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In the Ottawa 2018 Consensus framework for good assessment, a set of criteria was presented for systems of assessment. Currently, programmatic assessment is being established in an increasing number of programmes. In this Ottawa 2020 consensus statement for programmatic assessment insights from practice and research are used to define the principles of programmatic assessment. For fifteen programmes in health professions education affiliated with members of an expert group (n = 20), an inventory was completed for the perceived components, rationale, and importance of a programmatic assessment design. Input from attendees of a programmatic assessment workshop and symposium at the 2020 Ottawa conference was included. The outcome is discussed in concurrence with current theory and research. Twelve principles are presented that are considered as important and recognisable facets of programmatic assessment. Overall these principles were used in the curriculum and assessment design, albeit with a range of approaches and rigor, suggesting that programmatic assessment is an achievable education and assessment model, embedded both in practice and research. Knowledge on and sharing how programmatic assessment is being operationalized may help support educators charting their own implementation journey of programmatic assessment in their respective programmes. [ABSTRACT FROM AUTHOR]

Students perceive reflective writing as difficult. Concept mapping may be an alternative format for reflection, which provides support while allowing students to freely shape their thoughts. We examined (1) the quality of reflection in reflective concept maps created by first-year medical students and (2) students' perceptions about concept mapping as a tool for reflection. Mixed-method study conducted within the medical curriculum of Maastricht University, The Netherlands, consisting of: (1) Analysis of the quality of reflection in 245 reflective concept maps created by 40 first-year students. Reflection quality was analysed by assessing focus of reflection (technical/practical/sensitising) and depth of reflection (description/justification/critique/discussion). (2) Semi-structured interviews with 22 students to explore perceived effectiveness of reflective concept mapping. Depth of reflection reached at least the level of critique in 82% of maps. Three factors appeared to affect the perceived effectiveness of concept mapping for reflection: (1) reflective concept map structure; (2) alertness to meaningful experiences in practice and (3) learning by doing. These results yielded supportive evidence for concept mapping as a useful technique to teach novice learners the basics of effective reflection. Meaningful implementation requires a delicate balance between providing a supportive structure and allowing flexibility for the student. [ABSTRACT FROM AUTHOR]

Objectives: Programmatic assessment attempts to facilitate learning through individual assessments designed to be of low‐stakes and used only for high‐stake decisions when aggregated. In practice, low‐stake assessments have yet to reach their potential as catalysts for learning. We explored how teachers conceptualise assessments within programmatic assessment and how they engage with learners in assessment relationships. Methods: We used a constructivist grounded theory approach to explore teachers' assessment conceptualisations and assessment relationships in the context of programmatic assessment. We conducted 23 semi‐structured interviews at two different graduate‐entry medical training programmes following a purposeful sampling approach. Data collection and analysis were conducted iteratively until we reached theoretical sufficiency. We identified themes using a process of constant comparison. Results: Results showed that teachers conceptualise low‐stake assessments in three different ways: to stimulate and facilitate learning; to prepare learners for the next step, and to use as feedback to gauge the teacher's own effectiveness. Teachers intended to engage in and preserve safe, yet professional and productive working relationships with learners to enable assessment for learning when securing high‐quality performance and achievement of standards. When teachers' assessment conceptualisations were more focused on accounting conceptions, this risked creating tension in the teacher‐learner assessment relationship. Teachers struggled between taking control and allowing learners' independence. Conclusions: Teachers believe programmatic assessment can have a positive impact on both teaching and student learning. However, teachers' conceptualisations of low‐stake assessments are not focused solely on learning and also involve stakes for teachers. Sampling across different assessments and the introduction of progress committees were identified as important design features to support teachers and preserve the benefits of prolonged engagement in assessment relationships. These insights contribute to the design of effective implementations of programmatic assessment within the medical education context. Teachers conceptualise programmatic assessment in varied ways, as shown by Schut et al., creating tensions in teacher‐learner assessment relationships. [ABSTRACT FROM AUTHOR]

Reflective practice is an important characteristic of a knowledgeable health professional. Reflection is needed to maintain professional competence, practice-based learning, and an improvement focused attitude. Yet, learners struggle with reflective practice activities as they are perceived as challenging and time consuming. We used the idea of concept mapping to design an e‑portfolio tool that supports learners with their reflective practice activities. The purpose of this article is to demonstrate the design and rationale of e‑portfolio mapping and how this tool could be used to support reflective practice activities. Following the stepwise approach typical for the reflective cycle, two types of maps were designed, a trigger map and a competency map. In a trigger map, the learner reflects on a concrete learning or feedback experience. In a competency map the learner interprets and synthesizes several previous trigger maps which ultimately leads to the formulation of new learning objectives. The e‑portfolio mapping tool can be a useful and supportive tool to foster learners' reflective skills and provide mentors with in-depth insight into the students' learning and reflection processes. [ABSTRACT FROM AUTHOR]

The article discusses the report "Lessons from the implementation of developmental progress assessment (DPA): a scoping review," by C. Saint-Onge, E.V. Lachiver, S. Langevin, E. Boileau, F. Bernier, and A. Thomas, which was published within the issue. Topics mentioned include the integration of remediation in DPA models, and the importance of identifying learners with remediation needs.

Die kompetenzbasierte Ausbildung ist zum zentralen Element in der Weiterbildung und Beurteilung von postgraduierten medizinischen Auszubildenden oder Assistenzärzten geworden [1]. In kompetenzbasierter Ausbildung gibt es eine klare Fokussierung auf Ergebnisse und professionelle Leistungen. Typischerweise werden holistische Aufgaben verwendet, um definierte Ergebnisse oder Kompetenzen zu üben, zu praktizieren und zu bewerten. Während der Facharztausbildung sind diese Aufgaben Teil des klinischen Alltags. Die Leistung der Assistenzärzte am Arbeitsplatz muss erfasst und dokumentiert werden. Ein Portfolio ist als Instrument für die Speicherung und Sammlung von Be urteilung und Feedback am Arbeitsplatz in verschiedenen Ländern, wie den Niederlanden und den Vereinigten Staaten, verwendet worden. Die Sammlung von Informationen in einem Portfolio kann verschiedenen Zwecken dienen oder für verschiedene Zwecke verwendet werden. Diese sind: 1. Die Sammlung von Arbeitsproben, Beurteilungen, Feedback und Evaluationen in einem Portfolio ermöglicht dem Lernenden zurückzublicken, zu analysieren und zu reflektieren 2. Der Inhalt dient der Bewertung oder den Entscheidungen über den Fortschritt. Und 3. das Portfolio wird als Instrument für Qualitätssicherungsprozesse verwendet. Innerhalb der postgraduierten medizinischen Weiterbildung können diese Zwecke kombiniert werden, aber dies wird nicht immer transparent berichtet. In diesem Artikel werden die verschiedenen Perspektiven erörtert, wie ein Portfolio diese drei Zwecke erfüllen kann und was die Möglichkeiten und Herausforderungen sind, um verschiedene Nutzungen zu kombinieren. [ABSTRACT FROM AUTHOR]

