is the first study assessing the identification of paediatric skin conditions in different skin tones internationally. The correct identification of common/important paediatric conditions was poor, suggesting a possible difference in knowledge across skin tones. There is an urgent need to improve the representation of all skin tones to ensure equity in patient care.

Early expression of mature αß TCR in CD4-CD8- T cell progenitors enables MHC to drive development of T-ALL bearing NOTCH mutations.

During normal T cell development in mouse and human, a low-frequency population of immature CD4-CD8- double-negative (DN) thymocytes expresses early, mature αß T cell antigen receptor (TCR). We report that these early αß TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αß T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αß TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.

Medical Education Blog and Podcast Utilization During the COVID-19 Pandemic.

Introduction The coronavirus disease 2019 (COVID-19) pandemic disrupted traditional in-person learning models. Free Open Access Medical (FOAM) education resources naturally filled this void, so we evaluated how medical blog and podcast utilization changed during the early months of the pandemic. Methods Academic medical podcast and blog producers were surveyed on blog and podcast utilization immediately before (January-March 2020) and after (April-May 2020) the COVID-19 pandemic declaration and subsequent lockdown. Utilization is quantified in terms of blog post pageviews and podcast downloads. Linear regression was used to estimate the effect of publication during the COVID-19 period on 30-day downloads or pageviews. A linear mixed model was developed to confirm this relationship after adjustment for independent predictors of higher 30-day downloads or pageviews, using the podcast or blog as a random intercept. Results Compared to the pre-pandemic period, downloads and pageviews per unique blog and podcast publication significantly increased for blogs (median 30-day pageviews 802 to 1860, p<0.0001) but not for podcasts (median 30-day downloads 2726 to 1781, p=0.27). Publications that contained COVID-19 content were strongly associated with higher monthly utilization (ß=7.21, 95% CI 6.29-8.14 p<0.001), and even non-COVID-19 material had higher utilization in the early pandemic (median 30-day downloads/pageviews 868 to 1380, p<0.0001). Discussion The increased blog pageviews during the early months of the COVID-19 pandemic demonstrated the important role of blogs in rapid knowledge translation. Podcasts did not experience a similar increase in utilization.

Quantifying Tumor Heterogeneity via MRI Habitats to Characterize Microenvironmental Alterations in HER2+ Breast Cancer.

This study identifies physiological habitats using quantitative magnetic resonance imaging (MRI) to elucidate intertumoral differences and characterize microenvironmental response to targeted and cytotoxic therapy. BT-474 human epidermal growth factor receptor 2 (HER2+) breast tumors were imaged before and during treatment (trastuzumab, paclitaxel) with diffusion-weighted MRI and dynamic contrast-enhanced MRI to measure tumor cellularity and vascularity, respectively. Tumors were stained for anti-CD31, anti-ɑSMA, anti-CD45, anti-F4/80, anti-pimonidazole, and H&E. MRI data was clustered to identify and label each habitat in terms of vascularity and cellularity. Pre-treatment habitat composition was used stratify tumors into two "tumor imaging phenotypes" (Type 1, Type 2). Type 1 tumors showed significantly higher percent tumor volume of the high-vascularity high-cellularity (HV-HC) habitat compared to Type 2 tumors, and significantly lower volume of low-vascularity high-cellularity (LV-HC) and low-vascularity low-cellularity (LV-LC) habitats. Tumor phenotypes showed significant differences in treatment response, in both changes in tumor volume and physiological composition. Significant positive correlations were found between histological stains and tumor habitats. These findings suggest that the differential baseline imaging phenotypes can predict response to therapy. Specifically, the Type 1 phenotype indicates increased sensitivity to targeted or cytotoxic therapy compared to Type 2 tumors.

Impact of Diversity in Training Resources on Self-Confidence in Diagnosing Skin Conditions Across a Range of Skin Tones: An International Survey.

