Computed tomography pulmonary angiogram ordering, adherence to decision rules and yield in the emergency department: An observational study.

OBJECTIVE: Pulmonary embolism (PE) frequently requires diagnosis through CT pulmonary angiogram (CTPA). Appropriate application of evidence-based clinical decision tools can reduce unnecessary CTPAs. This study assessed adherence to and the efficacy of various aspects of the Queensland Health suspected PE diagnostic pathway, including Wells score, PE rule out criteria (PERC) and age-adjusted D-dimer interpretation. METHODS: Retrospective study of CTPAs ordered from 1 January to 30 April 2023 in a tertiary and urban ED in Southeast Queensland. Data on clinical variables, D-dimer and CTPA results were collected through medical record and radiology database review. Descriptive analyses were used to determine adherence to Queensland guidelines and performance of D-dimer interpretation tools (including comparison of age-adjusted PE with a new pre-test probability [PTP]-based model using D-dimer cut-off <1000 ng/mL for Wells score ≤4 and 500 ng/mL for Wells score 4.5-6). RESULTS: A total of 573 CTPAs were available for analysis with a 12.4% (95% confidence interval 10.0-15.4) diagnostic yield. Stratification by Wells score showed yields of 4.0%, 18.5% and 41% for low-, moderate- and high-risk patients, respectively. Twenty-five patients with low-PTP who received CTPA could have been excluded with the PERC rule. Age-adjusted D-dimer interpretation may have prevented 26 CTPAs with no false negatives, whereas PTP approach may have prevented 128 CTPAs with four false negatives. CONCLUSION: Guideline adherence can be improved, and adherence to existing clinical decision tools may reduce unnecessary CTPA ordering and increase diagnostic yield. The use of the age-adjusted D-dimer had good sensitivity, whereas the new PTP approach will require further prospective research.

Measuring wellbeing: A scoping review of metrics and studies measuring medical student wellbeing across multiple timepoints.

PURPOSE: Studies have demonstrated poor mental health in medical students. However, there is wide variation in study design and metric use, impairing comparability. The authors aimed to examine the metrics and methods used to measure medical student wellbeing across multiple timepoints and identify where guidance is necessary. METHODS: Five databases were searched between May and June 2021 for studies using survey-based metrics among medical students at multiple timepoints. Screening and data extraction were done independently by two reviewers. Data regarding the manuscript, methodology, and metrics were analyzed. RESULTS: 221 studies were included, with 109 observational and 112 interventional studies. There were limited studies (15.4%) focused on clinical students. Stress management interventions were the most common (40.2%). Few (3.57%) interventional studies followed participants longer than 12 months, and 38.4% had no control group. There were 140 unique metrics measuring 13 constructs. 52.1% of metrics were used only once. CONCLUSIONS: Unique guidance is needed to address gaps in study design as well as unique challenges surrounding medical student wellbeing surveys. Metric use is highly variable and future research is necessary to identify metrics specifically validated in medical student samples that reflect the diversity of today's students.

Design thinking sprints as a facilitation process to enact change in the residency match process and beyond.

Implication Statement: Enacting change in medical education requires effective facilitation processes. Medical education lags behind other fields in systems innovation and radically disruptive approaches to the challenges we encounter. Design thinking "sprints," widely used in many other settings, serve as an opportunity to fill the gap as a facilitation process during periods requiring extensive and/or rapid change. Though resource-intensive, our experience using design thinking sprints for a situation requiring urgent change management with high-stakes implications for Canadian medical education to demonstrate their utility. A more widespread, adoption can contribute to innovation within all aspects of education including curriculum design, policy development, and educational process renewal. Énoncé des implications de la recherche: La mise en œuvre de changements dans la formation médicale exige un processus de facilitation efficace. Comparée à d'autres disciplines, l'éducation médicale est à la traîne en ce qui concerne l'innovation des systèmes et l'adoption d'approches radicalement transformatrices en réponse aux défis rencontrés. Le sprint de conception creative (design thinking sprints), approche largement utilisée dans de nombreux contextes, pourraient permettre de combler le manque de processus de facilitation lorsque des changements importants ou rapides sont à l'œuvre. Notre expérience de l'utilisation de tels sprints dans une situation nécessitant une gestion urgente de changements à enjeux importants pour l'éducation médicale au Canada démontre son utilité, malgré les ressources considérables qui ont dû être mobilisées. Une adoption plus large de cette approche peut contribuer à l'innovation dans tous les aspects de l'éducation, y compris la conception des programmes d'études, l'élaboration de politiques et le renouvellement des processus éducatifs.

