Robust, defensible, and fair: The AMEE guide to selection into medical school: AMEE Guide No. 153.

Selection is the first assessment of medical education and training. Medical schools must select from a pool of academically successful applicants and ensure that the way in which they choose future clinicians is robust, defensible, fair to all who apply and cost-effective. However, there is no comprehensive and evidence-informed guide to help those tasked with setting up or rejuvenating their local selection process. To address this gap, our guide draws on the latest research, international case studies and consideration of common dilemmas to provide practical guidance for designing, implementing and evaluating an effective medical school selection system. We draw on a model from the field of instructional design to frame the many different activities involved in doing so: the ADDIE model. ADDIE provides a systematic framework of Analysis (of the outcomes to be achieved by the selection process, and the barriers and facilitators to achieving these), Design (what tools and content are needed so the goals of selection are achieved), Development (what materials and resources are needed and available), Implementation (plan [including piloting], do study and adjust) and Evaluation (quality assurance is embedded throughout but the last step involves extensive evaluation of the entire process and its outcomes).HIGHLIGHTSRobust, defensible and fair selection into medical school is essential. This guide systematically covers the processes required to achieve this, from needs analysis through design, development and implementation, to evaluation of the success of a selection process.

Advancing quality culture in health professions education: experiences and perspectives of educational leaders.

The concept of quality culture has gained increased attention in health professions education, drawing on insights that quality management processes and positive work-related attitudes of staff in synergy lead to continuous improvement. However, the directions that guide institutions from quality culture theory to educational practice have been missing so far. A prospective qualitative case study of three health professions education programmes was conducted to explore how a quality culture can be enhanced according to the experiences and perspectives of educational leaders. The data collection was structured by an appreciative inquiry approach, supported with vignette-based interviews. A total of 25 participants (a selection of course coordinators, bachelor coordinators and directors of education) reflected on quality culture themes to learn about the best of what is (Discover), envision positive future developments (Dream), identify actions to reach the desired future (Design), and determine how to support and sustain improvement actions (Destiny) within their own educational setting. The results are presented as themes subsumed under these four phases. The experiences and perspectives of educational leaders reveal that peer learning in teams and communities, attention to professional development, and embedding support- and innovation networks, are at the heart of quality culture enhancement. An emphasis on human resources, (inter)relations and contextual awareness of leaders stood out as quality culture catalysts. Educational leaders are therefore encouraged to especially fuel their networking, communication, coalition building, and reflection competencies.

Leucocyte and platelet adhesion in different layers of the small bowel during experimental total warm ischaemia and reperfusion.

BACKGROUND: Ischaemia and reperfusion (IR) of the small bowel is involved in many clinical conditions. A key component in IR-induced tissue damage is microvascular dysfunction. The aim was to investigate the role of leucocytes and platelets in capillary flow impediment and tissue damage. METHODS: Anaesthetized rats were subjected to 30 min warm ischaemia of the small bowel, followed by 1 h reperfusion. To elucidate the influence of leucocytes on platelet adhesion, leucocyte-vessel wall interactions induced by IR were prevented by anti-platelet activating factor (PAF) or anti-intercellular adhesion molecule (ICAM)-1. Intravital videomicroscopy was performed and tissue injury was evaluated histologically. RESULTS: In submucosal venules, IR induced an increase in the median number of interacting leucocytes from 3 to 10 and 20 leucocytes per 100-microm venule segment after 10 and 60 min reperfusion respectively. Anti-PAF or anti-ICAM-1 completely attenuated this increase, resulting in an eightfold improvement in submucosal capillary flow and reduced tissue injury. Shedding of villi no longer occurred. Platelet-vessel wall interactions occurred particularly in submucosal venules, but were not affected by anti-PAF or anti-ICAM-1. CONCLUSION: Small bowel IR initiated an inflammatory and thrombotic response in the submucosal layer only. Attenuation of leucocyte adhesion improved submucosal capillary perfusion, preventing shedding of mucosal villi.

Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production.