Competency-based education has become central to the training and assessment of post-graduate medical trainees or residents [1]. In competency-based education, there is a strong focus on outcomes and professional performance. Typically, holistic tasks are used to train, practice and assess the defined outcomes or competencies. In residency training, these tasks are part of the day-to-day clinical practice. The performance of residents in the workplace needs to be captured and stored. A portfolio has been used as an instrument for storage and collection of workplace-based assessment and feedback in various countries, like the Netherlands and the United States. The collection of information in a portfolio can serve or be used for a variety of purposes. These are: 1. The collection of work samples, assessment, feedback and evaluations in a portfolio enables the learner to look back, analyze and reflect. 2. The content is used for assessment or making decisions about progress. And 3. the portfolio is used as an instrument for quality assurance processes. In post-graduate medical education, these purposes can be combined but this is not always reported transparently. In this paper, we will discuss the different perspectives, how a portfolio can serve these three purposes and what are opportunities and challenges of combining multiple purposes. [ABSTRACT FROM AUTHOR]

Background:In medical education, students need to acquire skills to self-direct(ed) learning (SDL), to enable their development into self-directing and reflective professionals. This study addressed the mentor perspective on how processes in the mentor–student interaction influenced development of SDL. Methods:n = 22 mentors of a graduate-entry medical school with a problem-based curriculum and longitudinal mentoring system were interviewed (n = 1 recording failed). Using activity theory (AT) as a theoretical framework, thematic analysis was applied to the interview data to identify important themes. Results:Four themes emerged: centered around the role of the portfolio, guiding of students’ SDL in the context of assessment procedures, mentor-role boundaries and longitudinal development of skills by both the mentor and mentee. Application of AT showed that in the interactions between themes tensions or supportive factors could emerge for activities in the mentoring process. Conclusion:The mentors’ perspective on coaching and development of reflection and SDL of medical students yielded important insights into factors that can hinder or support students’ SDL, during a longitudinal mentor–student interaction. Coaching skills of the mentor, the interaction with a portfolio and the context of a mentor community are important factors in a longitudinal mentor–student interaction that can translate to students’ SDL skills. [ABSTRACT FROM PUBLISHER]

Background:Progress tests (PT) are used to assess students on topics from all medical disciplines. Progress testing is usually one of the assessment methods of the cognitive domain. There is limited knowledge on how positioning of the PT in a program of assessment (PoA) influences students’ PT scores, use of PT feedback and perceived learning value. Methods:We compared PT total scores and use of a PT test feedback (ProF) system in two medical courses, where the PT is either used as a summative assessment or embedded in a comprehensive PoA and used formatively. In addition, an interview study was used to explore the students’ perception on use of PT feedback and perceived learning value. Results:PT total scores were higher, with considerable effect sizes (ESs) and students made more use of ProF when the PT was embedded in a comprehensive PoA. Analysis of feedback in the portfolio stimulated students to look for patterns in PT results, link the PT to other assessment results, follow-up on learning objectives, and integrate the PT in their learning for the entire PoA. Conclusions:Embedding the PT in an assessment program designed according to the principles of programmatic assessment positively affects PT total scores, use of PT feedback, and perceived learning value. [ABSTRACT FROM PUBLISHER]

Programmatic assessment requires labour and cost intensive activities such as feedback in a quantitative and qualitative form, a system of learner support in guiding feedback uptake and self-directed learning, and a decision-making arrangement that includes committees of experts making a holistic professional judgment while using due process measures to achieve trustworthy decisions. This can only be afforded if we redistribute the resources of assessment in a curriculum. Several strategies are suggested. One is to introduce progress testing as a replacement for costly cognitive assessment formats in modules. In addition, all assessments should be replaced by assessment formats that are maximally aligned with the learning tasks. For performance-based assessment, OSCEs should be sparsely used, while education and work-embedded assessment should be maximized as part of the routine of ongoing instruction and assessment. Information technology may support affordable feedback strategies, as well as the creation of a paper trail on performance. By making more dramatic choices in the way we allocate resources to assessment, the cost-intensive activities of programmatic assessment may be realized. [ABSTRACT FROM AUTHOR]

Context It is widely acknowledged that assessment can affect student learning. In recent years, attention has been called to 'programmatic assessment', which is intended to optimise both learning functions and decision functions at the programme level of assessment, rather than according to individual methods of assessment. Although the concept is attractive, little research into its intended effects on students and their learning has been conducted. Objectives This study investigated the elements of programmatic assessment that students perceived as supporting or inhibiting learning, and the factors that influenced the active construction of their learning. Methods The study was conducted in a graduate-entry medical school that implemented programmatic assessment. Thus, all assessment information, feedback and reflective activities were combined into a comprehensive, holistic programme of assessment. We used a qualitative approach and interviewed students ( n = 17) in the pre-clinical phase of the programme about their perceptions of programmatic assessment and learning approaches. Data were scrutinised using theory-based thematic analysis. Results Elements from the comprehensive programme of assessment, such as feedback, portfolios, assessments and assignments, were found to have both supporting and inhibiting effects on learning. These supporting and inhibiting elements influenced students' construction of learning. Findings showed that: (i) students perceived formative assessment as summative; (ii) programmatic assessment was an important trigger for learning, and (iii) the portfolio's reflective activities were appreciated for their generation of knowledge, the lessons drawn from feedback, and the opportunities for follow-up. Some students, however, were less appreciative of reflective activities. For these students, the elements perceived as inhibiting seemed to dominate the learning response. Conclusions The active participation of learners in their own learning is possible when learning is supported by programmatic assessment. Certain features of the comprehensive programme of assessment were found to influence student learning, and this influence can either support or inhibit students' learning responses. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: We have previously shown that irradiation to the carotid arteries of hypercholesterolemic ApoE−/− mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions. We now investigated the mechanism underlying the development of radiation-induced atherosclerosis. Materials and methods: ApoE−/− and wildtype C57BL/6J mice received 0, 8 or 14Gy to the neck and the carotid arteries were harvested 1day, 1 or 4weeks later. Immunohistochemical stainings were performed to evaluate well-known inflammatory and thrombotic molecules. A hypothesis-generating approach was used to compare gene expression profiles of irradiated and unirradiated carotid arteries. Results: Basal levels of endothelial VCAM-1 and thrombomodulin immunoexpression were higher in ApoE−/− mice than in C57BL/6J mice. At 1week after 14Gy VCAM-1 immunoexpression was decreased in ApoE−/− mice, whereas ICAM-1 immunoexpression was decreased at 1 and 4weeks after 14Gy in C57BL/6J mice. Thrombomodulin and tissue factor immunoexpression were elevated at 4weeks after 14Gy in ApoE−/− mice and reduced in C57BL/6J mice. There were no changes in immunoexpression of eNOS, MCP-1 or endoglin. Several canonical pathways were differentially expressed after irradiation, including tight junction pathways, leukocyte extravasation signaling and PI3K/AKT signaling. Conclusion: ApoE−/− and C57BL/6J mice respond differently to irradiation. The thrombotic pathways were activated after irradiation in ApoE−/− mice only. Genes involved in tight junction regulation were up-regulated in ApoE−/− mice and decreased in C57BL/6J mice. These factors may have contributed to fatty-streak formation in ApoE−/− mice. [Copyright &y& Elsevier]

