Evaluating Competence by Design as a Large System Change Initiative: Readiness, Fidelity, and Outcomes.

Program evaluation is an essential, but often neglected, activity in any transformational educational change. Competence by Design was a large-scale change initiative to implement a competency-based time-variable educational system in Canadian postgraduate medical education. A program evaluation strategy was an integral part of the build and implementation plan for CBD from the beginning, providing insights into implementation progress, challenges, unexpected outcomes, and impact. The Competence by Design program evaluation strategy was built upon a logic model and three pillars of evaluation: readiness to implement, fidelity and integrity of implementation, and outcomes of implementation. The program evaluation strategy harvested from both internally driven studies and those performed by partners and invested others. A dashboard for the program evaluation strategy was created to transparently display a real-time view of Competence by Design implementation and facilitate continuous adaptation and improvement. The findings of the program evaluation for Competence by Design drove changes to all aspects of the Competence by Design implementation, aided engagement of partners, supported change management, and deepened our understanding of the journey required for transformational educational change in a complex national postgraduate medical education system. The program evaluation strategy for Competence by Design provides a framework for program evaluation for any large-scale change in health professions education.

Impact of Primary RPE Cells in a Porcine Organotypic Co-Cultivation Model.

The pathological events of age-related macular degeneration are characterized by degenerative processes involving the photoreceptor cells, retinal pigment epithelium (RPE), and the Bruch's membrane as well as choroidal alterations. To mimic in vivo interactions between photoreceptor cells and RPE cells ex vivo, complex models are required. Hence, the aim of this study was to establish a porcine organotypic co-cultivation model and enlighten the interactions of photoreceptor and RPE cells, with a special emphasis on potential neuroprotective effects. Porcine neuroretina explants were cultured with primary porcine RPE cells (ppRPE) or medium derived from these cells (=conditioned medium). Neuroretina explants cultured alone served as controls. After eight days, RT-qPCR and immunohistology were performed to analyze photoreceptors, synapses, macroglia, microglia, complement factors, and pro-inflammatory cytokines (e.g., IL1B, IL6, TNF) in the neuroretina samples. The presence of ppRPE cells preserved photoreceptors, whereas synaptical density was unaltered. Interestingly, on an immunohistological as well as on an mRNA level, microglia and complement factors were comparable in all groups. Increased IL6 levels were noted in ppRPE and conditioned medium samples, while TNF was only upregulated in the ppRPE group. IL1B was elevated in conditioned medium samples. In conclusion, a co-cultivation of ppRPE cells and neuroretina seem to have beneficial effects on the neuroretina, preserving photoreceptors and maintaining synaptic vesicles in vitro. This organotypic co-cultivation model can be used to investigate the complex interactions between the retina and RPE cells, gain further insight into neurodegenerative pathomechanisms occurring in retinal diseases, and evaluate potential therapeutics.

Coculture of ARPE-19 Cells and Porcine Neural Retina as an Ex Vivo Retinal Model.

Neural retinal organ cultures are used to investigate ocular pathomechanisms. However, these cultures lack the essential retinal pigment epithelium (RPE) cells, which are part of the actual in vivo retina. To simulate a more realistic ex vivo model, porcine neural retina explants were cocultured with ARPE-19 cells (ARPE-19 group), which are derived from human RPE. To identify whether the entire cells or just the cell factors are necessary, in a second experimental group, porcine neural retina explants were cultured with medium derived from ARPE-19 cells (medium group). Individually cultured neural retina explants served as controls (control group). After 8 days, all neural retinas were analysed to evaluate retinal thickness, photoreceptors, microglia, complement factors and synapses (n = 6-8 per group). The neural retina thickness in the ARPE-19 group was significantly better preserved than in the control group (p = 0.031). Also, the number of L-cones was higher in the ARPE-19 group, as compared to the control group (p < 0.001). Furthermore, the ARPE-19 group displayed an increased presynaptic glutamate uptake (determined via vGluT1 labelling) and enhanced post-synaptic density (determined via PSD-95 labelling). Combined Iba1 and iNOS detection revealed only minor effects of ARPE-19 cells on microglial activity, with a slight downregulation of total microglia activity apparent in the medium group. Likewise, only minor beneficial effects on photoreceptors and synaptic structure were found in the medium group. This novel system offers the opportunity to investigate interactions between the neural retina and RPE cells, and suggests that the inclusion of a RPE feeder layer has beneficial effects on the ex vivo maintenance of neural retina. By modifying the culture conditions, this coculture model allows a better understanding of photoreceptor death and photoreceptor-RPE cell interactions in retinal diseases.