BACKGROUND: Nebivolol is a beta(1)-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production. METHODS AND RESULTS: Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca(2+) concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment. CONCLUSIONS: In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial beta(2)-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca(2+)](i) and endothelial NO synthase-dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.

Endogenous nitric oxide and prostaglandins synergistically counteract thromboembolism in arterioles but not in venules.

It has been shown that NO and prostacyclin (prostaglandin I(2)) from cultured endothelium synergistically inhibit blood platelet aggregation in vitro. However, it is unknown whether this synergism is also effective in the inhibition of thromboembolism in vivo and, if it is, whether it differs between vessel types. Therefore, the effect of endogenous NO and prostacyclin, in combination or alone, on thromboembolism was studied in an in vivo model. Thromboembolism was induced by micropipette puncture of rabbit mesenteric arterioles and venules (diameter 18 to 40 micrometer). In addition, the influence of wall shear rate was analyzed. In arterioles, the combined inhibition of NO synthase (N(G)-nitro-L-arginine [L-NA] 0.1 mmol/L; local superfusion) and of cyclooxygenase (aspirin [ASA] 100 mg/kg IV) resulted in a pronounced, significant prolongation of embolization duration (median >600 seconds) compared with control (median 153 seconds) or treatment with either L-NA (234 seconds) or ASA (314 seconds). This combined effect of L-NA+ASA was greater than the sum of the individual effects of L-NA and ASA. In contrast, in venules L-NA+ASA had no additional effect on embolization duration (209 seconds) compared with the effect of L-NA alone (230 seconds); ASA alone had no effect (122 seconds; control 72 seconds). Interestingly, only in the L-NA+ASA arterioles did embolization correlate positively with wall shear rate (r(s)=0.687; P=0.028). In conclusion, this study indicates that in arterioles, but not in venules, endogenous NO and prostaglandins synergistically counteract ongoing thromboembolism after vessel wall injury and that the combination of endogenous NO and prostaglandins appears to protect against enhancement of arteriolar thromboembolism by wall shear rate.

Different roles of prostaglandins in thromboembolic processes in arterioles and venules in vivo.

The involvement of prostaglandins in thromboembolic processes, as induced by wall puncture, was studied in rabbit mesenteric arterioles and venules using intravital videomicroscopy. Inhibition of prostaglandin formation with aspirin (100 mg/kg, i.v.) significantly increased in arterioles duration of embolization (from 91 to 200 s) and number of emboli produced (from 4 to 8.5 per vessel), while rate of embolus production was not influenced. In venules, aspirin only influenced embolization rate (a significant decrease from one embolus/14 s to one/23 s). Specific blockade of TXA2-receptors by sulotroban (30 mg/kg, i.v.) only influenced the arteriolar reaction: it significantly decreased embolization duration (from 560 to 218 s) and number of emboli produced (from 23 to 10 emboli per vessel), without affecting embolization rate. These findings indicate that both platelet activating and inhibiting prostaglandins play a more important role in thromboembolism in arterioles than in venules; this suggests a difference in prostaglandin synthetic capacity between arteriolar and venular endothelium.

Thromboembolic reaction following wall puncture in arterioles and venules of the rabbit mesentery.

The walls of rabbit mesenteric arterioles and venules (diameter 20 to 40 microns) were punctured with glass micropipets (tip diameter 6 to 8 microns). Thromboembolic reactions resulting from this standardized, small mechanical vessel wall injury could be quantified in vivo with the use of intravital video-microscopy. Following induction of the injury thrombus growth started immediately (less than 0.1 s). Bleeding times were short, on the average less than 2 s, and did not differ between arterioles and venules. The duration of the embolization process was significantly longer in arterioles than in venules (median 101 and 17 s, respectively), and more emboli were produced in arterioles than in venules (median 6 and 1, respectively). Arteriolar thrombi were more effective in plugging the punctured holes than venular thrombi. The differences in thromboembolic reaction between arterioles and venules, as found in the present study, can probably not be explained by fluid dynamic factors.

