International online mentorship for translational researchers.

BACKGROUND: Translational researchers (TRs) fulfill various roles across clinical, educational, and research domains with the ultimate goal of positively impacting patients. Mentorship has been recognized as an important means of career support for TRs, particularly when navigating the complex translational research pipeline and adapting to evolving roles. In response, the Erasmus + PATHWAY project developed and piloted an extra-curricular online preparatory course and mentorship program in 2019 and 2020 to help TRs build mentorship skills, develop their careers, and create online peer-to-peer learning opportunities. METHODS: To assess the pilot online mentorship program, a longitudinal exploratory mixed method study was conducted. RESULTS: Mentees and mentors from both years reported that they joined the program to learn mentorship skills, gain career support, and expand their (international) network. Analysis of evaluation forms indicated that the online preparatory course was evaluated largely positively, with participants suggesting improvements for future iterations. Results of a follow-up survey in 2022 revealed that mentorship was considered helpful in supporting TRs' work in translational research, and an online mentorship program was useful, provided it included interactive online training, multiple mentee-mentor matching rounds, compatible time zones and professional experience for matched pairs, active program moderation with offline activities, and effective online tools. CONCLUSIONS: This study revealed the mentorship needs of TRs and their recommendations for international online mentorship. The innovative PATHWAY program's online format, mentee-driven matching, and preparatory training for both mentees and mentors contribute to the development of mentorship for the general translational community that could potentially have broader applications, especially in a post-COVID-19 environment.

One size does not fit all: an exploratory interview study on how translational researchers navigate the current academic reward system.

Introduction: Translational research is a subfield of the biomedical life sciences that focuses on clinically driven healthcare innovations. The workforce of this subfield, i.e., translational researchers, are diversely specialized and collaborate with a multitude of stakeholders from diverse disciplines in and outside academia in order to navigate the complex path of translating unmet clinical needs into research questions and ultimately into advancements for patient care. Translational researchers have varying responsibilities in the clinical, educational, and research domains requiring them to split their time two- or three-ways. Working between these domains and alongside peers who do not split their time as such, raises questions about the academic reward system used to recognize their performance, which mainly focuses on publication metrics within the research domain. What is unclear is how combining research tasks with tasks in the clinical and/or educational domains effects translational researchers and how they navigate the academic reward system. Methods: In this exploratory interview study, semi-structured interviews were conducted to gain a deeper understanding of the current academic reward system for translational researchers. Stratified purposeful sampling was used to recruit 14 translational researchers from varying countries, subspecialties, and career stages. The interviews were coded after data collection was complete and arranged into three overarching result categories: intrinsic motivation, extrinsic factors, and ideal academic reward system and advice. Results: We found that these 14 translational researchers were intrinsically motivated to achieve their translational goals while working in settings where clinical work was reported to take priority over teaching which in turn took priority over time for research. However, it is the latter that was explained to be essential in the academic reward system which currently measures scientific impact largely based on publications metrics. Conclusion: In this study, translational researchers were asked about their thoughts regarding the current academic reward system. Participants shared possible structural improvements and ideas for specialized support on an individual, institutional, and also international level. Their recommendations focused on acknowledging all aspects of their work and led to the conclusion that traditional quantitative academic reward metrics do not fully align with their translational goals.

Ten caveats of learning analytics in health professions education: A consumer's perspective.

A group of 22 medical educators from different European countries, gathered in a meeting in Utrecht in July 2019, discussed the topic of learning analytics (LA) in an open conversation and addressed its definition, its purposes and potential risks for learners and teachers. LA was seen as a significant advance with important potential to improve education, but the group felt that potential drawbacks of using LA may yet be under-exposed in the literature. After transcription and interpretation of the discussion's conclusions, a document was drafted and fed back to the group in two rounds to arrive at a series of 10 caveats educators should be aware of when developing and using LA, including too much standardized learning, with undue consequences of over-efficiency and pressure on learners and teachers, and a decrease of the variety of 'valid' learning resources. Learning analytics may misalign with eventual clinical performance and can run the risk of privacy breaches and inescapability of documented failures. These consequences may not happen, but the authors, on behalf of the full group of educators, felt it worth to signal these caveats from a consumers' perspective.

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.

Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.

A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy.

Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy. Methods and results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation-negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation. Conclusion: This study provides the first evidence for a modulatory effect of co-existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals.

Students generate items for an online formative assessment: Is it motivating?

BACKGROUND: A reported problem with e-learning is sustaining students' motivation. We propose a framework explaining to what extent an e-learning task is motivating. This framework includes students' perceived Value of the task, Competence in executing the task, Autonomy over how to carry out the task, and Relatedness. METHODS: To test this framework, students generated items in an online environment and answered questions developed by their fellow students. Motivation was measured by analyzing engagement with the task, with an open-ended questionnaire about engagement, and with the motivated strategies for learning questionnaire (MSLQ). RESULTS: Students developed 59 questions and answered 1776 times on the questions. Differences between students who did or did not engage in the task are explained by the degree of self-regulation, time management, and effort regulation students report. There was a significant relationship between student engagement and achievement after controlling for previous academic achievement. CONCLUSIONS: This study proposes a way of explaining the motivational value of an e-learning task by looking at students' perceived competence, autonomy, value of the task, and relatedness. Student-generated items are considered of high task value, and help to perceive relatedness between students. With the right instruction, students feel competent to engage in the task.

At the cross-point of connexins, calcium, and ATP: blocking hemichannels inhibits vasoconstriction of rat small mesenteric arteries.

AIMS: Connexins form gap-junctions (GJs) that directly connect cells, thereby coordinating vascular cell function and controlling vessel diameter and blood flow. GJs are composed of two hemichannels contributed by each of the connecting cells. Hemichannels also exist as non-junctional channels that, when open, lead to the entry/loss of ions and the escape of ATP. Here we investigated cross-talk between hemichannels and Ca2+/purinergic signalling in controlling blood vessel contraction. We hypothesized that hemichannel Ca2+ entry and ATP release contributes to smooth muscle cell (SMC) Ca2+ dynamics, thereby influencing vessel contractility. We applied several peptide modulators of hemichannel function and inhibitors of Ca2+ and ATP signalling to investigate their influence on SMC Ca2+ dynamics and vessel contractility. METHODS AND RESULTS: Confocal Ca2+ imaging studies on small mesenteric arteries (SMAs) from rat demonstrated that norepinephrine-induced SMC Ca2+ oscillations were inhibited by blocking IP3 receptors with xestospongin-C and by interfering with hemichannel function, most notably by the specific Cx43 hemichannel blocking peptide TAT-L2 and by TAT-CT9 that promotes Cx43 hemichannel opening. Evidence for hemichannel involvement in SMC function was supported by the fact that TAT-CT9 significantly increased SMC resting cytoplasmic Ca2+ concentration, indicating it facilitated Ca2+ entry, and by the observation that norepinephrine-triggered vessel ATP release was blocked by TAT-L2. Myograph tension measurements on isolated SMAs showed significant inhibition of norepinephrine-triggered contractility by the ATP receptor antagonist suramin, but the strongest effect was observed with TAT-L2 that gave ∼80% inhibition at 37 °C. TAT-L2 inhibition of vessel contraction was significantly reduced in conditional Cx43 knockout animals, indicating the effect was Cx43 hemichannel-dependent. Computational modelling suggested these results could be explained by the opening of a single hemichannel per SMC. CONCLUSIONS: These results indicate that Cx43 hemichannels contribute to SMC Ca2+ dynamics and contractility, by facilitating Ca2+ entry, ATP release, and purinergic signalling.

Peer-instructed seminar attendance is associated with improved preparation, deeper learning and higher exam scores: a survey study.