Abstract: Aims: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis. Methods and results: Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n =27), without Type 2 diabetes (nonDM, n =22), or hyperglycaemia (HG, n =17). Iron (P <0.05), zinc (P <0.01) and calcium (P =0.01) were lower in T2DM compared to nonDM subjects. Copper levels were comparable. A strong correlation (r =0.618; P <0.001) between EPR-detectable and total iron in nonDM patients was not seen in T2DM. X-ray fluorescence microscopy revealed “hot spots” of iron in both T2DM and nonDM. Calcium and zinc co-localised and levels correlated strongly. F2-isoprostanes (P <0.05) and di-Tyr/Tyr ratio (P <0.025), oxidative damage markers were decreased in T2DM compared to nonDM, or HG. Conclusion: Advanced atherosclerotic lesions from T2DM subjects unexpectedly contained lower levels of transition metal ions, and protein and lipid oxidation products, compared to nonDM and HG. These data do not support the hypothesis that elevated metal ion levels may be a major causative factor in the aggravated atherosclerosis observed in T2DM patients. [Copyright &y& Elsevier]

Abstract: Background and purpose: We previously showed that irradiating the carotid arteries of ApoE−/− mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis. Material and methods: ApoE−/− mice were given 0 or 14Gy to the neck and the carotid arteries were harvested at 4 or 28weeks after irradiation. Atorvastatin (15mg/kg/day) or clopidogrel (20mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L−/−/ApoE−/− and ApoE−/− littermates were also given 0 or 14Gy to the neck and the carotid arteries were harvested after 30weeks. Results: Clopidogrel decreased MCP-1 expression in the carotid artery at 4weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis. Conclusions: The effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis. [Copyright &y& Elsevier]

Background: We previously showed that irradiation to the carotid arteries of ApoE-/- mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions, prone to intra-plaque hemorrhage. In this study we investigated the potential of anti-inflammatory and anti-coagulant intervention strategies to inhibit age-related and radiation-induced atherosclerosis. Methodology/Principal Findings: ApoE-/- mice were given 0 or 14 Gy to the neck and the carotid arteries and aortic arches were harvested at 4 or 30 weeks after irradiation. Nitric oxide releasing aspirin (NCX 4016, 60 mg/kg/day) or aspirin (ASA, 30 or 300 mg/kg/day) were given continuously in the chow. High dose ASA effectively blocked platelet aggregation, while the low dose ASA or NCX 4016 had no significant effect on platelet aggregation. High dose ASA, but not NCX 4016, inhibited endothelial cell expression of VCAM-1 and thrombomodulin in the carotid arteries at 4 weeks after irradiation; eNOS and ICAM-1 levels were unchanged. After 30 weeks of follow-up, NCX 4016 significantly reduced the total number of lesions and the number of initial macrophage-rich lesions in the carotid arteries of unirradiated mice, but these effects were not seen in the brachiocephalic artery of the aortic arch (BCA). In contrast, high dose ASA lead to a decrease in the number of initial lesions in the BCA, but not in the carotid artery. Both high dose ASA and NCX 4016 reduced the collagen content of advanced lesions and increased the total plaque burden in the BCA of unirradiated mice. At 30 weeks after irradiation, neither NCX 4016 nor ASA significantly influenced the number or distribution of lesions, but high dose ASA lead to formation of collagen-rich ''stable'' advanced lesions in carotid arteries. The total plaque area of the irradiated BCA was increased after ASA, but the plaque burden was very low compared with the carotid artery. Conclusions/Significance: The development and characteristics of radiation-induced atherosclerosis varied between different arteries but could not be circumvented by anti-inflammatory and anti-coagulant therapies. This implicates other underlying mechanistic pathways compared to age-related atherosclerosis. [ABSTRACT FROM AUTHOR]

Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin''s lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE−/− mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE−/− mice were given 8 or 14 Gy, or 20 × 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaque size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8–14 Gy and 20 × 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE−/− mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype. [Copyright &y& Elsevier]

Under conditions where apoptosis is prevented, peroxides disrupt the endothelial monolayer by inducing cytoskeletal rearrangements, cell retraction and formation of arrays of membrane blebs. In human umbilical vein endothelial cells (HUVEC), the H2O2-induced membrane blebbing was found to be a transient process executed by two parallel signaling mechanisms: (i) mobilization of cytosolic [Ca2+]i through a pathway requiring oxidation of reduced glutathione (GSH), and (ii) activation of p38 mitogen-activated protein kinases (MAPK) independently of GSH oxidation and Ca2+ mobilization. In the HUVEC, membrane blebbing was thus blocked by inhibition of GSH oxidation, Ca2+ mobilization or p38 MAPK activation. Stimulation of GSH peroxidation with ebselen potentiated the H2O2-induced oscillating Ca2+ response and the bleb formation, but not p38 phosphorylation. Chelation of [Ca2+]i abolished the blebbing process but not p38 activation. In addition, in the GSH peroxidase-resistant cell line ECV304, H2O2 was unable to promote membrane blebbing or significant Ca2+ release, while p38 became phosphorylated. However, [Ca2+]i was increased and blebs were formed, when the ECV304 were treated with ebselen before H2O2. Together, this leads to a model where oxidative stress, through both Ca2+-dependent and p38 kinase-mediated phosphorylation events, causes reassembly of the actin cytoskeleton and subsequent appearance of membrane blebs at the plasma membrane. [Copyright &y& Elsevier]

Presents information on a study which investigated the role of the CD40L-CD40 pathway in a model of progressive atherosclerosis. Methodology; Results and discussion.

