Human embryonic stem cells derived by somatic cell nuclear transfer.

Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer (NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors that are responsible for these outcomes. Optimized SCNT approaches designed to circumvent these limitations allowed derivation of human NT-ESCs. When applied to premium quality human oocytes, NT-ESC lines were derived from as few as two oocytes. NT-ESCs displayed normal diploid karyotypes and inherited their nuclear genome exclusively from parental somatic cells. Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state.

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation.

BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype.

Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavß2a expression (ß2a-Tg mice) showed increased cytosolic CM Ca2+, and modest levels of CM hypertrophy, and fibrosis. This study aimed to determine if ß2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, high-fat diet (HFD) and Nω-nitro-l-arginine methyl ester (l-NAME, LN). Four-month-old wild-type (WT) and ß2a-Tg mice were given either normal chow (WT-N, ß2a-N) or HFD and/or l-NAME (WT-HFD, WT-LN, WT-HFD-LN, ß2a-HFD, ß2a-LN, and ß2a-HFD-LN). Some animals were treated with the histone deacetylase (HDAC) (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (ß2a-HFD-LN-SAHA). Echocardiography was performed monthly. After 4 mo of treatment, terminal studies were performed including invasive hemodynamics and organs weight measurements. Cardiac tissue was collected. Four months of HFD plus l-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. ß2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased atrial natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M2-macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model, by attenuating these effects. The 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and increased M2-macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies.NEW & NOTEWORTHY Our study shows that three independent pathological stressors (increased Ca2+ influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M2-macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This "3-Hit" mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF.

Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca2+ Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca2+ Dynamics.

RATIONALE: Ca2+-induced Ca2+ release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules) and RyR (ryanodine receptors) within the junctional sarcoplasmic reticulum. CICR is disrupted in cardiac hypertrophy and heart failure, which is associated with loss of T-tubules and disruption of cardiac dyads. In these conditions, LTCCs are redistributed from the T-tubules to disrupt CICR. The molecular mechanism responsible for LTCCs recruitment to and from the T-tubules is not well known. JPH (junctophilin) 2 enables close association between T-tubules and the junctional sarcoplasmic reticulum to ensure efficient CICR. JPH2 has a so-called joining region that is located near domains that interact with T-tubular plasma membrane, where LTCCs are housed. The idea that this joining region directly interacts with LTCCs and contributes to LTCC recruitment to T-tubules is unknown. OBJECTIVE: To determine if the joining region in JPH2 recruits LTCCs to T-tubules through direct molecular interaction in cardiomyocytes to enable efficient CICR. METHODS AND RESULTS: Modified abundance of JPH2 and redistribution of LTCC were studied in left ventricular hypertrophy in vivo and in cultured adult feline and rat ventricular myocytes. Protein-protein interaction studies showed that the joining region in JPH2 interacts with LTCC-α1C subunit and causes LTCCs distribution to the dyads, where they colocalize with RyRs. A JPH2 with induced mutations in the joining region (mutPG1JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mutPG1JPH2 caused asynchronous Ca2+-release with impaired excitation-contraction coupling after ß-adrenergic stimulation. The disturbed Ca2+ regulation in mutPG1JPH2 overexpressing myocytes caused calcium/calmodulin-dependent kinase II activation and altered myocyte bioenergetics. CONCLUSIONS: The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes.

Under- and post-graduate training to manage the acutely unwell patient: a scoping review.

BACKGROUND: Junior doctors are often the first responders to acutely unwell patients and yet frequently report feeling under-prepared to do so. To understand whether this is consequential of how medical students and doctors are trained to manage acutely unwell patients, a scoping review was conducted using a systematic approach. METHODS: The review, informed by the Arksey and O'Malley and PRISMA-ScR guidelines, identified educational interventions targeting the management of acutely unwell adults. Seven major literature databases were searched for journal articles published in English from 2005 to 2022, in addition to the Association of Medical Education in Europe (AMEE) conference proceedings from 2014 to 2022. RESULTS: Seventy-three articles and abstracts were eligible for the review, the majority of which were from the UK or USA, and demonstrated that educational interventions were more commonly targeted at medical students than qualified doctors. The majority of studies used simulation, but very few integrated complexities of the clinical environment within scenarios such as multidisciplinary working, distraction-handling techniques and other non-technical skills. A wide range of learning objectives pertaining to acute patient management were stated across studies, but few explicitly cited educational theory underpinning their study. CONCLUSIONS: The results of this review encourages future educational initiatives to consider enhancing authenticity within simulation to promote transfer of learning to clinical practice, and use educational theory to augment the sharing of educational approaches within the community of clinical education practice. Additionally, increasing the focus on post-graduate learning, building upon undergraduate educational foundations, is essential to promoting lifelong learning within the ever-changing healthcare environment.