BACKGROUND: Active engagement in education improves learning outcomes. To enhance active participation in seminars, a student-centered course design was implemented and evaluated in terms of self-reported preparation, student motivation and exam scores. We hypothesized that small group learning with intensive peer interaction, using buzz-groups followed by plenary discussion, would motivate students to prepare seminar assignments at home and to actively engage in the seminars. Active engagement involved discussion of the preparatory assignments until consensus was reached. METHODS: In total seven seminars were scheduled in a 10-week physiology course of an undergraduate Biomedical Sciences program. After each seminar, students were asked to fill out their perceptions of preparation and quality of the seminar (deepening of knowledge and confidence in answers) on a five-point scale using electronic questionnaires. Student motives were first collected using open questions. In the final questionnaire students were asked to indicate on a five-point scale how each motive was perceived. Students overall explanations why they had learned from seminars were collected via open questions in the final questionnaire. One hundred and twenty-four students of the cohort from November 2012 to February 2013 (82.6 %) voluntarily participated. Students' motives to prepare and attend seminars were analyzed by inspection of descriptive statistics. Linear regression analysis was conducted to relate student preparation to the quality of seminars, seminar attendance to exam scores, and exam scores to the quality of seminars. Answers to open questions were deductively clustered. RESULTS: Studying the material, training for exams and comparing answers with peers motivated students to prepare the seminars. Students were motivated to participate actively because they wanted to keep track of correct answers themselves, to better understand the content and to be able to present their findings in plenary discussions. Perceived preparation of peers was positively associated with the perceived quality of seminars. Also, seminar attendance was positively associated with exam scores. Students' overall explanations suggest that discussing with peers and applying knowledge in pathophysiology cases underlies this association. CONCLUSION: Discussion with well-prepared peers during seminars improves student perceptions of deeper learning and peer-instructed seminar attendance was associated with higher exam scores.

Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent.

AIM: In healthy hearts, ventricular gap junctions are mainly composed by connexin43 (Cx43) and localize in the intercalated disc, enabling appropriate electrical coupling. In diseased hearts, Cx43 is heterogeneously down-regulated, whereas activity of calmodulin/calcium-calmodulin protein kinase II (CaM/CaMKII) signalling increases. It is unclear if CaM/CaMKII affects Cx43 expression/localization or impulse propagation. We analysed different models to assess this. METHODS AND RESULTS: AC3-I mice with CaMKII genetically inhibited were subjected to pressure overload (16 weeks, TAC vs. sham). Optical and epicardial mapping was performed on Langendorff-perfused rabbit and AC3-I hearts, respectively. Cx43 subcellular distribution from rabbit/mouse ventricles was evaluated by immunoblot after Triton X-100-based fractionation. In mice with constitutively reduced CaMKII activity (AC3-I), conduction velocity (CV) was augmented (n = 11, P < 0.01 vs. WT); in AC3-I, CV was preserved after TAC, in contrast to a reduction seen in TAC-WT mice (-20%). Cx43 expression was preserved after TAC in AC3-I mice, though arrhythmias and fibrosis were still present. In rabbits, W7 (CaM inhibitor, 10 µM) increased CV (6-13%, n= 6, P< 0.05), while susceptibility to arrhythmias decreased. Immunoconfocal microscopy revealed enlarged Cx43 cluster sizes at intercalated discs of those hearts. Total Cx43 did not change by W7 (n= 4), whereas Triton X-100 insoluble Cx43 increased (+21%, n= 4, P< 0.01). Similar findings were obtained in AC3-I mouse hearts when compared with control, and in cultured dog cardiomyocytes. Functional implication was shown through increased intercellular coupling in cultured neonatal rat cardiomyocytes. CONCLUSION: Both acute and chronic CaM/CaMKII inhibition improves conduction characteristics and enhances localization of Cx43 in the intercalated disc. In the absence of fibrosis, this reduced the susceptibility for arrhythmias.

Beat-to-Beat Variability in Preload Unmasks Latent Risk of Torsade de Pointes in Anesthetized Chronic Atrioventricular Block Dogs.

BACKGROUND: Beat-to-beat variability in ventricular repolarization (BVR) associates with increased arrhythmic risk. Proarrhythmic remodeling in the dog with chronic AV-block (CAVB) compromises repolarization reserve and associates with increased BVR, which further increases upon dofetilide infusion and correlates with Torsade de Pointes (TdP) arrhythmias. It was hypothesized that these pro-arrhythmia-associated increases in BVR are induced by beat-to-beat variability in preload. METHODS AND RESULTS: Left ventricular monophasic action potential duration (LVMAPD) was recorded in acute (AAVB) and CAVB dogs, before and after dofetilide infusion. BVR was quantified as short-term variability of LVMAPD. The PQ-interval was controlled by pacing: either a constant or an alternating preload pattern was established, verified by PV-loop. The effect of the stretch-activated channel blocker, streptomycin, on BVR was evaluated in a second CAVB group. At alternating preload only, BVR was increased after proarrhythmic remodeling (0.45±0.14 ms AAVB vs. 2.2±1.1 ms CAVB, P<0.01). At CAVB, but not at AAVB, dofetilide induced significant proarrhythmia. Preload variability augmented the dofetilide-induced BVR increase at CAVB (+1.5±0.8 ms vs. +0.9±0.9 ms, P=0.058). In the second group, the increase in baseline BVR by alternating preload (0.3±0.03 ms to 1.0±0.8 ms, P<0.01) was abolished by streptomycin (0.5±0.2 ms, P<0.05). CONCLUSIONS: In CAVB dogs, the inverse relation between BVR and repolarization reserve originates from an augmented sensitivity of ventricular repolarization to beat-to-beat preload changes. Stretch-activated channels appear to be involved in the mechanism of BVR. (Circ J 2016; 80: 1336-1345).