Exploring the lived experience of patients and families who speak language other than English (LOE) for healthcare: developing a qualitative study.

BACKGROUND: Patients who use Languages other than English (LOE) for healthcare communication in an English-dominant region are at increased risk for experiencing adverse events and worse health outcomes in healthcare settings, including in pediatric hospitals. Despite the knowledge that individuals who speak LOE have worse health outcomes, they are often excluded from research studies on the basis of language and there is a paucity of data on ways to address these known disparities. Our work aims to address this gap by generating knowledge to improve health outcomes for children with illness and their families with LEP. BODY: We describe an approach to developing a study with individuals marginalized due to using LOE for healthcare communication, specifically using semi-structured qualitative interviews. The premise of this study is participatory research-our overall goal with this systematic inquiry is to, in collaboration with patients and families with LOE, set an agenda for creating actionable change to address the health information disparities these patients and families experience. In this paper we describe our overarching study design principles, a collaboration framework in working with different stakeholders and note important considerations for study design and execution. CONCLUSIONS: We have a significant opportunity to improve our engagement with marginalized populations. We also need to develop approaches to including patients and families with LOE in our research given the health disparities they experience. Further, understanding lived experience is critical to advancing efforts to address these well-known health disparities. Our process to develop a qualitative study protocol can serve as an example for engaging this patient population and can serve as a starting point for other groups who wish to develop similar research in this area. Providing high-quality care that meets the needs of marginalized and vulnerable populations is important to achieving an equitable, high-quality health care system. Children and families who use a Language other than English (LOE) in English dominant regions for healthcare have worse health outcomes including a significantly increased risk of experiencing adverse events, longer lengths of stay in hospital settings, and receiving more unnecessary tests and investigations. Despite this, these individuals are often excluded from research studies and the field of participatory research has yet to meaningfully involve them. This paper aims to describe an approach to conducting research with a marginalized population of children and families due to using a LOE. We detail protocol development for a qualitative study exploring the lived experiences of patients and families who use a LOE during hospitalization. We aim to share considerations when conducting research within this population of families with LOE. We highlight learning applied from the field of patient-partner and child and family-centred research and note specific considerations for those with LOE. Developing strong partnerships and adopting a common set of research principles and collaborative framework underlies our approach and initial learnings, which we hope spark additional work in this area.

Elements and Definitions of Continuing Professional Development Leadership: A Scoping Review.

INTRODUCTION: Leaders are being asked to transform the way that continuing professional development (CPD) is delivered to focus on better, safer, and higher quality care. However, there is scarce literature on CPD leadership. We set out to study what CPD leadership means and describe the competencies required for CPD leadership. METHODS: A scoping review following Preferred Reporting Items for Systematic Reviews and Meta-analyses extension guidelines for scoping reviews guidelines was conducted. With librarian support, four databases were searched for publications related to leadership, medical education, and CPD. Publications were screened by two reviewers and three reviewers extracted data. RESULTS: Among 3886 publications, 46 were eligible for a full-text review and 13 met the final inclusion criteria. There was no agreed upon definition of CPD leadership and variable models and approaches to leadership in the literature. Contextual issues shaping CPD (eg, funding, training, and information technology) are evolving. We identified several attitudes and behaviors (eg, strategic thinking), skills (eg, collaboration), and knowledge (eg, organizational awareness) important to CPD leadership, but no established set of unique competencies. DISCUSSION: These results offer the CPD community a foundation on which competencies, models, and training programs can build. This work suggests the need to build consensus on what CPD leadership means, what CPD leaders do, and what they will need to create and sustain change. We suggest the adaptation of existing leadership frameworks to a CPD context to better guide leadership and leadership development programs.