Cardiac Remodeling During Pregnancy With Metabolic Syndrome: Prologue of Pathological Remodeling.

BACKGROUND: The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders. METHODS: The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet-feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)-induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat). RESULTS: Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery. CONCLUSIONS: These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.

Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF.

Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared with males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2 and 4 mo postsurgery to document the effects of slow progressive pressure overload. At 4 mo, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single-nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross-sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females.NEW & NOTEWORTHY We performed a comprehensive assessment to evaluate the effects of slow progressive pressure overload on cardiopulmonary function in a large animal model of heart failure with preserved ejection fraction (HFpEF) in males and females. Functional and structural assessments were performed at the organ, tissue, cellular, protein, and transcriptional levels. This is the first study to compare snRNAseq and ECM mass spectrometry of HFpEF myocardium from males and females. The results broaden our understanding of the pathophysiological response of both sexes to pressure overload. Both sexes developed a robust cardiopulmonary phenotype, but the phenotype was equal or a bit less robust in females.

Cortical bone stem cells modify cardiac inflammation after myocardial infarction by inducing a novel macrophage phenotype.

Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound-healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably macrophage colony-stimulating factor (M-CSF) and transforming growth factor-ß, but not IL-4. CBSC therapy increased the number of galectin-3+ macrophages, CD4+ T cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a proreparative phenotype are characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-ß, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased α-smooth muscle actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function.NEW & NOTEWORTHY Cortical bone stem cell (CBSC) therapy after myocardial infarction alters the inflammatory response to cardiac injury. We found that cortical bone stem cell therapy induces a unique macrophage phenotype in vitro and can modulate macrophage/fibroblast cross talk.

Cortical bone stem cell-derived exosomes' therapeutic effect on myocardial ischemia-reperfusion and cardiac remodeling.

Heart failure is the one of the leading causes of death in the United States. Heart failure is a complex syndrome caused by numerous diseases, including severe myocardial infarction (MI). MI occurs after an occlusion of a cardiac artery causing downstream ischemia. MI is followed by cardiac remodeling involving extensive remodeling and fibrosis, which, if the original insult is severe or prolonged, can ultimately progress into heart failure. There is no "cure" for heart failure because therapies to regenerate dead tissue are not yet available. Previous studies have shown that in both post-MI and post-ischemia-reperfusion (I/R) models of heart failure, administration of cortical bone stem cell (CBSC) treatment leads to a reduction in scar size and improved cardiac function. Our first study investigated the ability of mouse CBSC-derived exosomes (mCBSC-dEXO) to recapitulate mouse CBSCs (mCBSC) therapeutic effects in a 24-h post-I/R model. This study showed that injection of mCBSCs and mCBSC-dEXOs into the ischemic region of an infarct had a protective effect against I/R injury. mCBSC-dEXOs recapitulated the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's beneficial effects. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with transforming growth factor ß (TGFß) to activate fibrotic signaling before treatment with mCBSC- and human CBSC (hCBSC)-dEXOs. hCBSC-dEXOs caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-dEXO treatment. The group treated with both TGFß and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability.NEW & NOTEWORTHY Our work is noteworthy due to the identification of factors within stem cell-derived exosomes (dEXOs) that alter fibroblast activation through the hereto-unknown mechanism of decreasing small nucleolar RNA (snoRNA) signaling within cardiac fibroblasts. The study also shows that the injection of stem cells or a stem-cell-derived exosome therapy at the onset of reperfusion elicits cardioprotection, emphasizing the importance of early treatment in the post-ischemia-reperfusion (I/R) wounded heart.

Twelve tips for facilitating medical students prescribing learning on clinical placement.

Prescribing is a complex clinical skill requiring mastery by the end of basic medical training. Prescribing errors are common in newly qualified doctors, aligned with expressed anxiety about prescribing, particularly with high-risk medications. Learning about prescribing needs to start early in medical training, underpinned by regular opportunities for reflective practice. Authentic learning within the clinical work environment is more effective than lecture based learning and allows potential immediate feedback. Educational strategies should support prescribing learning underpinned by appropriate formative and summative assessments. Students should routinely be expected to use resources including an online formulary, sustained through tracking individual progress through use of their own personal formulary or 'p' drugs. Regular prescribing practice with embedded feedback during undergraduate training will help to ensure newly qualified doctors are more confident and competent prescribers.

Revisiting the Diabetes-Heart Failure Connection.