Background: Medical images are invaluable in facilitating recognition of clinical signs. Recent studies highlight a lack of diversity of skin tone images used within medical education. However, there is a paucity of data on the impact of this on patient care. Aims: To investigate diversity in training resources used by users of an International online teaching platform and self-confidence in diagnosing skin conditions in all skin tones. Methods: Users of an online teaching platform (www.dftbskindeep.com) were invited to participate in a survey evaluating key points including geographical location, ethnicity, profession, specialty, years of experience, training resources and confidence in diagnosing skin conditions. Data analyses were performed using SPSS. Categorical variables were presented as proportions. Chi-squared or Fisher's exact tests were used to compare the distribution between groups as appropriate. Results: Of 600 participants, 74% reported training resources featuring predominantly white skin. Participants were "generally uncertain" in 43% cases, "sometimes uncertain but clinically safe" (52%), and "confident across a range of skin tones" in a minority (5%). Self-confidence was associated with location [higher in Africa (29%) and Latin America (11%), (p < 0.001)]; diversity of training resources [higher with a mix (10%) or darker tones (20%) (p < 0.001)]; clinical experience [6-10 (5%) or >10 years of practice (11%) (p < 0.001)] and specialty [highest in dermatologists (53%, p < 0.001)]. Self-confidence was lowest among pediatricians, emergency medicine and pediatric emergency medicine specialists (<5%). Conclusions: These data provide preliminary evidence that training resources used by healthcare professionals on a global scale may lack enough diversity on representation of skin images, and a lack of self-confidence in diagnosing pediatric skin conditions. Further work is needed to understand the impact on knowledge and patient care to ensure equitable healthcare for all.

Longitudinal FRET Imaging of Glucose and Lactate Dynamics and Response to Therapy in Breast Cancer Cells.

PURPOSE: The reprogramming of cellular metabolism is a hallmark of cancer. The ability to noninvasively assay glucose and lactate concentrations in cancer cells would improve our understanding of the dynamic changes in metabolic activity accompanying tumor initiation, progression, and response to therapy. Unfortunately, common approaches for measuring these nutrient levels are invasive or interrupt cell growth. This study transfected FRET reporters quantifying glucose and lactate concentration into breast cancer cell lines to study nutrient dynamics and response to therapy. PROCEDURES: Two FRET reporters, one assaying glucose concentration and one assaying lactate concentration, were stably transfected into the MDA-MB-231 breast cancer cell line. Correlation between FRET measurements and ligand concentration were measured using a confocal microscope and a cell imaging plate reader. Longitudinal changes in glucose and lactate concentration were measured in response to treatment with CoCl2, cytochalasin B, and phloretin which, respectively, induce hypoxia, block glucose uptake, and block glucose and lactate transport. RESULTS: The FRET ratio from the glucose and lactate reporters increased with increasing concentration of the corresponding ligand (p < 0.005 and p < 0.05, respectively). The FRET ratio from both reporters was found to decrease over time for high initial concentrations of the ligand (p < 0.01). Significant differences in the FRET ratio corresponding to metabolic inhibition were found when cells were treated with glucose/lactate transporter inhibitors. CONCLUSIONS: FRET reporters can track intracellular glucose and lactate dynamics in cancer cells, providing insight into tumor metabolism and response to therapy over time.

A time-resolved experimental-mathematical model for predicting the response of glioma cells to single-dose radiation therapy.

PURPOSE: To develop and validate a mechanism-based, mathematical model that characterizes 9L and C6 glioma cells' temporal response to single-dose radiation therapy in vitro by explicitly incorporating time-dependent biological interactions with radiation. METHODS: We employed time-resolved microscopy to track the confluence of 9L and C6 glioma cells receiving radiation doses of 0, 2, 4, 6, 8, 10, 12, 14 or 16 Gy. DNA repair kinetics are measured by γH2AX expression via flow cytometry. The microscopy data (814 replicates for 9L, 540 replicates for C6 at various seeding densities receiving doses above) were divided into training (75%) and validation (25%) sets. A mechanistic model was developed, and model parameters were calibrated to the training data. The model was then used to predict the temporal dynamics of the validation set given the known initial confluences and doses. The predictions were compared to the corresponding dynamic microscopy data. RESULTS: For 9L, we obtained an average (± standard deviation, SD) Pearson correlation coefficient between the predicted and measured confluence of 0.87 ± 0.16, and an average (±SD) concordance correlation coefficient of 0.72 ± 0.28. For C6, we obtained an average (±SD) Pearson correlation coefficient of 0.90 ± 0.17, and an average (±SD) concordance correlation coefficient of 0.71 ± 0.24. CONCLUSION: The proposed model can effectively predict the temporal development of 9L and C6 glioma cells in response to a range of single-fraction radiation doses. By developing a mechanism-based, mathematical model that can be populated with time-resolved data, we provide an experimental-mathematical framework that allows for quantitative investigation of cells' temporal response to radiation. Our approach provides two key advances: (i) a time-resolved, dynamic death rate with a clear biological interpretation, and (ii) accurate predictions over a wide range of cell seeding densities and radiation doses.