Introduction: With multisource feedback (MSF) physicians might overrate their own performance compared with scores received from assessors. However, there is limited insight into how perceived divergent feedback affects physicians' subsequent performance scores. Methods: During 2012 to 2018, 103 physicians were evaluated twice by 684 peers, 242 residents, 999 coworkers, and themselves in three MSF performance domains. Mixed-effect models quantified associations between the outcome variable "score changes" between first and second MSF evaluations, and the explanatory variable "negative discrepancy score" (number of items that physicians rated themselves higher compared with their assessors' scores) at the first MSF evaluation. Whether associations differed across assessor groups and across a physician's years of experience as a doctor was analyzed too. Results: Forty-nine percent of physicians improved their total MSF score at the second evaluation, as assessed by others. Number of negative discrepancies was negatively associated with score changes in domains "organization and (self)management" (b = 20.02; 95% confidence interval [CI], 20.03 to 20.02; SE = 0.004) and "patient-centeredness" (b = 20.03; 95% CI, 20.03 to 20.02; SE = 0.004). For "professional attitude," only negative associations between score changes and negative discrepancies existed for physicians with more than 6-year experience (b6-10yearsofexperience = 20.03; 95% CI, 20.05 to 20.003; SE = 0.01; b16-20yearsofexperience = 20.03; 95% CI, 20.06 to 20.004; SE = 0.01). Discussion: The extent of performance improvement was less for physicians confronted with negative discrepancies. Performance scores actually declined when physicians overrated themselves on more than half of the feedback items. PA score changes of more experienced physicians confronted with negative discrepancies and were affected more adversely. These physicians might have discounted feedback due to having more confidence in own performance. Future work should investigate how MSF could improve physicians' performance taking into account physicians' confidence. [ABSTRACT FROM AUTHOR]

Introduction: Programmatic assessment was introduced as an approach to design assessment programmes with the aim to simultaneously optimize the decision-making and learning function of assessment. An integrative review was conducted to review and synthesize results from studies investigating programmatic assessment in health care professions education in practice. Methods: The authors systematically searched PubMed, Web of Science, and ERIC to identify studies published since 2005 that reported empirical data on programmatic assessment. Characteristics of the included studies were extracted and synthesized, using descriptive statistics and thematic analysis. Results: Twenty-seven studies were included, which used quantitative methods (n = 10), qualitative methods (n = 12) or mixed methods (n = 5). Most studies were conducted in clinical settings (77.8%). Programmatic assessment was found to enable meaningful triangulation for robust decision-making and used as a catalyst for learning. However, several problems were identified, including overload in assessment information and the associated workload, counterproductive impact of using strict requirements and summative signals, lack of a shared understanding of the nature and purpose of programmatic assessment, and lack of supportive interpersonal relationships. Thematic analysis revealed that the success and challenges of programmatic assessment were best understood by the interplay between quantity and quality of assessment information, and the influence of social and personal aspects on assessment perceptions. Conclusion: Although some of the evidence may seem compelling to support the effectiveness of programmatic assessment in practice, tensions will emerge when simultaneously stimulating the development of competencies and assessing its result. The identified factors and inferred strategies provide guidance for navigating these tensions. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to explore GP residents' knowledge retention and residents' and clinical teachers' perception on the learning value of a dermatology E-learning programme. Methods: The study used a mixed-method design with a convergent parallel collection of data. GP residents (n=21) were selected through purposive sampling and were randomized to an E-learning group (n=12) or a traditional teaching methods group (n=9). The pre-and post-intervention knowledge tests of the E-learning group were compared using paired-samples t-tests. Post-knowledge tests scores of both groups were compared using independent t-tests. Cronbach's coefficient α was used to calculate the internal consistency of the questions used in the knowledge tests. Individual semi-structured interviews and clinical teachers (n=16) were conducted and analyzed using King's template analysis. Results: The E-learning group showed a significant increase in mean knowledge test scores from 58.92% (SD=9.55%) to 64.92% (SD=13.65%) (t(11)=2.258, p=0.045, Cohen’s d=0.51). The pre-knowledge test consisted of 46 items (Alpha=0.78), and the post-knowledge tests consisted of 45 items (Alpha= 0.90). Interview data showed that the E-learning programme aided GP trainees' learning process and favoured a mixed-method teaching design, in which E-learning is used in parallel to the traditional teaching methods . Conclusions: A dermatology E-learning programme appeared an effective strategy in resident's knowledge acquiring. The key users' perceptions, both residents and clinical teachers, indicated that E-learning was feasible and helpful for learning processes. Further research is required to evaluate the implementation of E-learning programmes in parallel to regular teaching programs. [ABSTRACT FROM AUTHOR]

Any form of assessment activity will act as a stimulus and provoke an educational response. There is a risk however that the response will not result in a beneficial educational response, thus there is a need to monitor and understand the relationship between assessment and learning. This is true at any level of education including postgraduate medical education. To understand how residents perceived assessment, we interviewed 20 residents from the departments of internal medicine and paediatrics. Our goal was to determine how assessment influenced their motivation to accumulate knowledge and skills and attain the competence levels expected of a specialist. We utilised grounded theory to analyse the data. Our results showed that the trainees acknowledged that assessment, in general, has a positive influence on their learning, it motivated them to study and fostered an active learning attitude. A high degree of self-directed learning was also present among the residents. An interplay of new or interesting patient cases, concern for the welfare of the patients, engagement with the consultants, and a supportive environment contributed to creating the motivation for the residents to study. [ABSTRACT FROM AUTHOR]

Embedding formative assessment into everyday pedagogical practice is a complex matter for teachers. In this study, we used teacher-researcher co-design to investigate how a one-year collaboration between seven elementary school teachers and three researchers supports the design- and implementation process of formative assessment in each of the teachers' classrooms. Our findings indicate that teacher-researcher co-design supports the implementation of a unified approach to formative assessment through teachers' evolving conceptions. The co-design facilitated open dialogue, ongoing exchange of ideas between participants, led to a shared understanding in a teacher community and improved the teachers' sense of ownership. • Improving the congruence between teachers' and researchers' perspectives helps teachers to reconceptualize formative assessment. • Teacher-researcher co-design supports teachers with implementing formative assessment through teachers' evolving conceptions. • Successful teacher-researcher co-design should focus on enabling teacher communities, leading to a shared understanding, and improving teachers' sense of ownership. [ABSTRACT FROM AUTHOR]

Introduction: Portfolio use to support self-regulated learning (SRL) during clinical workplace learning is widespread, but much is still unknown regarding its effectiveness. This review aimed to gain insight in the extent to which portfolio use supports SRL and under what circumstances. Methods: A realist review was conducted in two phases. First, stakeholder interviews and a scoping search were used to formulate a program theory that explains how portfolio use could support SRL. Second, an in-depth literature search was conducted. The included papers were coded to extract context–mechanism–outcome configurations (CMOs). These were synthesized to answer the research question. Results: Sixteen papers were included (four fulfilled all qualitative rigor criteria). Two primary portfolio mechanisms were established: documenting as a moment of contemplation (learners analyze experiences while writing portfolio reports) and documentation as a reminder of past events (previous portfolio reports aid recall). These mechanisms may explain the positive relationship between portfolio use and self-assessment, reflection, and feedback. However, other SRL outcomes were only supported to a limited extent: formulation of learning objectives and plans, and monitoring. The partial support of the program theory can be explained by interference of contextual factors (e.g., system of assessment) and portfolio-related mechanisms (e.g., mentoring). Discussion: Portfolio research is falling short both theoretically—in defining and conceptualizing SRL—and methodologically. Nevertheless, this review indicates that portfolio use has potential to support SRL. However, the working mechanisms of portfolio use are easily disrupted. These disruptions seem to relate to tensions between different portfolio purposes, which may undermine learners' motivation. [ABSTRACT FROM AUTHOR]