PURPOSE OF THE REVIEW: To summarize current clinical data investigating the link between diabetes and heart failure pathophysiology, the association of glucose control with heart failure, and the impact of current antihyperglycemic drugs on heart failure. RECENT FINDINGS: Although heart failure is one of the most prevalent outcomes occurring in real life and cardiovascular outcome trials, insufficient attention was given to this condition in diabetes research over the last decades. With both beneficial and detrimental findings for heart failure hospitalization in the health authority-mandated outcome trials for new antihyperglycemic agents, research on heart failure and its interplay with diabetes mellitus gained momentum. Diabetes mellitus and heart failure are both prevalent and intertwined conditions. While currently available heart failure therapies have a similar degree of effectiveness in patients with and without diabetes, the choice of glucose-lowering agents can substantially affect heart failure-related outcome.

Pre-University education curriculum reform and the generic learning skills of medical school entrants: Lessons learned from South Africa.

Background: Pre-university education curriculum changes may increase the skills and knowledge gap between secondary (high school) and tertiary (university) education that have been identified as having a major impact on the success of students from underresourced educational backgrounds. This study investigated the impact of extensive pre-university curriculum revision on the generic learning skills of entrants to South African medical schools, which admit students directly from high school. Methods: In this prospective study, students entering four medical schools during 2008-2011 were surveyed to determine their practice of and confidence in information handling, managing own learning, technical and numeracy skills, and computer, organizational, and presentation skills in the 12-month preceding entry. The 2008 entrants were the final cohort of the old secondary school curriculum. The mean levels of practice or confidence of entrants to the four medical schools, during 2008-2011, were compared using analysis of variance. The Bonferroni's test was used for further pair-wise comparison of cohorts of students either entering in different years or different institutions. Results: While entrants at the four medical schools did not demonstrate a consistent or sustained change in their practice of or confidence in each skill category over the period of study, there were some significant differences between entrants at the respective institutions. Furthermore, entrants to one medical school were consistently less confident of their skills, despite more practice. These findings are best accounted for by the long-standing history of inequitably resourced pre-university education in South Africa. Discussion: These findings highlight the need for close monitoring of the impact of pre-university education changes on the learning skill profiles of university entrants, in order to design effective university programs which enable students from diverse backgrounds to participate and adequately meet curricula demands.

Feedback mapping - The curricular cornerstone of an "educational alliance".

PURPOSE: The "educational alliance" concept articulates a collaborative framework to facilitate effective feedback through transparency of opportunities aligned with learner stage and intended educational outcomes. Using this framework, we evaluated feedback across a 5 year undergraduate medical program to support embedding a successful learner - teacher "educational alliance". METHOD: A comprehensive mapping exercise used an iterative action research process of source documentary analysis, consultations with key curriculum stakeholders and qualitative analysis. The "educational alliance" model provided a critical lens through which to ensure feedback opportunities aligned with intended learning outcomes and developmental progression. RESULTS: Key information about the type, frequency and timing of feedback opportunities was identified within 188 curricular components. The purpose and intended learning outcomes were mapped, aligning with the stage of learning and with an expectation of supporting learners' capacity for self-regulation. This focus providing clear articulation of feedback opportunities supported the longitudinal developmental curricular review, and facilitated enhanced awareness of dialogic feedback within the "educational alliance". CONCLUSIONS: Explicit alignment of learning intentions between learner and educator is key to forming a successful "educational alliance". The feedback map provides clarity ensuring mutual understanding of intended learning outcomes. The iterative process additionally certified feedback aligned with maturing learner developmental needs across the program.

Appreciative inquiry in medical education.

The practice of medicine, and also medical education, typically adopts a problem-solving approach to identify "what is going wrong" with a situation. However, an alternative is Appreciative Inquiry (AI), which adopts a positive and strengths-based approach to identify "what is going well" with a situation. The AI approach can be used for the development and enhancement of the potential of both individuals and organizations. An essential aspect of the AI approach is the generative process, in which a new situation is envisioned and both individual and collective strengths are mobilized to make changes to achieve the valued future situation. The AI approach has been widely used in the world of business and general education, but is has an exciting potential for medical education, including curriculum development, faculty development, supporting learners through academic advising and mentoring, but also for enhancing the teaching and learning of both individuals and groups. This AMEE Guide describes the core principles of AI and their practical application in medical education.

What can medical educators learn from the Rio 2016 Olympic Games?

Medical Educators face an ongoing challenge in optimizing preparedness for practice for newly qualified doctors. Junior doctors have highlighted specific areas in which they do not feel adequately equipped to undertake their duties, including managing the acutely unwell patient. In these highly stressful, time-critical scenarios it might be assumed that a lack of knowledge underpins these feelings of apprehension from junior medics; however, having studied, trained and passed examinations to demonstrate such knowledge, perhaps other factors should be considered. The recent Olympic Games in Rio demonstrated the impact of sport psychology techniques in allowing athletes to achieve their optimum performance in the face of adversity. The use of mental and behavioral strategies to control feelings of anxiety and low self-efficacy are pivotal for athletes to deliver their best performance under extreme pressure. We consider whether such techniques could improve the preparedness of the newest recruits to the healthcare system, and the impact this could have on patient care. Finally, suggestions for potential research directions within this area are offered to stimulate interest amongst the research community.