Classifying the Acquisition Sequence for Brain MRIs Using Neural Networks on Single Slices.

Background Neural networks for analyzing MRIs are oftentimes trained on particular combinations of perspectives and acquisition sequences. Since real-world data are less structured and do not follow a standard denomination of acquisition sequences, this impedes the transition from deep learning research to clinical application. The purpose of this study is therefore to assess the feasibility of classifying the acquisition sequence from a single MRI slice using convolutional neural networks. Methods A total of 113 MRI slices from 52 patients were used in a transfer learning approach to train three convolutional neural networks of different complexities to predict the acquisition sequence, while 27 slices were used for internal validation. The model then underwent external validation on 600 slices from 273 patients belonging to one of four classes (T1-weighted without contrast enhancement, T1-weighted with contrast enhancement, T2-weighted, and diffusion-weighted). Categorical accuracy was noted, and the results of the predictions for the validation set are provided with confusion matrices. Results The neural networks achieved a categorical accuracy of 0.79, 0.81, and 0.84 on the external validation data. The implementation of Grad-CAM showed no clear pattern of focus except for T2-weighted slices, where the network focused on areas containing cerebrospinal fluid. Conclusion Automatically classifying the acquisition sequence using neural networks seems feasible and could be used to facilitate the automatic labelling of MRI data.

Implementation of competence committees during the transition to CBME in Canada: A national fidelity-focused evaluation.

PURPOSE: This study evaluated the fidelity of competence committee (CC) implementation in Canadian postgraduate specialist training programs during the transition to competency-based medical education (CBME). METHODS: A national survey of CC chairs was distributed to all CBME training programs in November 2019. Survey questions were derived from guiding documents published by the Royal College of Physicians and Surgeons of Canada reflecting intended processes and design. RESULTS: Response rate was 39% (113/293) with representation from all eligible disciplines. Committee size ranged from 3 to 20 members, 42% of programs included external members, and 20% included a resident representative. Most programs (72%) reported that a primary review and synthesis of resident assessment data occurs prior to the meeting, with some data reviewed collectively during meetings. When determining entrustable professional activity (EPA) achievement, most programs followed the national specialty guidelines closely with some exceptions (53%). Documented concerns about professionalism, EPA narrative comments, and EPA entrustment scores were most highly weighted when determining resident progress decisions. CONCLUSIONS: Heterogeneity in CC implementation likely reflects local adaptations, but may also explain some of the variable challenges faced by programs during the transition to CBME. Our results offer educational leaders important fidelity data that can help inform the larger evaluation and transformation of CBME.

Operationalizing Programmatic Assessment: The CBME Programmatic Assessment Practice Guidelines.

PROBLEM: Assessing the development and achievement of competence requires multiple formative and summative assessment strategies and the coordinated efforts of trainees and faculty (who often serve in multiple roles, such as academic advisors, program directors, and competency committee members). Operationalizing programmatic assessment (PA) in competency-based medical education (CBME) requires comprehensive practice guidelines, written in accessible language with descriptions of stakeholder activities, to move assessment theory into practice and to help guide the trainees and faculty who enact PA. APPROACH: Informed by the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework, the authors used a multiphase, multimethod approach to develop the CBME Programmatic Assessment Practice Guidelines (PA Guidelines). The 9 guidelines are organized by phases of assessment and include descriptions of stakeholder activities. A user guide provides a glossary of key terms and summarizes how the guidelines can be used by different stakeholder groups across postgraduate medical education (PGME) contexts. The 4 phases of guideline development, including internal stakeholder consultations and external expert review, occurred between August 2016 and March 2020. OUTCOMES: Local stakeholders and external experts agreed that the PA Guidelines hold potential for guiding initial operationalization and ongoing refinement of PA in CBME by individual stakeholders, residency programs, and PGME institutions. Since July 2020, the PA Guidelines have been used at Queen's University to inform faculty and resident development initiatives, including online CBME modules for faculty, workshops for academic advisors/competence committee members, and a guide that supports incoming residents' transition to CBME. NEXT STEPS: Research exploring the use of the PA Guidelines and user guide in multiple programs and institutions will gather further evidence of their acceptability and utility for guiding operationalization of PA in different contexts.