Programmatic assessment is an approach to assessment aimed at optimizing the learning and decision function of assessment. It involves a set of key principles and ground rules that are important for its design and implementation. However, despite its intuitive appeal, its implementation remains a challenge. The purpose of this paper is to gain a better understanding of the factors that affect the implementation process of programmatic assessment and how specific implementation challenges are managed across different programs. An explanatory multiple case (collective) approach was used for this study. We identified 6 medical programs that had implemented programmatic assessment with variation regarding health profession disciplines, level of education and geographic location. We conducted interviews with a key faculty member from each of the programs and analyzed the data using inductive thematic analysis. We identified two major factors in managing the challenges and complexity of the implementation process: knowledge brokers and a strategic opportunistic approach. Knowledge brokers were the people who drove and designed the implementation process acting by translating evidence into practice allowing for real-time management of the complex processes of implementation. These knowledge brokers used a 'strategic opportunistic' or agile approach to recognize new opportunities, secure leadership support, adapt to the context and take advantage of the unexpected. Engaging in an overall curriculum reform process was a critical factor for a successful implementation of programmatic assessment. The study contributes to the understanding of the intricacies of implementation processes of programmatic assessment across different institutions. Managing opportunities, adaptive planning, awareness of context, were all critical aspects of thinking strategically and opportunistically in the implementation of programmatic assessment. Future research is needed to provide a more in-depth understanding of values and beliefs that underpin the assessment culture of an organization, and how such values may affect implementation. [ABSTRACT FROM AUTHOR]

Aims Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms. Methods and results We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n  = 22 of 30, 73.3%) compared to non-smokers (n  = 11 of 32, 34.3%; P  < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro , nicotine - induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels. Conclusion In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination. Methodology/Principal Findings: We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin (FII−/WT:ApoE−/−) was remarkably effective in limiting disease compared to control ApoE−/− mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in TMPro/Pro:ApoE−/− mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic TMPro/Pro:ApoE−/− mice. Conclusions/Significance: We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Vascular disease is increased after radiotherapy and is an important determinant of late treatment-induced morbidity and excess mortality. This study evaluates the nature of underlying pathologic changes occurring in medium-sized muscular arteries following irradiation. Materials and methods: Biopsies of irradiated medium-sized arteries and unirradiated control arteries were taken from 147 patients undergoing reconstructive surgery with a vascularised free flap following treatment for head and neck (H&N) or breast cancer (BC). Relative intimal thickening was derived from the ratio of the thickness of the intima to the thickness of the media (IMR) on histological sections. Proteoglycan, collagen and inflammatory cell content were also scored. Results: Intimal thickness was significantly increased in irradiated vessels: in the H&N group the IMR was 1.5-fold greater without correction for the control artery (p =0.018); in the BC group the IMR increased 1.4-fold after correction for the control artery (p =0.056) at a mean of 4years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73% (p =0.024). Inflammatory cell content was increased in the intima of the irradiated H&N vessels (p =0.014). Conclusions: Radiation-induced vascular pathology differs quantitatively and qualitatively from age-related atherosclerosis. [Copyright &y& Elsevier]

Programmatic assessment is a longitudinal, developmental approach that fosters and harnesses the learning function of assessment. Yet the implementation, a critical step to translate theory into practice, can be challenging. As part of the Ottawa 2020 consensus statement on programmatic assessment, we sought to provide descriptions of the implementation of the 12 principles of programmatic assessment and to gain insight into enablers and barriers across different institutions and contexts. After the 2020 Ottawa conference, we surveyed 15 Health Profession Education programmes from six different countries about the implementation of the 12 principles of programmatic assessment. Survey responses were analysed using a deductive thematic analysis. A wide range of implementations were reported although the principles remained, for the most part, faithful to the original enunciation and rationale. Enablers included strong leadership support, ongoing faculty development, providing students with clear expectations about assessment, simultaneous curriculum renewal and organisational commitment to change. Most barriers were related to the need for a paradigm shift in the culture of assessment. Descriptions of implementations in relation to the theoretical principles, across multiple educational contexts, coupled with explanations of enablers and barriers, provided new insights and a clearer understanding of the strategic and operational considerations in the implementation of programmatic assessment. Future research is needed to further explore how contextual and cultural factors affect implementation. [ABSTRACT FROM AUTHOR]

Background: In many healthcare systems, physicians are accustomed to periodically participate in individual performance appraisals to guide their professional development. For the purpose of revalidation, or maintenance of certification, they need to demonstrate that they have engaged with the outcomes of these appraisals. The combination of taking ownership in professional development and meeting accountability requirements may cause undesirable interference of purposes. To support physicians in their professional development, new Dutch legislation requires that they discuss their performance data with a non-hierarchical (peer)coach and draft a personal development plan. In this study, we report on the design of this system for performance appraisal in a Dutch academic medical center.Methods: Using a design-based research approach, a hospital-based research group had the lead in drafting and implementing a performance appraisal protocol, selecting a multisource feedback tool, co-developing and piloting a coaching approach, implementing a planning tool, recruiting peer coaches and facilitating their training and peer group debriefings.Results: The system consisted of a two-hour peer-to-peer conversation based on the principles of appreciative inquiry and solution-focused coaching. Sessions were rated as highly motivating, development-oriented, concrete and valuable. Peer coaches were considered suitable, although occasionally physicians preferred a professional coach because of their expertise. The system honored both accountability and professional development purposes. By integrating the performance appraisal system with an already existing internal performance system, physicians were enabled to openly and safely discuss their professional development with a peer, while also being supported by their superior in their self-defined developmental goals. Although the peer-to-peer conversation was mandatory and participation in the process was documented, it was up to the physician whether or not to share its results with others, including their superior.Conclusions: In the context of mandatory revalidation, professional development can be supported when the appraisal process involves three characteristics: the appraisal process is appreciative and explores developmental opportunities; coaches are trustworthy and skilled; and the physician has control over the disclosure of the appraisal output. Although the peer-to-peer conversations were positively evaluated, the effects on physicians' professional development have yet to be investigated in longitudinal research designs. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the conceptions of teaching and learning of postgraduate medical teachers. Methods: We invited postgraduate clinical teachers to fill out COLT (Conceptions on Learning and Teaching) questionnaire, an 18-item instrument designed to measure the conceptions of faculty in undergraduate medical education, and did a confirmatory factor analysis (CFA) to test if it was valid to be used in a postgraduate situation. Cluster analysis was done to determine different teacher profiles. We subsequently did a qualitative study among 12 clinical teachers to further explore issues related to conceptions of teaching. We used a semi-structured interview guide with vignettes summarizing five perspectives of teaching. Results: Four criteria of goodness of fit indices were met, although six items had to be removed from the original COLT items. Three clusters were identified, and 51% of participants favored a transmission teaching-style perspective. For the qualitative part, three themes were identified. Majority of the teachers preferred apprenticeship and nurturing teaching-style perspective, even if they were educated through a transmission teaching-style perspective. Conclusions: Our study has shown that the COLT, although initially designed for undergraduate medical setting in the Netherlands was a valid tool in a different setting and population, with some modifications. Both the survey and the interview studies showed that the majority of the faculty chose the transmission perspective initially, but when introduced to the other perspectives, preferred apprenticeship and nurturing. The faculty readily embraced other perspectives of teaching that they believe to take into consideration the wellbeing of the trainees. [ABSTRACT FROM AUTHOR]