The human internal thoracic artery releases more nitric oxide in response to vascular endothelial growth factor than the human saphenous vein.

OBJECTIVE: Endothelial nitric oxide inhibits smooth muscle cell proliferation, reducing the chance of vascular intimal thickening. In this study we investigated whether the superior long-term patency of the internal thoracic artery in human coronary bypass grafting compared with that of the saphenous vein could be explained by different levels of nitric oxide production. METHODS: The baseline endogenous nitric oxide production appeared to be 50% higher in the internal thoracic artery than in the saphenous vein. Previously, it was shown that vascular endothelial growth factor and the vascular endothelial growth factor receptors KDR (Flk-1) and Flt-1 are expressed in both internal thoracic arteries and saphenous veins and that vascular endothelial growth factor receptor density was higher in internal thoracic arteries than in saphenous veins. Therefore, we also investigated the influence of vascular endothelial growth factor on nitric oxide release in both the internal thoracic artery and the saphenous vein. RESULTS: Vascular endothelial growth factor augmented nitric oxide production by approximately 50% in the saphenous vein and 100% in the internal thoracic artery. As shown by means of immunohistochemistry, expression of endothelial constitutive nitric oxide synthase was similar in the internal thoracic artery and the saphenous vein, and no inducible nitric oxide synthase was expressed in any of the vascular segments. CONCLUSION: Vascular endothelial growth factor augments endothelial constitutive nitric oxide synthase-dependent nitric oxide release to a greater extent in the internal thoracic artery than in the saphenous vein. These findings may help to explain the long-term superiority of the internal thoracic artery versus the saphenous vein as a conduit for coronary artery bypass.

Influence of hypercapnia and hypoxia on rabbit platelet aggregation.

The influence of changes in pCO2, pH and pO2 on the aggregation of rabbit blood platelets was studied in vitro, with emphasis on hypercapnia, acidosis and hypoxia. Hypercapnia combined with acidosis caused a reduction in rabbit platelet aggregation, as induced by collagen, thrombin and ADP; the effect being most pronounced with collagen and smallest with ADP. Hypoxia reduced thrombin induced platelet aggregation, but had no effect on ADP and collagen induced aggregation. Synergistic activation of rabbit platelets, as induced by the addition of serotonin to platelet rich plasma together with collagen or ADP, seemed to be equally sensitive to changes in pCO2 and pH as activation by the individual agents, and insensitive to changes in pO2.

The influence of prostaglandins on leukocyte-endothelium interactions in rabbit mesenteric venules.

Contradictory results have been reported concerning the effects of prostaglandins (PGs) on leukocyte-endothelium interactions. Therefore, we investigated the in vivo effects of PGE1, PGE2, Iloprost (a stable PGI2-analogue), and also of a combination of these PGs on leukocyte rolling and FMLP-induced leukocyte adhesion in venules of rabbit mesentery. This preparation was used because of its low level of vasoactivity, eliminating hemodynamic effects on leukocyte-endothelium interactions. The mesentery was superfused with PGs or vehicle. After 30 min FMLP was added to the PG-solution for 15 min, whereupon the tissue was superfused with the PG-solution alone for another 30 min. Neither the PGs nor the cocktail influenced leukocyte rolling. During FMLP administration leukocyte adhesion increased and leukocyte rolling decreased; adhesion was highest in the presence of PGE2. The FMLP-induced decrease in leukocyte rolling was similar in all groups. After FMLP administration had been stopped the number of adherent cells almost returned to baseline and the level of leukocyte rolling increased, the baseline level being reached only in the presence of PGE2. In conclusion, these findings indicate that the effects of PGs on leukocyte-endothelium interactions are limited.

Effect of repetitive asphyxia on leukocyte-vessel wall interactions in the developing chick intestine.