An adaptation-focused evaluation of Canada's first competency-based medical education implementation in radiology.

OBJECTIVES: Systematic program evaluation of the Queen's University diagnostic radiology residency program following transition to a competency-based medical education (CBME) curriculum. METHODS: Rapid Evaluation methodology and the Core Components Framework were utilized to measure CBME implementation. A combination of interviews and focus groups were held with program leaders (n = 6), faculty (n = 10), both CBME stream and traditional stream residents (n = 6), and program staff (n = 2). Interviews and focus groups were transcribed and analyzed abductively. Study team met with program leaders to review common themes and plan potential adaptations. RESULTS: Strengths of CBME implementation included more frequent and timely feedback as well as the role of the Academic Advisor. However, frontline faculty felt insufficiently supported with regards to the theory and practical implementation of the new curriculum and found assessment tools unintuitive. The circumstances surrounding the curricular implementation also resulted in some negative sentiment. Additional faculty and resident education workshops were identified as areas for improvement as well as changes to assessment tools for increased clarity. Residents overall viewed the changes favorably, with traditional stream residents indicating that they also had a desire for increased feedback. CONCLUSIONS: Rapid Evaluation is an effective method for program assessment following curricular change in diagnostic radiology. A departmental champion driving enthusiasm for change from within may be valuable. Adequate resident and faculty education is key to maximize change and smooth the transition. Advances in knowledge: This study provides insights for other radiology training programs transitioning to a CBME framework and provides a structure for programmatic assessment.

The ultrasound competency assessment tool for four-view cardiac POCUS.

BACKGROUND: Point-of-care ultrasound (POCUS) has been recognized as an essential skill across medicine. However, a lack of reliable and streamlined POCUS assessment tools with demonstrated validity remains a significant barrier to widespread clinical integration. The ultrasound competency assessment tool (UCAT) was derived to be a simple, entrustment-based competency assessment tool applicable to multiple POCUS applications. When used to assess a FAST, the UCAT demonstrated high internal consistency and moderate-to-excellent inter-rater reliability. The objective of this study was to validate the UCAT for assessment of a four-view transthoracic cardiac POCUS. RESULTS: Twenty-two trainees performed a four-view transthoracic cardiac POCUS in a simulated environment while being assessed by two observers. When used to assess a four-view cardiac POCUS the UCAT retained its high internal consistency ([Formula: see text] and moderate-to-excellent inter-rater reliability (ICCs = 0.61-0.91; p's ≤ 0.01) across all domains. The regression analysis suggestion that level of training, previous number of focused cardiac ultrasound, previous number of total scans, self-rated entrustment, and intent to pursue certification statistically significantly predicted UCAT entrustment scores [F (5,16) = 4.06, p = 0.01; R2 = 0.56]. CONCLUSION: This study confirms the UCAT is a valid assessment tool for four-view transthoracic cardiac POCUS. The findings from this work and previous studies on the UCAT demonstrate the utility and flexibility of the UCAT tool across multiple POCUS applications and present a promising way forward for POCUS competency assessment.

Comparing the Quality of Narrative Comments by Rotation Setting.