Introduction: Since clinical practice is a group-oriented process, it is crucial to evaluate performance on the group level. The Group Monitor (GM) is a multisource feedback tool that evaluates the performance of specialty-specific physician groups in hospital settings, as perceived by four different rater classes. In this study, we explored the validity of this tool. Methods: We explored three sources of validity evidence: (1) content, (2) response process, and (3) internal structure. Participants were 254 physicians, 407 staff, 621 peers, and 282 managers of 57 physician groups (in total 479 physicians) from 11 hospitals. Results: Content was supported by the fact that the items were based on a review of an existing instrument. Pilot rounds resulted in reformulation and reduction of items. Four subscales were identified for all rater classes: Medical practice, Organizational involvement, Professionalism, and Coordination. Physicians and staff had an extra subscale, Communication. However, the results of the generalizability analyses showed that variance in GM scores could mainly be explained by the specific hospital context and the physician group specialty. Optimization studies showed that for reliable GM scores, 3 to 15 evaluations were needed, depending on rater class, hospital context, and specialty. Discussion: The GM provides valid and reliable feedback on the performance of specialty-specific physician groups. When interpreting feedback, physician groups should be aware that rater classes' perceptions of their group performance are colored by the hospitals' professional culture and/or the specialty. [ABSTRACT FROM AUTHOR]

GLO:1C4K/01aug20:tct13207-fig-0001.jpg PHOTO (COLOR): . gl As a result of the COVID-19 pandemic, medical schools across the world have been faced with the unprecedented situation of closing their doors and cancelling clinical teaching and examinations. Programmatic assessment involves the longitudinal collection of information about a student based on multiple low-stakes assessments. Having assessment data over time may help to ease some of our angst about learners' assessment decisions during such unprecedented times. [Extracted from the article]

OBJECTIVES Within programmatic assessment, the ambition is to simultaneously optimise the feedback and the decisionmaking function of assessment. In this approach, individual assessments are intended to be low stakes. In practice, however, learners often perceive assessments designed to be low stakes as high stakes. In this study, we explored how learners perceive assessment stakes within programmatic assessment and which factors influence these perceptions. METHODS Twenty-six learners were interviewed from three different countries and five different programmes, ranging from undergraduate to postgraduate medical education. The interviews explored learners' experience with and perception of assessment stakes. An open and qualitative approach to data gathering and analyses inspired by the constructivist grounded theory approach was used to analyse the data and reveal underlying mechanisms influencing learners' perceptions. RESULTS Learners' sense of control emerged from the analysis as key for understanding learners' perception of assessment stakes. Several design factors of the assessment programme provided or hindered learners' opportunities to exercise control over the assessment experience, mainly the opportunities to influence assessment outcomes, to collect evidence and to improve. Teacher-learner relationships that were characterised by learners' autonomy and in which learners feel safe were important for learners' believed ability to exercise control and to use assessment to support their learning. CONCLUSIONS Knowledge of the factors that influence the perception of assessment stakes can help design effective assessment programmes in which assessment supports learning. Learners' opportunities for agency, a supportive programme structure and the role of the teacher are particularly powerful mechanisms to stimulate the learning value of programmatic assessment. [ABSTRACT FROM AUTHOR]

Objectives: To obtain a deeper understanding of how the e-learning program, Education in Dermatology (ED), affects the acquisition of dermatological knowledge and the underlying learning processes of medical students in their clinical phase. Methods: The study used a mixed method design with a convergent parallel collection of data. Medical students (n=62) from Maastricht University (The Netherlands) were randomized to either a conventional teaching group (control group n=30) or conventional teaching plus the e-learning program (application on smartphone) group (e-learning group n=32). Pre- and post-intervention knowledge test results were analysed using an independent ttest. Individual semi-structured interviews (n=9) were conducted and verbatim-transcribed recordings were analysed using King's template analysis. Results: The e-learning program positively influenced students' level of knowledge and their process of learning. A significant difference was found in the post-test scores for the control group (M=51.4, SD=6.43) and the e-learning group (M=73.09, SD=5.12); t(60)=-14.75, p<0.000). Interview data showed that the e-learning program stimulated students' learning as the application promoted the identification and recognition of skin disorders, the use of references, creation of documents and sharing information with colleagues. Conclusions: This study demonstrated that use of the e-learning program led to a significant improvement in basic dermatological knowledge. The underlying learning processes indicated that e-learning programs in dermatology filled a vital gap in the understanding of clinical reasoning in dermatology. These results might be useful when developing (clinical) teaching formats with a special focus on visual disciplines. [ABSTRACT FROM AUTHOR]