All of Residency's a Stage: Fostering Authenticity and Individuality Among Learners.

Understanding the process of professional identity formation, and its susceptibility to the hidden curriculum, is of increasing importance in medical education. Through a lens of performance, this commentary explores the impact of the culture, the hidden curriculum, and the socialization process of the medical training environment on the professional identity formation of learners. We emphasize the need to train physicians with diverse interests and skills, capable of creative problem solving in response to the rapidly evolving challenges facing the profession and society more broadly. Opportunities for learners to drive cultural change and promote authenticity and unique professional identity formation are identified.

Learning by doing: A phenomenological study of medical student leaders.

INTRODUCTION: Despite being recognised as a key physician competency, leadership development is an area of improvement especially in undergraduate medical education. We sought to explore the lived experience of leaders who served in elected, representative roles during their time in medical school. METHODS: We used a hermeneutic phenomenological approach to uncover the essence of the medical student leader experience. From late 2020 to early 2021, we interviewed 12 medical residents who served in elected leadership roles from 2015 to 2019. Each participant graduated from a different Canadian medical school. We deliberately chose a limited and historic time period in order for participants to be able to reflect on their past experiences while accounting for differences in the medical student leadership experience over time. We then engaged in a reflexive thematic analysis to generate the final themes. RESULTS: We identified the following five themes: (i) living with busyness, (ii) the role of faculty mentorship and support, (iii) competing demands of leadership, (iv) medical student leadership as enriching and (v) creating better physicians. Though demanding, medical student leadership was found to be rewarding and particularly key in the development of a more well-rounded physician. Furthermore, being well supported by faculty contributed to an overall positive leadership experience. DISCUSSION: In addition to describing the hardships and rewards that make up their experience, this study suggests that medical student leadership can enhance core physician competencies. The findings also support the notion that faculties have an important role to play in supporting medical student leaders.

The 4C's of influence framework: fostering leadership development through character, competence, connection and culture.

PURPOSE: The purpose of this paper is to describe the 4C's of Infuence framework and it's application to medicine and medical education. Leadership development is increasingly recognised as an integral physician skill. Competence, character, connection and culture are critical for effective influence and leadership. The theoretical framework, "The 4C's of Influence", integrates these four key dimensions of leadership and prioritises their longitudinal development, across the medical education learning continuum. DESIGN/METHODOLOGY/APPROACH: Using a clinical case-based illustrative model approach, the authors provide a practical, theoretical framework to prepare physicians and medical learners to be engaging influencers and leaders in the health-care system. FINDINGS: As leadership requires foundational skills and knowledge, a leader must be competent to best exert positive influence. Character-based leadership stresses development of, and commitment to, values and principles, in the face of everyday situational pressures. If competence confers the ability to do the right thing, character is the will to do it consistently. Leaders must value and build relationships, fostering connection. Building coalitions with diverse networks ensures different perspectives are integrated and valued. Connected leadership describes leaders who are inspirational, authentic, devolve decision-making, are explorers and foster high levels of engagement. To create a thriving, learning environment, culture must bring everything together, or will become the greatest barrier. ORIGINALITY/VALUE: The framework is novel in applying concepts developed outside of medicine to the medical education context. The approach can be applied across the medical education continuum, building on existing frameworks which focus primarily on what competencies need to be taught. The 4C's is a comprehensive framework for practically teaching the leadership for health care today.

Fostering a Health-Promoting Learning Environment in Medical Education: Adapting the Okanagan Charter for Administrators and Medical Educators.