BACKGROUND/PURPOSE: Information on leukocyte-vessel wall interactions (LVWI) during development of the immature intestine is scarce. The authors designed an experimental model for studying the microcirculation in the developing intestine of chick fetuses at days 13 (n = 12), 15 (n = 17), and 17 (n = 19) of incubation (0.6, 0.7, and 0.8 of the incubation time, respectively) using intravital microscopy. METHODS: The authors investigated whether episodes of asphyxia increase LVWI and induce tissue damage in the developing intestine. Asphyxia was induced by clamping of the chorioallantoic vein for 6 periods of 5 minutes each, with 5-minute intervals, whereas in sham groups a sham procedure was performed. Video recordings were made before as well as 10, 20, and 30 minutes after the end of the asphyxia or sham protocol. RESULTS: Baseline number of rolling leukocytes per minute significantly increased (P < .001) from 0 at 0.6 incubation to 1.5 and to 4 at 0.7 and 0.8 incubation time, respectively. At 0.6 and 0.7 incubation no adherent leukocytes were observed under baseline conditions, whereas at 0.8 incubation single leukocytes adhered to the venular wall. LVWI variably increased during the course of the experiments. Asphyxia neither enhanced LVWI nor induced histological damage in the intestine. CONCLUSIONS: These findings indicate that (1) leukocyte-vessel wall interactions mature during fetal development, and (2) repetitive episodes of asphyxia induce neither an inflammatory response nor histological tissue injury in the developing intestine from 0.6 to 0.8 incubation. The authors hypothesize that immaturity of leukocyte-vessel wall interactions, as part of the nonspecific host defense to invading bacteria, might play a role in the development of necrotizing enterocolitis in premature neonates.

Ischemia/reperfusion injury in rat mesenteric venules: red blood cell velocity and leukocyte rolling.

The authors determined the effects of 15 (n = 9) and 30 (n = 12) minutes of warm ischemia on the rat mesentery and compared the results with those of a sham-operated group (n = 10). Red blood cell velocity and number of rolling leukocytes were assessed before ischemia as well as 10, 20, 30, 60, 90, and 120 minutes after the start of reperfusion. Leukocyte rolling is considered to be an early step of the inflammatory process. Leukocytes roll along the vessel wall at a velocity that is clearly lower than that of the other blood cells. The preischemic values of red blood cell velocity and number of rolling leukocytes in the 15- and 30-minute ischemia groups did not differ from those of the sham group. In the sham group, no significant changes in red blood cell velocity and number of rolling leukocytes were observed over time. Compared with the sham group, the red blood cell velocity of the 15-minute ischemia group was significantly lower at 30, 60, 90, and 120 minutes after the start of reperfusion the number of rolling leukocytes did not differ significantly. For the 30-minute ischemia group, red blood cell velocity also was significantly lower at 20, 30, 60, 90, and 120 minutes after the start of reperfusion, and the number of rolling leukocytes was higher at 10, 20, and 30 minutes after the start of reperfusion. The results of this study indicate that short periods of total warm ischemia of the rat small bowel and subsequent reperfusion result in a significantly impaired microcirculatory blood flow in the mesentery. However, a prolonged period of ischemia is required to increase leukocyte-vessel wall interactions. In the future, this model will enable us to study the effect of pharmacological interventions during an early stage of the inflammatory response to ischemia/reperfusion in the gut.

Capillaries and flow redistribution play an important role in muscle blood flow reserve capacity.

Perfusion of skeletal muscle varies considerably during rest, exercise, or when arteries are occluded. The extent that a muscle can adapt to changes in flow demand is often expressed as the ratio of the highest inducible flow and control flow, the microvascular blood flow reserve capacity (MBFRC). However, perfusion of the nutritive capillaries of skeletal muscle may not only be improved by the increase in blood flow proportional to the increase in arterial flow, but also by diverting originally shunted flow towards the muscle proper. Consequently, MBFRC is not a good measure of capillary flow reserve, unless the assessed flow in both conditions is purely nutritive in nature. Therefore, in critical conditions, flow measurements in large vessels are not appropriate to assess MBFRC. In muscle, capillaries are compliant, i.e., with varying transmural pressure capillary diameter varies. During high perfusion states, when capillary transmural pressure is increased, capillary compliance results in increased capillary diameter and, hence, in reduced resistance and increased exchange surface area. This results in improved perfusion and enlarged capillary exchange surface area. In low perfusion states, capillary diameter is reduced. This augments the detrimental effects of the low perfusion status. Operative restoration of perfusion pressure not only increases the driving force for perfusion, but also leads to (passive) dilatation of the capillary bed and an extra reduction in resistance to flow, and, hence, a disproportional increase in flow.