Background: Patients with a recent ischemic stroke have a higher risk of recurrent stroke compared to (ocular) transient ischemic attack (TIA) patients. Plaque microvasculature is considered as a feature of plaque vulnerability and can be quantified with carotid dynamic contrast-enhanced MRI (DCE-MRI). The purpose of this cross-sectional study was to explore the association between plaque microvasculature and the type of recent cerebrovascular events in symptomatic patients with mild-to-moderate carotid stenosis. Methods: A total of 87 symptomatic patients with a recent stroke (n = 35) or (ocular) TIA (n = 52) underwent carotid DCE-MRI examination. Plaque microvasculature was studied in the vessel wall and adventitia using DCEMRI and the pharmacokinetic modeling parameter Ktrans. Statistical analysis was performed with logistic regression, correcting for associated clinical risk factors. Results: The 75th percentile adventitial (OR 1.97, 95% CI 1.18-3.29) Ktrans was significantly associated with a recent ischemic stroke compared to (ocular) TIA in multivariate analysis, while clinical risk factors were not significantly associated with the type of event. Conclusions: This study indicates a positive association of leaky plaque microvasculature with a recent ischemic stroke compared to (ocular) TIA. Prospective longitudinal studies are needed to investigate whether Ktrans or other plaque characteristics may serve as an imaging marker for predicting (the type of) future cerebrovascular events. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of a heart rate (HR) lowering agent (Ivabradine) on features of atherosclerotic plaque vulnerability with magnetic resonance imaging (MRI), ultrasound imaging, and histology. Approach and results: Atherosclerosis was induced in the abdominal aorta of 19 rabbits. Nine rabbits were treated with Ivabradine (17 mg/kg/day) during the entire study period. At week 14, imaging was performed. Plaque size was quantified on contrast-enhanced T1-weighted MR images. Microvascular flow, density, and permeability was studied with dynamic contrast-enhanced MRI. Plaque biomechanics was studied by measuring the aortic distension with ultrasound. After, animals were sacrificed and histology was performed. HR was reduced by 16% (p = 0.026) in Ivabradine-treated animals. No differences in absolute and relative vessel wall beat-to-beat distension were found, but due to the reduction in HR, the frequency of the biomechanical load on the plaque was reduced. Plaque size (MR and histology) was similar between groups. Although microvessel density (histology) was similar between groups, AUC and Ktrans, indicative for plaque microvasculature flow, density, and permeability, were decreased by 24% (p = 0.029) and 32% (p = 0.037), respectively. Macrophage content (relative RAM11 positive area) was reduced by 44% (p<0.001) on histology in Ivabradine-treated animals. Conclusions: HR lowering treatment with Ivabradine in an atherosclerotic rabbit model is associated with a reduction in vulnerable plaque features. The current study suggests that HR reduction may be beneficial for inducing or maintaining a more stable plaque phenotype. [ABSTRACT FROM AUTHOR]

Introduction: Multisource feedback (MSF) instruments are used to and must feasibly provide reliable and valid data on physicians' performance from multiple perspectives. The "INviting Co-workers to Evaluate Physicians Tool" (INCEPT) is a multisource feedback instrument used to evaluate physicians' professional performance as perceived by peers, residents, and coworkers. In this study, we report on the validity, reliability, and feasibility of the INCEPT. Methods: The performance of 218 physicians was assessed by 597 peers, 344 residents, and 822 coworkers. Using explorative and confirmatory factor analyses, multilevel regression analyses between narrative and numerical feedback, item-total correlations, interscale correlations, Cronbach's a and generalizability analyses, the psychometric qualities, and feasibility of the INCEPT were investigated. Results: For all respondent groups, three factors were identified, although constructed slightly different: "professional attitude," "patient-centeredness," and "organization and (self)-management." Internal consistency was high for all constructs (Cronbach's a $ 0.84 and item-total correlations $ 0.52). Confirmatory factor analyses indicated acceptable to good fit. Further validity evidence was given by the associations between narrative and numerical feedback. For reliable total INCEPT scores, three peer, two resident and three coworker evaluations were needed; for subscale scores, evaluations of three peers, three residents and three tofour coworkers were sufficient. Discussion: The INCEPT instrument provides physicians performance feedback in a valid and reliable way. The number of evaluations to establish reliable scores is achievable in a regular clinical department. When interpreting feedback, physicians should consider that respondent groups' perceptions differ as indicated by the different item clustering per performance factor [ABSTRACT FROM AUTHOR]

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE−/− mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. Material and methods: ApoE−/− mice (28weeks old) received local irradiation with 14 or 0Gy (sham-treated) at the aortic arch and were examined after 4 and 12weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. Results: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. Conclusions: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque. [Copyright &y& Elsevier]

Abstract: Introduction: Consumption of n-3 polyunsaturated fatty acids (PUFA) and antioxidant polyphenols is considered to decline the risk of cardiovascular disease. Materials and Methods: To provide an explanation for this cardioprotective effect, we performed an intervention study with proatherogenic Apoe −/− mice which were fed during eight weeks with a high fat diet supplemented with either walnuts (rich in n-3 PUFA and antioxidant compounds), walnut oil (with n-3 PUFA only) or sunflower oil as a control (12 mice per group). Results: Feeding walnuts, but not walnut oil, caused a 55% reduction in atherosclerotic plaque development in the aortic arch in comparison to the control diet. This was associated with reduced staining of plaques for CD36, a scavenger receptor expressed by macrophages. Feeding mice with walnuts also lowered plasma levels of triglycerides, cholesterol and prothrombin with 36%, 23% and 21 %, respectively, compared to control diet. In addition, accumulation of lipids in the liver was decreased, while plasma antioxidant capacity was increased. On the other hand, feeding mice with walnut oil did not provoke significant changes in these parameters in comparison to the control diet. Platelet activation and thrombus formation under flow remained unchanged with either diet. Conclusions: In Apoe −/− mice on high fat diet, intake of dietary walnut (but not walnut oil) beneficially influences lipid metabolism and atherosclerotic plaque development, with no more than limited effects on platelet and coagulation function. [Copyright &y& Elsevier]

Abstract: Background and purpose: Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. Material and methods: Hypercholesterolemic and atherosclerosis-prone ApoE−/− mice received local heart irradiation with a single dose of 0, 2, 8 or 16Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40weeks. Results: Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40weeks after 8 and 16Gy. Microvascular density decreased at both follow-up time-points after 8 and 16Gy. Remaining vessels had decreased alkaline phosphatase activity (2–16Gy) and increased von Willebrand Factor expression (16Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16Gy, with foam cell accumulations at 20weeks, and fibrosis and protein leakage at 40weeks. Despite an accelerated coronary atherosclerotic lesion development at 20weeks after 16Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20weeks. Conclusions: The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE−/− mice was maintained. [Copyright &y& Elsevier]

Abstract: Background: Radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiotoxicity, but the underlying mechanisms are unclear. Methods: Single doses of 2, 8, or 16Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60weeks, relative to age matched controls. Single photon emission computed tomography (SPECT/CT) and ultrasound were used to measure cardiac geometry and function, which was related to histo-morphology and microvascular damage. Results: Gated SPECT/CT and ultrasound demonstrated decreases in end diastolic and systolic volumes, while the ejection fraction was increased at 20 and 40weeks after 2, 8, and 16Gy. Cardiac blood volume was decreased at 20 and 60weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40weeks after 8 and 16Gy. Microvascular density in the left ventricle was decreased at 40 and 60weeks after 8 and 16Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16Gy), and amyloidosis (16Gy). 16Gy lead to sudden death between 30 and 40weeks in 38% of mice. Conclusions: Irradiation with 2 and 8Gy induced modest changes in murine cardiac function within 20weeks but this did not deteriorate further, despite progressive structural and microvascular damage. This indicates that heart function can compensate for significant structural damage, although higher doses, eventually lead to sudden death. [Copyright &y& Elsevier]