OBJECTIVE: To investigate the effect of rotation setting on trainee-directed narrative comments within a Canadian General Surgery Residency Program. The primary outcome was to use the McMaster Narrative Comment Rating Scale (MNCRS) to evaluate the quality of narrative comments across five domains: valence of language, degree of correction versus reinforcement, specificity, actionability and overall usefulness. As distributed medical education in the postgraduate training context becomes more prevalent, delineating differences in feedback between various sites will be imperative, as it may affect how narrative comments are interpreted by clinical competency committee (CCC) members. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 2,469 assessments obtained between July 1, 2014 and May 5, 2019 from the General Surgery Residency Program at the University of British Columbia (UBC) was conducted. Narrative comments were rated using the McMaster Narrative Comment Rating Scale (MNCRS), a validated instrument for evaluating the quality of narrative comments. A repeated measures Analysis of Variance (ANOVA) was conducted to explore the impact of rotation setting, academic, urban tertiary, distributed urban, and distributed rural on the quality of narrative feedback. RESULTS: Overall, the quality of the narrative comments varied substantially between and within rotation settings. Academic sites tended to provide more actionable comments (p = 0.01) and more corrective versus reinforcing comments, compared with other sites (p's < 0.01). Comments produced by the urban tertiary rotation setting were consistently lower in quality across all scale categories compared with other settings (p's < 0.01). CONCLUSION: The type of rotation setting has a significant effect on the quality of faculty feedback for trainees. Faculty development on the provision of feedback is necessary, regardless of rotation setting, and should appropriately combine rotation-specific needs and overarching program goals to ensure trainees and clinical competence committees receive high quality narrative.

Exploring the use of rating scales with entrustment anchors in workplace-based assessment.

PURPOSE: Competency-based medical education (CBME) has prompted widespread implementation of workplace-based assessment (WBA) tools using entrustment anchors. This study aimed to identify factors that influence faculty's rating choices immediately following assessment and explore their experiences using WBAs with entrustment anchors, specifically the Ottawa Surgical Competency Operating Room Evaluation scale. METHOD: A convenience sample of 50 semi-structured interviews with Emergency Medicine (EM) physicians from a single Canadian hospital were conducted between July and August 2019. All interviews occurred within two hours of faculty completing a WBA of a trainee. Faculty were asked what they considered when rating the trainee's performance and whether they considered an alternate rating. Two team members independently analysed interview transcripts using conventional content analysis with line-by-line coding to identify themes. RESULTS: Interviews captured interactions between 70% (26/37) of full-time EM faculty and 86% (19/22) of EM trainees. Faculty most commonly identified the amount of guidance the trainee required as influencing their rating. Other variables such as clinical context, trainee experience, past experiences with the trainee, perceived competence and confidence were also identified. While most faculty did not struggle to assign ratings, some had difficulty interpreting the language of entrustment anchors, being unsure whether their assessment should be retrospective or prospective in nature, and if/how the assessment should change whether they were 'in the room' or not. CONCLUSIONS: By going to the frontline during WBA encounters, this study captured authentic and honest reflections from physicians immediately engaged in assessment using entrustment anchors. While many of the factors identified are consistent with previous retrospective work, we highlight how some faculty consider factors outside the prescribed approach and struggle with the language of entrustment anchors. These results further our understanding of 'in-the-moment' assessments using entrustment anchors and may facilitate effective faculty development regarding WBA in CBME.

Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction.

Retinal ischemia is a common pathomechanism in various eye diseases. Recently, evidence accumulated suggesting that the extracellular matrix (ECM) glycoprotein tenascin-C (Tnc) plays a key role in ischemic degeneration. However, the possible functional role of Tnc in retinal ischemia is not yet known. The aim of our study was to explore retinal function and rod-bipolar/photoreceptor cell degeneration in wild type (WT) and Tnc knock-out (KO) mice after ischemia/reperfusion (I/R) injury. Therefore, I/R was induced by increasing intraocular pressure in the right eye of wild type (WT I/R) and Tnc KO (KO I/R) mice. The left eye served as untreated control (WT CO and KO CO). Scotopic electroretinogram (ERG) recordings were performed to examine rod-bipolar and rod-photoreceptor cell function. Changes of Tnc, rod-bipolar cells, photoreceptors, retinal structure and apoptotic and synaptic alterations were analyzed by immunohistochemistry, Hematoxylin and Eosin staining, Western blot, and quantitative real time PCR. We found increased Tnc protein levels 3 days after ischemia, while Tnc immunoreactivity decreased after 7 days. Tnc mRNA expression was comparable in the ischemic retina. ERG measurements after 7 days showed lower a-/b-wave amplitudes in both ischemic groups. Nevertheless, the amplitudes in the KO I/R group were higher than in the WT I/R group. We observed retinal thinning in WT I/R mice after 3 and 7 days. Although compared to the KO CO group, retinal thinning was not observed in the KO I/R group until 7 days. The number of PKCα+ rod-bipolar cells, recoverin+ photoreceptor staining and Prkca and Rcvrn expression were comparable in all groups. However, reduced rhodopsin protein as well as Rho and Gnat1 mRNA expression levels of rod-photoreceptors were found in the WT I/R, but not in the KO I/R retina. Additionally, a lower number of activated caspase 3+ cells was observed in the KO I/R group. Finally, both ischemic groups displayed enhanced vesicular glutamate transporter 1 (vGlut1) levels. Collectively, KO mice showed diminished rod-photoreceptor degeneration and retinal dysfunction after I/R. Elevated vGlut1 levels after ischemia could be related to an impaired glutamatergic photoreceptor-bipolar cell signaling and excitotoxicity. Our study provides novel evidence that Tnc reinforces ischemic retinal degeneration, possibly by synaptic remodeling.