Endothelial glycocalyx thickness and platelet-vessel wall interactions during atherogenesis.

The endothelial glycocalyx (EG), the luminal cover of endothelial cells, is considered to be atheroprotective. During atherogenesis, platelets adhere to the vessel wall, possibly triggered by simultaneous EG modulation. It was the objective of this study to investigate both EG thickness and platelet-vessel wall interactions during atherogenesis in the same experimental model. Intravital fluorescence microscopy was used to study platelet-vessel wall interactions in vivo in common carotid arteries and bifurcations of C57bl6/J (B6) and apolipoprotein E knock-out (ApoE-/-) mice (age 7 - 31 weeks). At the same locations, EG thickness was determined ex vivo using two-photon laser scanning microscopy. In ApoE-/- bifurcations the overall median level of adhesion was 48 platelets/mm2 (interquartile range: 16 - 80), which was significantly higher than in B6 bifurcations (0 (0 - 16), p = 0.001). This difference appeared to result from a significant age-dependent increase in ApoE-/- mice, while no such change was observed in B6 mice. At the same time, the EG in ApoE-/- bifurcations was significantly thinner than in B6 bifurcations (2.2 vs. 2.5 µm, respectively; p < 0.05). This resulted from the fact that in B6 bifurcations EG thickness increased with age (from 2.4 µm in young mice to 3.0 µm in aged ones), while in bifurcations of ApoE-/- mice this growth appeared to be absent (2.2 µm at all ages). During atherogenesis, platelet adhesion to the wall of the carotid artery bifurcation increases significantly. At the same location, EG growth with age is hampered. Therefore, glycocalyx-reinforcing strategies could possibly ameliorate atherosclerosis.

Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model.

BACKGROUND: Atherothrombosis is a major cause of cardiovascular events. However, animal models to study this process are scarce. OBJECTIVES: We describe the first murine model of acute thrombus formation upon plaque rupture to study atherothrombosis by intravital fluorescence microscopy. METHODS: Localized rupture of an atherosclerotic plaque in a carotid artery from Apoe(-/-) mice was induced in vivo using ultrasound. Rupture of the plaque and formation of localized thrombi were verified by two-photon laser scanning microscopy (TPLSM) in isolated arteries, and by immunohistochemistry. The thrombotic reaction was quantified by intravital fluorescence microscopy. RESULTS: Inspection of the ultrasound-treated plaques by histochemistry and TPLSM demonstrated local damage, collagen exposure, luminal thrombus formation as well as intra-plaque intrusion of erythrocytes and fibrin. Ultrasound treatment of healthy carotid arteries resulted in endothelial damage and limited platelet adhesion. Real-time intravital fluorescence microscopy demonstrated rapid platelet deposition on plaques and formation of a single thrombus that remained subocclusive. The thrombotic process was antagonized by thrombin inhibition, or by blocking of collagen or adenosine diphosphate receptor pathways. Multiple thrombi were formed in 70% of mice lacking CD40L. CONCLUSIONS: Targeted rupture of murine plaques results in collagen exposure and non-occlusive thrombus formation. The thrombotic process relies on platelet activation as well as on thrombin generation and coagulation, and is sensitive to established and novel antithrombotic medication. This model provides new possibilities to study atherothrombosis in vivo.

Two-photon microscopy of vital murine elastic and muscular arteries. Combined structural and functional imaging with subcellular resolution.