Towards an Image-Informed Mathematical Model of In Vivo Response to Fractionated Radiation Therapy.

Fractionated radiation therapy is central to the treatment of numerous malignancies, including high-grade gliomas where complete surgical resection is often impractical due to its highly invasive nature. Development of approaches to forecast response to fractionated radiation therapy may provide the ability to optimize or adapt treatment plans for radiotherapy. Towards this end, we have developed a family of 18 biologically-based mathematical models describing the response of both tumor and vasculature to fractionated radiation therapy. Importantly, these models can be personalized for individual tumors via quantitative imaging measurements. To evaluate this family of models, rats (n = 7) with U-87 glioblastomas were imaged with magnetic resonance imaging (MRI) before, during, and after treatment with fractionated radiotherapy (with doses of either 2 Gy/day or 4 Gy/day for up to 10 days). Estimates of tumor and blood volume fractions, provided by diffusion-weighted MRI and dynamic contrast-enhanced MRI, respectively, were used to calibrate tumor-specific model parameters. The Akaike Information Criterion was employed to select the most parsimonious model and determine an ensemble averaged model, and the resulting forecasts were evaluated at the global and local level. At the global level, the selected model's forecast resulted in less than 16.2% error in tumor volume estimates. At the local (voxel) level, the median Pearson correlation coefficient across all prediction time points ranged from 0.57 to 0.87 for all animals. While the ensemble average forecast resulted in increased error (ranging from 4.0% to 1063%) in tumor volume predictions over the selected model, it increased the voxel wise correlation (by greater than 12.3%) for three of the animals. This study demonstrates the feasibility of calibrating a model of response by serial quantitative MRI data collected during fractionated radiotherapy to predict response at the conclusion of treatment.

The Baby Shark (Songs Heard Affecting Resuscitation Kinetics) study.

Previous research has examined the utilisation of musical cues to improve the performance of cardiopulmonary resuscitation (CPR) delivered in training environments. We postulated a musical cue that is both contemporary and transcends cultures may improve CPR performance. Our aim was to establish whether chest compressions are performed with improved rate and depth if a song of a fixed beat (PinkFong's 'Baby Shark' with a tempo of 115 beats per minute (bpm) and 15 beats in each verse) is played to a healthcare professional immediately before undertaking CPR compared to whale noises (a non-metronomic rhythm). 58 Participants of a paediatric conference (majority doctors) were randomly assigned to listen to a minute of Baby Shark (28) or whale song (30) and then undertake a minute of CPR. There was no significant difference in the mean compression rate between the Baby Shark and control groups, with the groups achieving 121 and 125 bpm, respectively (p=0.18). In relation to compression depth within the target zone, the Baby Shark group had more compressions completed within the target zone (55%) than the control group (39%) although this difference was not significant (p=0.08). Listening to Baby Shark prior to undertaking simulated CPR does not improve overall performance, but there is a potential tendency to improve adequate compression depth which may be beneficial in training exercises.

Women and children first? Gender equity in paediatric medicine.

There has been an increased focus on diversity and inclusion in medicine in recent years-the field of medicine still has a long way to go to reach gender equity. We assess how paediatrics is performing by examining the role gender plays in our specialty; and we propose some practical solutions to reach an equitable state. Achieving gender equity is not a simple or easy option and will require an ongoing commitment from all facets of the profession.

CD4 T-cell immune stimulation of HER2 + breast cancer cells alters response to trastuzumab in vitro.

INTRODUCTION: The HER2 + tumor immune microenvironment is composed of macrophages, natural killer cells, and tumor infiltrating lymphocytes, which produce pro-inflammatory cytokines. Determining the effect of T-cells on HER2 + cancer cells during therapy could guide immunogenic therapies that trigger antibody-dependent cellular cytotoxicity. This study utilized longitudinal in vitro time-resolved microscopy to measure T-cell influence on trastuzumab in HER2 + breast cancer. METHODS: Fluorescently-labeled breast cancer cells (BT474, SKBR3, MDA-MB-453, and MDA-MB-231) were co-cultured with CD4 + T-cells (Jurkat cell line) and longitudinally imaged to quantify cancer cell viability when treated with or without trastuzumab (10, 25, 50 and 100 µg/mL). The presence and timing of T-cell co-culturing was manipulated to determine immune stimulation of trastuzumab-treated HER2 + breast cancer. HER2 and TNF-α expression were evaluated with western blot and ELISA, respectively. Significance was calculated using a two-tailed parametric t-test. RESULTS: The viability of HER2 + cancer cells significantly decreased when exposed to 25 µg/mL trastuzumab and T-cells, compared to cancer cells exposed to trastuzumab without T-cells (p = 0.01). The presence of T-cells significantly increased TNF-α expression in trastuzumab-treated cancer cells (p = 0.02). Conversely, cancer cells treated with TNF-α and trastuzumab had a similar decrease in viability as trastuzumab-treated cancer cells co-cultured with T-cells (p = 0.32). CONCLUSIONS: The presence of T-cells significantly increases the efficacy of targeted therapies and suggests trastuzumab may trigger immune mediated cytotoxicity. Increased TNF-α receptor expression suggest cytokines may interact with trastuzumab to create a state of enhanced response to therapy in HER2 + breast cancer, which has potential to reducing tumor burden.