The Ultrasound Competency Assessment Tool (UCAT): Development and Evaluation of a Novel Competency-based Assessment Tool for Point-of-care Ultrasound.

OBJECTIVES: Point-of-care ultrasound (POCUS) has become an integral diagnostic and interventional tool. Barriers to POCUS training persist, and it continues to remain heterogeneous across training programs. Structured POCUS assessment tools exist, but remain limited in their feasibility, acceptability, reliability, and validity; none of these tools are entrustment-based. The objective of this study was to derive a simple, entrustment-based POCUS competency assessment tool and pilot it in an assessment setting. METHODS: This study was composed of two phases. First, a three-step modified Delphi design surveyed 60 members of the Canadian Association of Emergency Physicians Emergency Ultrasound Committee (EUC) to derive the anchors for the tool. Subsequently, the derived ultrasound competency assessment tool (UCAT) was used to assess trainee (N = 37) performance on a simulated FAST examination. The intraclass correlation (ICC) for inter-rater reliability and Cronbach's alpha for internal consistency were calculated. A statistical analysis was performed to compare the UCAT to other competency surrogates. RESULTS: The three-round Delphi had 22, 26, and 26 responses from the EUC members. Consensus was reached, and anchors for the domains of preparation, image acquisition, image optimization, and clinical integration achieved approval rates between 92 and 96%. The UCAT pilot revealed excellent inter-rater reliability (with ICC values of 0.69-0.89; p < 0.01) and high internal consistency (α = 0.91). While UCAT scores were not impacted by level of training, they were significantly impacted by the number of previous POCUS studies completed. CONCLUSIONS: We developed and successfully piloted the UCAT, an entrustment-based bedside POCUS competency assessment tool suitable for rapid deployment. The findings from this study indicate early validity evidence for the use of the UCAT as an assessment of trainee POCUS competence on FAST. The UCAT should be trialed in different populations performing several POCUS study types.

Microglia Activation in Retinal Ischemia Triggers Cytokine and Toll-Like Receptor Response.

Mechanisms and progression of ischemic injuries in the retina are still incompletely clarified. Therefore, the time course of microglia activation as well as resulting cytokine expression and downstream signaling were investigated. Ischemia was induced in one eye by transiently elevated intraocular pressure (60 min) followed by reperfusion; the other eye served as a control. Eyes were processed for RT-qPCR and immunohistochemistry analyses at 2, 6, 12, and 24 h as well as at 3 and 7 days. Already 2 h after ischemia, more microglia/macrophages were in an active state in the ischemia group. This was accompanied by an upregulation of pro-inflammatory cytokines, like IL-1ß, IL-6, TNFα, and TGFß. Activation of TLR3, TLR2, and the adaptor molecule Myd88 was also observed after 2 h. NFκB revealed a wave-like activation pattern. In addition, an extrinsic caspase pathway activation was noted at early time points, while enhanced numbers of cleaved caspase 3+ cells could be observed in ischemic retinae throughout the study. Retinal ischemia induced an early and strong microglia/macrophage response as well as cytokine and apoptotic activation processes. Moreover, in early and late ischemic damaging processes, TLR expression and downstream signaling were involved, suggesting an involvement in neuronal death in ischemic retinae. Graphical Abstract.