Understanding vascular pathologies requires insight in the structure and function, and, hence, an imaging technique combining subcellular resolution, large penetration depth, and optical sectioning. We evaluated the applicability of two-photon laser-scanning microscopy (TPLSM) in large elastic and small muscular arteries under physiological conditions. Elastic (carotid) and muscular (uterine, mesenteric) arteries of C57BL/6 mice were mounted in a perfusion chamber. TPLSM was used to assess the viability of arteries and to visualize the structural components elastin, collagen, nuclei, and endothelial glycocalyx (EG). Functionality was determined using diameter changes in response to noradrenaline and acetylcholine. Viability and functionality were maintained up to 4 h, enabling the assessment of structure-function relationships. Structural vessel wall components differed between elastic and muscular arteries: size (1.3 vs. 2.1 microm) and density (0.045 vs. 0.57 microm(-2)) of internal elastic lamina fenestrae, smooth muscle cell density (3.50 vs. 1.53 microm(-3)), number of elastic laminae (3 vs. 2), and adventitial collagen structure (tortuous vs. straight). EG in elastic arteries was 4.5 microm thick, covering 66% of the endothelial surface. TPLSM enables visualization and quantification of subcellular structures in vital and functional elastic and muscular murine arteries, allowing unraveling of structure-function relationships in healthy and diseased arteries.

Pain relief in complex regional pain syndrome due to spinal cord stimulation does not depend on vasodilation.

BACKGROUND: Spinal cord stimulation (SCS) is known to relieve pain in patients with complex regional pain syndrome (CRPS) and, in general, to cause vasodilation. The vasodilatory effect of SCS is hypothesized to be secondary to inhibition of sympathetically mediated vasoconstriction, or through antidromic impulses resulting in release of vasoactive substances. The aim of the present study was to assess whether pain relief in CRPS after SCS is, in fact, dependent on vasodilation. In addition, we tried to determine which of the potential mechanisms may cause the vasodilatory effect that is generally found after SCS. METHODS: Twenty-four of 36 patients with unilateral CRPS responded to the test of SCS. Twenty-two of these 24 responders (hand, n = 14; foot, n = 8) who had undergone previous sympathectomy were enrolled for the study. In addition, 20 control subjects (10 controls for each extremity) were studied. By means of laser Doppler flowmetry, the skin microcirculation of the patients was measured bilaterally while the SCS system was switched off and while it was activated. Control subjects (n = 20) were tested once only. The ratio of the rest flow at heart level and the dependent position was defined as the vasoconstriction index. RESULTS: Both in affected hands and feet, patients were found to have lower vasoconstriction indices (P < 0.01) as compared with controls, indicating a decreased sympathetic tone. Applying SCS did not result in any microcirculatory change as compared with baseline or the contralateral clinically unaffected side. CONCLUSIONS: The current study failed to show that SCS influences skin microcirculation in patients with CRPS and a low sympathetic tone. Therefore, we may conclude that pain relief in CRPS due to SCS is possible without vasodilation. Because sympathetic activity was greatly decreased in our patients, these results support the hypothesis that the vasodilation that is normally found with SCS is due to an inhibitory effect on sympathetically maintained vasoconstriction.

Fluid dynamics and the thromboembolic reaction in mesenteric arterioles and venules.

In the mesentery of the anesthetized rabbit, the thromboembolic reaction after wall puncture lasts six times longer in arterioles than in venules, a difference that cannot be explained by fluid dynamic conditions before puncture. In the present study, it was investigated whether this difference in response between arterioles and venules results from a different degree of stenosis by the thrombus and/or a difference in velocity changes resulting in a different pressure drop over the thrombus. Arteriolar and venular mean red blood cell velocity and vessel diameter were measured before puncture and after this injury in the stenosed vessel segment and upstream. Thrombi with similar heights were formed in arterioles and venules and induced similar degrees of stenosis. A surface area reduction less than 55% induced only a small and similar decrease in volume flow (less than 10%) in arterioles and venules. Reduced velocity, a measure of wall shear rate, increased similarly in both vessel types for similar degrees of stenosis. In conclusion, changes in fluid dynamic factors, as induced by thrombus formation, cannot be held responsible for the difference in thromboembolic reaction between arterioles and venules.