Anti-HER2 induced myeloid cell alterations correspond with increasing vascular maturation in a murine model of HER2+ breast cancer.

BACKGROUND: Therapy targeted to the human epidermal growth factor receptor type 2 (HER2) is used in combination with cytotoxic therapy in treatment of HER2+ breast cancer. Trastuzumab, a monoclonal antibody that targets HER2, has been shown pre-clinically to induce vascular changes that can increase delivery of chemotherapy. To quantify the role of immune modulation in treatment-induced vascular changes, this study identifies temporal changes in myeloid cell infiltration with corresponding vascular alterations in a preclinical model of HER2+ breast cancer following trastuzumab treatment. METHODS: HER2+ tumor-bearing mice (N = 46) were treated with trastuzumab or saline. After extraction, half of each tumor was analyzed by immunophenotyping using flow cytometry. The other half was quantified by immunohistochemistry to characterize macrophage infiltration (F4/80), vascularity (CD31 and α-SMA), proliferation (Ki67) and cellularity (H&E). Additional mice (N = 10) were used to quantify differences in tumor cytokines between control and treated groups. RESULTS: Immunophenotyping showed an increase in macrophage infiltration 24 h after trastuzumab treatment (P ≤ 0.05). With continued trastuzumab treatment, the M1 macrophage population increased (P = 0.02). Increases in vessel maturation index (i.e., the ratio of α-SMA to CD31) positively correlated with increases in tumor infiltrating M1 macrophages (R = 0.33, P = 0.04). Decreases in VEGF-A and increases in inflammatory cytokines (TNF-α, IL-1ß, CCL21, CCL7, and CXCL10) were observed with continued trastuzumab treatment (P ≤ 0.05). CONCLUSIONS: Preliminary results from this study in a murine model of HER2+ breast cancer show correlations between immune modulation and vascular changes, and reveals the potential for anti-HER2 therapy to reprogram immunosuppressive components of the tumor microenvironment. The quantification of immune modulation in HER2+ breast cancer, as well as the mechanistic insight of vascular alterations after anti-HER2 treatment, represent novel contributions and warrant further assessment for potential clinical translation.

The Role of Ultrasound in the Diagnosis of Pediatric Nasal Fractures.

BACKGROUND: Nasal fractures are the most commonly encountered facial fracture in children presenting to emergency departments. Though plain radiographs have long been used to aid the diagnosis of fractures, its limited diagnostic accuracy has led to the increasing use of ultrasound. Ultrasound offers a cheap, safe, and readily available imaging modality. Evidence in the adult population has shown ultrasound to be far more accurate in identifying nasal fractures. The efficacy of ultrasound in the pediatric setting though remains uncertain. METHODS: A systematic review of the Pubmed and EmBase databases was undertaken. The search terms (nose OR nasal) AND (fracture) AND (ultrasound OR ultrasonography OR sonography) and associated MeSH terms were searched. The search was limited to those <18 years of age. RESULTS: Following review and exclusion, 3 papers met the inclusion criteria. All 3 studies showed ultrasound was able to detect nasal fractures in children. Two studies showed that ultrasound diagnosed fractures with a greater accuracy than plain radiographs. One study used ultrasound alone and reported a sensitivity of 75% and specificity as 92.3%. CONCLUSION: With the limited evidence to date in the pediatric population, ultrasound appears to offer a more accurate radiological investigation in nasal fractures. It could be considered diagnostically superior to plain radiographs and reduces radiation exposure in children. Further work is required to better determine its true utility and improve its diagnostic accuracy.