Spatial Heterogeneity of Cx43 is an Arrhythmogenic Substrate of Polymorphic Ventricular Tachycardias during Compensated Cardiac Hypertrophy in Rats.

BACKGROUND: Ventricular remodeling increases the propensity of ventricular tachyarrhythmias and sudden death in patients. We studied the mechanism underlying these fatal arrhythmias, electrical and structural cardiac remodeling, as well as arrhythmogeneity during early, compensated hypertrophy in a rat model of chronic pressure overload. METHODS: Twenty-six Wistar rats were subjected to transverse aortic constriction (TAC) (n = 13) or sham operation (n = 13). Four weeks postoperative, echo- and electrocardiography was performed. Epicardial (208 or 455 sites) and transmural (30 sites) ventricular activation mapping was performed on Langendorff perfused hearts. Subsequently, hearts were processed for (immuno)histological and molecular analyses. RESULTS: TAC rats showed significant hypertrophy with preserved left ventricular (LV) function. Epicardial conduction velocity (CV) was similar, but more dispersed in TAC. Transmural CV was slowed in TAC (37.6 ± 2.9 cm s(-1)) compared to sham (58.5 ± 3.9 cm s(-1); P < 0.01). Sustained polymorphic ventricular tachycardias were induced from LV in 8/13 TAC and in 0/13 sham rats. During VT, electrical activation patterns showed variable sites of earliest epicardial activation and altering sites of functional conduction block. Wandering epicardial reentrant activation was sporadically observed. Collagen deposition was significantly higher in TAC compared to sham, but not different between arrhythmogenic and non-arrhythmogenic TAC animals. Connexin43 (Cx43) expression was heterogeneous with a higher prevalence of non-phosphorylated Cx43 in arrhythmogenic TAC animals. CONCLUSION: In TAC rats with compensated cardiac hypertrophy, dispersion of conduction correlated to arrhythmogenesis, an increased heterogeneity of Cx43, and a partial substitution with non-phosphorylated Cx43. These alterations may result in the increased vulnerability to polymorphic VTs.

CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload.

BACKGROUND: One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. However, recent studies have questioned the role of CTGF as a pro-fibrotic factor. Therefore, we aimed to investigate the effect of CTGF on cardiac fibrosis, and on functional, structural, and electrophysiological parameters in a mouse model of CTGF knockout (KO) and chronic pressure overload. METHODS AND RESULTS: A new mouse model of global conditional CTGF KO induced by tamoxifen-driven deletion of CTGF, was subjected to 16weeks of chronic pressure overload via transverse aortic constriction (TAC, control was sham surgery). CTGF KO TAC mice presented with hypertrophic hearts, and echocardiography revealed a decrease in contractility on a similar level as control TAC mice. Ex vivo epicardial mapping showed a low incidence of pacing-induced ventricular arrhythmias (2/12 in control TAC vs. 0/10 in CTGF KO TAC, n.s.) and a tendency towards recovery of the longitudinal conduction velocity of CTGF KO TAC hearts. Picrosirius Red staining on these hearts unveiled increased fibrosis at a similar level as control TAC hearts. Furthermore, genes related to fibrogenesis were also similarly upregulated in both TAC groups. Histological analysis revealed an increase in fibronectin and vimentin protein expression, a significant reduction in connexin43 (Cx43) protein expression, and no difference in NaV1.5 expression of CTGF KO ventricles as compared with sham treated animals. CONCLUSION: Conditional CTGF inhibition failed to prevent TAC-induced cardiac fibrosis and hypertrophy. Additionally, no large differences were found in other parameters between CTGF KO and control TAC mice. With no profound effect of CTGF on fibrosis formation, other factors or pathways are likely responsible for fibrosis development.