Synthesis, Characterization, and in vivo Evaluation of a Novel Potent Autotaxin-Inhibitor.

The autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway plays a role in a variety of autoimmune diseases, such as rheumatoid arthritis or neurodegeneration. A link to the pathogenesis of glaucoma is suggested by an overactive ATX-LPA axis in aqueous humor samples of glaucoma patients. Analysis of such samples suggests that the ATX-LPA axis contributes to the fibrogenic activity and resistance to aqueous humor outflow through the trabecular meshwork. In order to inhibit or modulate this pathway, we developed a new series of ATX-inhibitors containing novel bicyclic and spirocyclic structural motifs. A potent lead compound (IC50 against ATX: 6 nM) with good in vivo PK, favorable in vitro property, and safety profile was generated. This compound leads to lowered LPA levels in vivo after oral administration. Hence, it was suitable for chronic oral treatment in two rodent models of glaucoma, the experimental autoimmune glaucoma (EAG) and the ischemia/reperfusion models. In the EAG model, rats were immunized with an optic nerve antigen homogenate, while controls received sodium chloride. Retinal ischemia/reperfusion (I/R) was induced by elevating the intraocular pressure (IOP) in one eye to 140 mmHg for 60 min, followed by reperfusion, while the other untreated eye served as control. Retinae and optic nerves were evaluated 28 days after EAG or 7 and 14 days after I/R induction. Oral treatment with the optimized ATX-inhibitor lead to reduced retinal ganglion cell (RGC) loss in both glaucoma models. In the optic nerve, the protective effect of ATX inhibition was less effective compared to the retina and only a trend to a weakened neurofilament distortion was detectable. Taken together, these results provide evidence that the dysregulation of the ATX-LPA axis in the aqueous humor of glaucoma patients, in addition to the postulated outflow impairment, might also contribute to RGC loss. The observation that ATX-inhibitor treatment in both glaucoma models did not result in significant IOP increases or decreases after oral treatment indicates that protection from RGC loss due to inhibition of the ATX-LPA axis is independent of an IOP lowering effect.

Recent evidence on visual-spatial ability in surgical education: A scoping review.

BACKGROUND: Understanding the relationships between structures is critical for surgical trainees. However, the heterogeneity of the literature on visual-spatial ability (VSA) in surgery makes it challenging for educators to make informed decisions on incorporating VSA into their programs. We conducted a scoping review of the literature on VSA in surgery to provide a map of the literature and identify where gaps still exist for future research. METHODS: We searched databases until December 2019 using keywords related to VSA and surgery. The resulting articles were independently screened by two researchers for inclusion in our review. RESULTS: We included 117 articles in the final review. Fifty-nine articles reported significant correlations between VSA tests and surgical performance, and this association is supported by neuroimaging studies. However, it remains unclear whether VSA should be incorporated into trainee selection and whether there is a benefit of three-dimensional (3D) over two-dimensional (2D) training. CONCLUSIONS: It appears that VSA correlates with surgical performance in the simulated environment, particularly for novice learners. Based on our findings, we make suggestions for how surgical educators may use VSA to support novice learners. Further research should determine whether VSA remains correlated to surgical performance when trainees move into the operative environment.