The supervisor's toolkit: A framework for doctoral supervision in health professions education: AMEE Guide No. 104.

Doctoral studies represent a complex undertaking for students and supervisors. Some research describes the experience of students while there are volumes of advice for students considering a doctorate. Yet the terrain for supervisors is less well-trodden and the concept of a pedagogy of supervision is only really starting to emerge. Texts on the doctoral journey from the supervisor's perspective are uncommon and less yet has been written in the context of health professions education. The aim of this Guide, therefore, is to provide guidance for the supervisor's journey, drawing on our collective experience and such literature as there is. We explore the doctoral journey of students and their supervisors, highlighting what the implications are for supervisory practice. Recognising the doctorate as much more than merely conducting a research project, and seeing it as a shared educational endeavour is fundamental to understanding the doctoral journey - a journey that is complex and mutable, constantly shifting as the candidate moves from novice to expert, from dependence to growing autonomy. Our intention is to present this Guide as a toolkit for both the novice and the experienced supervisor as it, on the one hand, seeks to make the practice of supervision more transparent while on the other, challenges the reader to critically reflect on the supervisory space in which they currently reside. Our hope is that the Guide opens up opportunities for generative conversations about the practice of doctoral supervision in health professions education.

A model of professional self-identity formation in student doctors and dentists: a mixed method study.

BACKGROUND: Professional self-identity [PSI] can be defined as the degree to which an individual identifies with his or her professional group. Several authors have called for a better understanding of the processes by which healthcare students develop their professional identities, and suggested helpful theoretical frameworks borrowed from the social science and psychology literature. However to our knowledge, there has been little empirical work examining these processes in actual healthcare students, and we are aware of no data driven description of PSI development in healthcare students. Here, we report a data driven model of PSI formation in healthcare students. METHODS: We interviewed 17 student doctors and dentists who had indicated, on a tracking questionnaire, the most substantial changes in their PSI. We analysed their perceptions of the experiences that had influenced their PSI, to develop a descriptive model. Both the primary coder and the secondary coder considered the data without reference to the existing literature; i.e. we used a bottom up approach rather than a top down approach. RESULTS: The results indicate that two overlapping frames of reference affect PSI formation: the students' self-perception and their perception of the professional role. They are 'learning' both; neither is static. Underpinning those two learning processes, the following key mechanisms operated: [1] When students are allowed to participate in the professional role they learn by trying out their knowledge and skill in the real world and finding out to what extent they work, and by trying to visualise themselves in the role. [2] When others acknowledge students as quasi-professionals they experience transference and may respond with counter-transference by changing to meet expectations or fulfil a prototype. [3] Students may also dry-run their professional role (i.e., independent practice of professional activities) in a safe setting when invited. CONCLUSIONS: Students' experiences, and their perceptions of those experiences, can be evaluated through a simple model that describes and organises the influences and mechanisms affecting PSI. This empirical model is discussed in the light of prevalent frameworks from the social science and psychology literature.

Electives in undergraduate medical education: AMEE Guide No. 88.

This Guide outlines the scope and potential roles an elective can contribute to undergraduate medical training and identifies ways to maximize learning opportunities, including within global health. The types of educational activity available for electives range from meeting individual educational need through to exploration of potential career pathways, with many factors influencing choice. Key areas of organization underpinning a successful elective before, during and after the placement include developing clarity of the intended educational outcomes as well as addressing practicalities such as travel and accommodation. Risk management including the implications for the participating schools as well as the student and their elective supervisors is crucial. This Guide would not be complete without some discussion around ethics and professional conduct during an elective, with consideration of the impact of elective placements, particularly in low-middle income countries.

How do undergraduate medical students perceive social accountability?

AIM: The concept of social accountability within undergraduate training is embedded within the remit of medical schools. Little is known of how medical students perceive social accountability, recognize aspects of their training contributing to the development of this concept and cultivate the underpinning values. METHODS: Students nearing graduation were recruited to participate in focus groups designed to explore their perceptions of social accountability, which curricular aspects had contributed to their understanding, and to investigate the implications of individual variations in training. RESULTS: Students expressed limited appreciation of the concept of social accountability and acknowledged little explicit teaching around underpinning core concepts such as awareness of local health needs, advocacy and nurturing of altruism. However, participants recognized numerous aspects of the course and learning initiatives as impacting on their attitudes towards this concept implicitly. CONCLUSION: This study highlights areas of their undergraduate training that students recognize as having the greatest impact on their development into socially accountable professionals. It poses some significant challenges for health care educators in addressing unintended consequences, including an outcome-driven educational approach, in reducing students' capacity or willingness to engage in curricular challenges often designed to embed this concept.

Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.

Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFß stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFß-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.