Arrhythmogenic Remodeling in Murine Models of Deoxycorticosterone Acetate-Salt-Induced and 5/6-Subtotal Nephrectomy-Salt-Induced Cardiorenal Disease.

BACKGROUND: Renal failure is associated with adverse cardiac remodeling and sudden cardiac death. The mechanism leading to enhanced arrhythmogenicity in the cardiorenal syndrome is unclear. The aim of this study was to characterize electrophysiological and tissue alterations correlated with enhanced arrhythmogenicity in two distinct mouse models of renal failure. METHODS: Thirty-week-old 129Sv mice received a high-salt diet and deoxycorticosterone acetate (DOCA) for 8 weeks, followed by an additional period of high-salt diet for 27 weeks (DOCA-salt aged model). Adult CD-1 mice were submitted to 5/6-subtotal nephrectomy (SNx) and treated for 11 weeks with a high-salt diet (SNx-salt adult model). Vulnerability to arrhythmia as well as conduction velocities (CVs) of the hearts were determined ex vivo with epicardial mapping. Subsequently, the hearts were characterized for connexin 43 (Cx43) and fibrosis. RESULTS: DOCA-salt and SNx-salt mice developed renal dysfunction characterized by albuminuria. Heart, lung and kidney weights were increased in DOCA-salt mice. Both DOCA-salt and SNx-salt mice were highly susceptible to ventricular arrhythmias. DOCA-salt mice had a significant decrease in both longitudinal and transversal CV in the left ventricle. Histological analysis revealed a significant reduction in Cx43 expression as well as an increase in interstitial fibrosis in both DOCA-salt and SNx-salt mice. CONCLUSION: DOCA-salt and SNx-salt treatment induced renal dysfunction, which resulted in structural and electrical cardiac remodeling and enhanced arrhythmogenicity. The reduced Cx43 expression and increased fibrosis levels in these hearts are likely candidates for the formation of the arrhythmogenic substrate.

Ex vivo and in vivo administration of fluorescent CNA35 specifically marks cardiac fibrosis.

Cardiac fibrosis is a major hallmark of cardiac diseases. For evaluation of cardiac fibrosis, the development of highly specific and preferably noninvasive methods is desired. Our aim was to evaluate CNA35, a protein known to specifically bind to collagen, as a specific marker of cardiac fibrosis. Fluorescently labeled CNA35 was applied ex vivo on tissue sections of fibrotic rat, mouse, and canine myocardium. After quantification of CNA35, sections were examined with picrosirius red (PSR) and compared to CNA35. Furthermore, fluorescently labeled CNA35 was administered in vivo in mice. Hearts were isolated, and CNA35 labeling was examined in tissue sections. Serial sections were histologically examined with PSR. Ex vivo application of CNA35 showed specific binding to collagen and a high correlation with PSR (Pearson r  =  .86 for mice/rats and r  =  .98 for canine; both p < .001). After in vivo administration, CNA35 labeling was observed around individual cardiomyocytes, indicating its ability to penetrate cardiac endothelium. High correlation was observed between CNA35 and PSR (r  =  .91, p < .001). CNA35 specifically binds to cardiac collagen and can cross the endothelial barrier. Therefore, labeled CNA35 is useful to specifically detect collagen both ex vivo and in vivo and potentially can be converted to a noninvasive method to detect cardiac fibrosis.

Changes in Cx43 and NaV1.5 expression precede the occurrence of substantial fibrosis in calcineurin-induced murine cardiac hypertrophy.