Objective: Functional studies show that disruption of endothelial surface layer (ESL) is accompanied by enhanced sensitivity of the vasculature towards atherogenic stimuli. However, relevance of ESL disruption as causal mechanism for vascular dysfunction remains to be demonstrated. We examined if loss of ESL through enzymatic degradation would affect vascular barrier properties in an atherogenic model. Methods: Eight week old male apolipoprotein E deficient mice on Western-type diet for 10 weeks received continuous active or heat-inactivated hyaluronidase (10 U/hr, i.v.) through an osmotic minipump during 4 weeks. Blood chemistry and anatomic changes in both macrovasculature and kidneys were examined. Results: Infusion with active hyaluronidase resulted in decreased ESL (0.32±0.22 mL) and plasma volume (1.03±0.18 mL) compared to inactivated hyaluronidase (0.52±0.29 mL and 1.28±0.08 mL, p<0.05 respectively).Active hyaluronidase increased proteinuria compared to inactive hyaluronidase (0.27±0.02 vs. 0.15±0.01 ¼g/¼g protein/creatinin, p<0.05) without changes in glomerular morphology or development of tubulo-interstitial inflammation. Atherosclerotic lesions in the aortic branches showed increased matrix production (collagen, 32±5 vs. 18±3%; glycosaminoglycans, 11±5 vs. 0.1±0.01%, active vs. inactive hyaluronidase, p<0.05). Conclusion: ESL degradation in apoE deficient mice contributes to reduced increased urinary protein excretion without significant changes in renal morphology. Second, the induction of compositional changes in atherogenic plaques by hyaluronidase point towards increased plaque vulnerability. These findings support further efforts to evaluate whether ESL restoration is a valuable target to prevent (micro) vascular disease progression. [ABSTRACT FROM AUTHOR]

Abstract: Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE−/− mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE−/− and catK−//−apoE−/− mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK−/−//apoE−/− versus apoE−/− mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE−/− mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK−/−//apoE−/− mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK−/−//apoE−/− compared to apoE−/− mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK−//−apoE−/− mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation. [Copyright &y& Elsevier]

Abstract: Background: Clinical presentation, maximal aortic diameter (Dmax), and growth rate are considered important clinical characteristics of the abdominal aortic aneurysm (AAA). Histologically, AAA is characterized by pathological changes of the media. In the present study, we investigated whether and how the histological features of AAA were related to clinical characteristics. Methods: Clinical characteristics and anterior aneurysm wall biopsies were collected prospectively. Histological characteristics were determined by immunohistochemistry and morphometric analysis. Results: Thirty-nine consecutive patients with elective or emergency aneurysm repair were included. AAA was located infra- or juxtarenal in 77% and 23%, respectively. Mean maximal aortic diameter was 67 mm with a mean growth rate of 6 mm/year. The histological features included a low elastin content, distorted elastin configuration, high collagen content, diminutive number of smooth muscle cells, and a high number of medial microvessels and inflammatory cells dominated by T cells. However, no intra- or interrelationship between histological and clinical characteristics was present. In particular, Dmax and clinical presentation were not related to media thickness or inflammatory cell count. Conclusions: We conclude that histologically AAA could not be classified in analogy to clinical characteristics. We suggest that progression of large AAA is mainly determined by parameters other than histological features of the diseased vessel wall. [Copyright &y& Elsevier]

One major intracellular signaling pathway involved in heart failure employs the phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T-cells (NFAT). In vivo evidence for the involvement of NFAT factors in heart failure development is still ill defined. Here we reveal that nfatc2 transcripts outnumber those from other nfat genes in the unstimulated heart by severalfold. Transgenic mice with activated calcineurin in the postnatal myocardium crossbred with nfatc2-null mice revealed a significant abrogation of calcineurin-provoked cardiac growth, indicating that NFATc2 plays an important role downstream of calcineurin and validates the original hypothesis that calcineurin mediates myocyte hypertrophy through activation of NFAT transcription factors. In the absence of NFATc2, a clear protection against the geometrical, functional, and molecular deterioration of the myocardium following biomechanical stress was also evident. In contrast, physiological cardiac enlargement in response to voluntary exercise training was not affected in nfatc2-null mice. Combined, these results reveal a major role for the NFATc2 transcription factor in pathological cardiac remodeling and heart failure. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis. Furthermore, cathepsins are involved in lipid metabolism. Cathepsins have the capability to degrade low-density lipoprotein and reduce cholesterol efflux from macrophages, aggravating foam cell formation. Although expression studies also demonstrated differential expression of cathepsins in cardiovascular diseases like aneurysm formation, neointima formation, and neovascularization, in vivo studies to define the exact role of cathepsins in these processes are lacking. Evaluation of the feasibility of cathepsins as a diagnostic tool revealed .that serum levels of cathepsins L and S seem to be promising as biomarkers in the diagnosis of atherosclerosis, whereas cathepsin B shows potential as an imaging tool. Furthermore, cathepsin K and S inhibitors showed effectiveness in (pre) clinical evaluation for the treatment of osteoporosis and osteoarthritis, suggesting that cathepsin inhibitors may also have therapeutic effects for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Mice are increasingly used to study the early molecular mechanisms inducing injury to the heart following myocardial infarction. To date, two-dimensional gel electrophoresis combined with mass spectrometry has not been applied to identify changes in protein expression in myocardial tissue of mice subjected in vivo to permanent ischaemia (PI) or ischaemia–reperfusion (IR). In the PI group, ischaemia was induced for 210 min by ligation of the left anterior descending coronary artery while in the IR group, ischaemia was maintained for 30 min and reperfusion was allowed for 180 min. In both groups, the area of the left ventricle at risk was processed for 2-dimensional gel electrophoresis. By comparing protein density changes in cytosolic as well as membrane fractions, we found a total of 32 protein spots that were differentially expressed. Twenty spots changed in expression level after PI alone, four spots after IR alone, and eight spots changed in both models. Identified proteins with MALDI TOF-TOF and LC-MS/MS can be classified into functional groups of anticoagulant proteins, structural proteins, inflammatory-related proteins, transcription- and translation-related proteins, heat shock proteins (HSPs), metabolism-related proteins and miscellaneous. A remarkable finding was the IR-specific translocation of annexins (A3 and A5) from the cytosolic to the membrane compartment, a phenomenon that was verified by Western blotting. Four proteins were changed in expression level at multiple spot locations, characterized by a difference in isoelectric point. In the case of cardiac troponin T and HSP-20, these changes were also dependent on the model. In addition, one spot for the proteins adenylate kinase 1, cardiac troponin T and HSP-20 was uniquely present in the IR and/or PI groups and not in the respective sham groups. The specific alterations in protein expression that took place after PI and IR may stimulate the search for new tools to diagnoze myocardial infarction and to characterize specific pathology-related changes in protein expression. [ABSTRACT FROM AUTHOR]