CONTEXTE: Il est fondamental pour les chirurgiens en formation de comprendre les liens qui unissent les diverses structures corporelles. Étant donné l'hétérogénéité de la littérature portant sur les habiletés visuo-spatiales (HVS) nécessaires en chirurgie, les éducateurs ont de la difficulté à prendre des décisions éclairées quant à l'enseignement des HVS dans leurs programmes. On a effectué une étude exploratoire de la littérature sur les HVS en chirurgie afin de répertorier la littérature et de cerner des lacunes pouvant faire l'objet de recherches ultérieures. MÉTHODOLOGIE: On a interrogé des bases de données jusqu'à décembre 2019 à l'aide de mots-clés reliés aux HVS et à la chirurgie. Les articles trouvés ont été évalués de façon indépendante par deux chercheurs pour déterminer leur inclusion à la revue. RÉSULTATS: Au total, 117 articles ont été inclus dans la revue finale. Cinquante-neuf faisaient état d'importantes corrélations entre les tests d'évaluation des HVS et la performance chirurgicale. Cette association est étayée par les résultats d'études en neuro-imagerie. Il n'est pas clair cependant si les HVS devraient faire partie des critères de sélection des résidents et si une formation sur les techniques de visualisation en trois dimensions (3D) est préférable à une formation sur les techniques de visualisation en deux dimensions (2D). CONCLUSIONS: Il semble exister un lien entre les HVS et la performance chirurgicale en contexte de simulation, particulièrement chez les apprenants novices. À la lumière de nos résultats, nous présentons des recommandations sur la façon dont les formateurs en chirurgie pourraient se servir des HVS pour aider les apprenants novices. D'autres travaux de recherche devraient permettre de savoir si les HVS restent reliés à la performance chirurgicale lorsque les stagiaires passent à un environnement opératoire réel.

Novel Porcine Retina Cultivation Techniques Provide Improved Photoreceptor Preservation.

Age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries among people over 60 years. It has multiple triggers and risk factors, but despite intense research efforts, its pathomechanisms are currently not completely understood. AMD pathogenesis is characterized by soft drusen in Bruch's membrane and involves the retinal pigment epithelium-Bruch's membrane-choroid complex and adjacent structures, like photoreceptors. This study explores the potential of novel cultivation techniques to preserve photoreceptors in retinal explants to gain better insights in AMD pathology. The porcine retina explants were cultured for 4 and 8 days using three different explantation techniques, namely, control (photoreceptors facing down, touching the filter), filter (photoreceptors facing up, turned sample using a filter), and tweezers (photoreceptors facing up, turned sample using tweezers). Optical coherence tomography revealed that the tweezers method had the best capacity to limit thinning of the retinal explants. Both novel methods displayed advantages in maintaining outer segment thickness. Additionally, immunofluorescence evaluation revealed a better preservation of opsin+ cells and rhodopsin signal intensity in both novel methods, especially the tweezers method. Furthermore, RT-qPCR analysis demonstrated an upregulation of OPSIN and RHODOPSIN mRNA expression in tweezers samples at 8 days. Amacrine and bipolar cell numbers were not altered at day 4 of cultivation, while cultivation until 8 days led to reduced bipolar cell numbers. At 4 days, CALRETININ mRNA was upregulated in filter samples, but protein kinase C alpha expression was downregulated. Retinal ganglion cells were diminished in both novel techniques due to a direct physical contact with the insert. Remarkably, no difference in TUBB3 mRNA expression was detected among the techniques. Nevertheless, both novel methods exhibited an improved retention of photoreceptor cells. In conclusion, the tweezers technique was the most promising one. Due to the high homology of the porcine to the human retina, it provides a reasonable alternative to in vivo rodent models. Consequently, an adapted coculture system based on the current findings may serve as an ex vivo model suitable to analyze AMD pathomechanisms and novel therapeutic approaches.

Retinal ischemia triggers early microglia activation in the optic nerve followed by neurofilament degeneration.

Retinal ischemia leads to an early severe damage of the retina and thus plays an important role in eye diseases such as angle-closure glaucoma or retinal vascular occlusion. In retinal diseases, there is common sense about the affection of the optic nerve by ischemic injury. However, the exact dynamic processes of this optic nerve degeneration are mainly unclear. In this study, retinal ischemia was induced in one eye of Brown-Norway rats by raising the intraocular pressure 60 min to 140 mmHg followed by natural reperfusion. Optic nerves were analyzed at six different points in time: 2, 6, 12, and 24 h as well as 3 and 7 days after ischemic injury. Cell infiltration and moreover signs of tissue demyelination and dissolution were noticed in optic nerves 7 days after ischemia (hematoxylin & eosin: p < 0.001, luxol fast blue: p = 0.04). Although microglial activation was verified already from 12 h on after ischemia (p = 0.030), the beginning of a structural degeneration of the neurofilament was seen at 3 days (p = 0.02). Interestingly, proliferative microglia were present later on (7 days: p = 0.017). At this point, the number of total microglia was also increased in ischemic nerves (p = 0.003). Concluding, our data indicate that not only retinal tissue is affected by an ischemia, the optic nerve also demonstrates progressive damage. Interestingly, a microglia activation was noted days before structural damage became visible.