In mice, the calcium-dependent phosphatase calcineurin A (CnA) induces a transcriptional pathway leading to pathological cardiac hypertrophy. Interestingly, induction of CnA has been frequently noticed in human hypertrophic and failing hearts. Independently, the arrhythmia vulnerability of such hearts has been regularly associated with remodeling of parameters determining electrical conduction (expression level of connexin43 (Cx43) and NaV1.5, connective tissue architecture), for which the precise molecular basis and sequence of events is still unknown. Recently, we observed reduced Cx43 and NaV1.5 expression in 4-week old mouse hearts, overexpressing a constitutively active form of CnA (MHC-CnA model), but the order of events is still unknown. Therefore, three key parameters of conduction (Cx43, NaV1.5 and connective tissue expression) were characterized in MHC-CnA ventricles versus wild-type (WT) during postnatal development on a weekly basis. At postnatal week 1, CnA overexpression induced cardiac hypertrophy in MHC-CnA. Moreover, protein and RNA levels of both Cx43 and NaV1.5 were reduced by at least 50% as compared to WT. Cx43 immunoreactive signal was reduced at week 2 in MHC-CnA. At postnatal week 3, Cx43 was less phosphorylated and RNA level of Cx43 normalized to WT values, although the protein level was still reduced. Additionally, MHC-CnA hearts displayed substantial fibrosis relative to WT, which was accompanied by increased RNA levels for genes previously associated with fibrosis such as Col1a1, Col1a2, Col3a1, Tgfb1, Ctgf, Timp1 and microRNA miR-21. In MHC-CnA, reduction in Cx43 and NaV1.5 expression thus coincided with overexpression of CnA and hypertrophy development and preceded significant presence of fibrosis. At postnatal week 4 the alterations in conductional parameters observed in the MHC-CnA model lead to abnormal conduction and arrhythmias, similar to those observed in cardiac remodeling in heart failure patients. The MHC-CnA model, therefore, provides for a unique model to resolve the molecular origin of conductional remodeling in detail.

Passive ventricular remodeling in cardiac disease: focus on heterogeneity.

Passive ventricular remodeling is defined by the process of molecular ventricular adaptation to different forms of cardiac pathophysiology. It includes changes in tissue architecture, such as hypertrophy, fiber disarray, alterations in cell size and fibrosis. Besides that, it also includes molecular remodeling of gap junctions, especially those composed by Connexin43 proteins (Cx43) in the ventricles that affect cell-to-cell propagation of the electrical impulse, and changes in the sodium channels that modify excitability. All those alterations appear mainly in a heterogeneous manner, creating irregular and inhomogeneous electrical and mechanical coupling throughout the heart. This can predispose to reentry arrhythmias and adds to a further deterioration into heart failure. In this review, passive ventricular remodeling is described in Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM), and Arrhythmogenic Cardiomyopathy (ACM), with a main focus on the heterogeneity of those alterations mentioned above.

Students' motives for using online formative assessments when preparing for summative assessments.

BACKGROUND: Formative assessments intend to provide feedback on student performance in order to improve and accelerate learning. Several studies have indicated that students using online formative assessments (OFAs), have better results on their exams. AIMS: The present study aims to provide insight in student reasons for using or not using available OFAs. METHOD: Three OFAs with feedback were available in a second year undergraduate course in physiology for biomedical sciences students (N = 147). First, students received an open questionnaire about why they did (not) complete the first two OFAs. Based on this data, a closed questionnaire was developed and distributed among students. Exploratory factor analysis (EFA) was applied. RESULTS: The results indicate reasons why students do (not) use the OFAs. The EFA for using the OFAs indicated three factors, that were interpreted as collecting (1) feed up, (2) feed forward, and (3) feed back information. The main reasons for not using the OFAs were lack of time and having completed the questions before. CONCLUSIONS: Students' reasons for using OFAs can be described in terms of collecting feed up, forward and back information and students' reasons for not using OFAs can be student-, teacher-, or mode-related.

Online formative tests linked to microlectures improving academic achievement.

BACKGROUND: Online formative tests (OFTs) are powerful tools to direct student learning behavior, especially when enriched with specific feedback. AIM: In the present study, we have investigated the effect of OFTs enriched with hyperlinks to microlectures on examination scores. METHODS: OFTs, available one week preceding each midterm and the final exams, could be used voluntarily. The use of OFTs was related to scores on midterm and final exams using ANOVA, with prior academic achievement as a covariate. RESULTS: On average, 74% of all students used the online formative tests (OFT+) while preparing for the summative midterm exam. OFT+ students obtained significantly higher grades compared to OFT-students, both without and with correction for previous academic achievement. Two out of three final exam scores did not significantly improve. CONCLUSION: Students using online formative tests linked to microlectures receive higher grades especially in highly aligned summative tests.