Expression Changes and Impact of the Extracellular Matrix on Etoposide Resistant Human Retinoblastoma Cell Lines.

Retinoblastoma (RB) represents the most common malignant childhood eye tumor worldwide. Several studies indicate that the extracellular matrix (ECM) plays a crucial role in tumor growth and metastasis. Moreover, recent studies indicate that the ECM composition might influence the development of resistance to chemotherapy drugs. The objective of this study was to evaluate possible expression differences in the ECM compartment of the parental human cell lines WERI-RB1 (retinoblastoma 1) and Y79 and their Etoposide resistant subclones via polymerase chain reaction (PCR). Western blot analyses were performed to analyze protein levels. To explore the influence of ECM molecules on RB cell proliferation, death, and cluster formation, WERI-RB1 and resistant WERI-ETOR cells were cultivated on Fibronectin, Laminin, Tenascin-C, and Collagen IV and analyzed via time-lapse video microscopy as well as immunocytochemistry. We revealed a significantly reduced mRNA expression of the proteoglycans Brevican, Neurocan, and Versican in resistant WERI-ETOR compared to sensitive WERI-RB1 cells. Also, for the glycoproteins α1-Laminin, Fibronectin, Tenascin-C, and Tenascin-R as well as Collagen IV, reduced expression levels were observed in WERI-ETOR. Furthermore, a downregulation was detected for the matrix metalloproteinases MMP2, MMP7, MMP9, the tissue-inhibitor of metalloproteinase TIMP2, the Integrin receptor subunits ITGA4, ITGA5 and ITGB1, and all receptor protein tyrosine phosphatase ß/ζ isoforms. Downregulation of Brevican, Collagen IV, Tenascin-R, MMP2, TIMP2, and ITGA5 was also verified in Etoposide resistant Y79 cells compared to sensitive ones. Protein levels of Tenascin-C and MMP-2 were comparable in both WERI cell lines. Interestingly, Fibronectin displayed an apoptosis-inducing effect on WERI-RB1 cells, whereas an anti-apoptotic influence was observed for Tenascin-C. Conversely, proliferation of WERI-ETOR cells was enhanced on Tenascin-C, while an anti-proliferative effect was observed on Fibronectin. In WERI-ETOR, cluster formation was decreased on the substrates Collagen IV, Fibronectin, and Tenascin-C. Collectively, we noted a different ECM mRNA expression and behavior of Etoposide resistant compared to sensitive RB cells. These findings may indicate a key role of ECM components in chemotherapy resistance formation of RB.

[Current State of Primary Neuroprotection in Glaucoma]. / Derzeitiger Stand zur primären Neuroprotektion beim Glaukom.

In view of the aging members of our society, there will be an increase in severe visual impairment and blindness, also due to glaucoma, in the coming years. Therapy options are limited to treat occurring symptoms. Currently, only a deceleration of the pathogenesis progression, but no cure, is available. Therefore, it is necessary to develop new therapeutic strategies to treat glaucoma adequately and effectively, thus improving the quality of life of those affected. One possible approach seems to be primary neuroprotection, which acts independently of an intraocular pressure reduction. There are indications that components of the immune system play a role in the context of the disease or the loss of retinal ganglion cells. Thus, evidence of an involvement of heat shock proteins, the complement system, but also, for example, microglial cells, were found. To this end, therapeutic modulation of these factors seems to be an interesting new target for neuroprotection. Studies in animal models have shown that an inhibition of the complement system or microglia leads to a protection. Modulation of heat shock proteins may enhance their protective properties or inhibit their destroying function to prevent glaucoma damage. These neuroprotective substances could expand the treatment options of glaucoma patients in the future.