Medical students enter medical school with similar or even better well-being than their age-matched peers in other educational programs, but there is predictable erosion of their well-being following matriculation. Interventions to counter this erosion predominantly focus on the individual level; however, significant systemic issues persist that thwart meaningful change. Effectively reforming the learning environment and more broadly targeting problematic aspects of the culture of medical education are essential steps to advance efforts to improve medical learner well-being. Although a healthy environment may allow learners to be well in the educational setting, a health-promoting learning environment strives to promote and embed well-being across all aspects of the learner's experience. Health-promoting learning environments operate by infusing health principles into all aspects of operations, practices, mandates, and businesses. The Okanagan Charter is a widely adopted international framework with principles for best practices of adoption. This charter has the recent endorsement of the Association of Faculties of Medicine of Canada, representing all faculties of medicine in Canada, and serves as a framework for reassessing work on well-being in medical education. In response to this endorsement, the authors have adapted the 5 strategies from the charter for pragmatic integration into the medical education environment and added a sixth strategy: (1) embed health in all policies; (2) develop sustainable, supportive spaces; (3) create thriving medical communities and culture; (4) encourage, support, and sustain meaningful personal development; (5) review, develop, and strengthen faculty-level health services; and (6) collaborate and invest in continuous improvement and evaluation. For each of these 6 strategic directions, actionable steps for implementation in academic medicine are provided to create sustainable and meaningful change.

To lead or to influence?

One skill set identified within the CanMEDS Framework (CanMEDS) as essential to training future physicians is the Leader role. Arguably however, the term Leader carries certain connotations that are inconsistent with the abilities outlined by CanMEDS as necessary for physicians. For example, the term Leader may connote hierarchical authority and formalized responsibilities, while de-emphasising informal day-to-day influencing. This CanMEDS role was first labelled Manager, but was re-named Leader in 2015. Perhaps the focus of this CanMEDS role should be further refined by adopting a more representative term that reflects the concept of intentional influence. Through this lens, learners can discern significant opportunities to influence positively each of the clinical and non-clinical environments they encounter. We suggest that reframing the Leader role as an Influencer role will be more comprehensive and inclusive of its full scope and potential. Accordingly, given the potential for broader applicability and resonance with learners, collaborators, and the populations we serve, consideration should be given to re-characterizing the CanMEDS role of Leader as that of Influencer.

Le rôle de Leader est une des compétences du Référentiel CanMEDS jugées essentielles dans la formation des futurs médecins. Cependant, on peut soutenir que la notion de leadership comporte certaines connotations qui sont incompatibles avec les compétences exigées dans CanMEDS. Par exemple, le terme « leader ¼ peut évoquer une autorité hiérarchique et des responsabilités formelles, tout en minimisant l'influence informelle exercée au quotidien. Avant 2015, ce rôle était désigné par le mot « gestionnaire ¼. Peut-être l'orientation de ce rôle CanMEDS devrait-elle être redéfinie et une appellation correspondante choisie pour refléter la notion d'influence intentionnelle. Une telle reformulation inciterait les apprenants à cerner les occasions importantes d'influencer positivement les environnements cliniques et non-cliniques dans lesquels ils travaillent. Nous sommes d'avis qu'un recadrage du rôle de leader en influenceur engloberait toute la portée et tout le potentiel auxquels le rôle renvoie. Le rôle d'Influenceur promet une applicabilité et une résonance plus larges auprès des apprenants, des collaborateurs et des populations que nous servons, d'où la pertinence de la redéfinition du rôle CanMEDS actuel.

Six ways to get a grip by calling-out racism and enacting allyship in medical education.

Actively addressing racism in our faculties of medicine is needed now, more than ever. One way to do this is through allyship, the practice of unlearning and re-evaluating, in which a person in a position of privilege and power seeks to operate in solidarity with a traditionally marginalized group. In this paper, we provide practical tips on how to practice allyship, giving educators and leaders background understanding and important tools on how to actively promote equity and diversity. We also share tips on how to promote inclusivity to more accurately reflect the communities we serve. Through six broad actions of being, knowing, feeling, doing, promoting, and acting, we can empower individuals to become allies and address racism in medical education and beyond. Creating psychologically safe spaces, educating ourselves on our complex histories and how they influence the present, recognizing racism, and advocating for change, augments awareness from which we can pivot conversations. Acknowledging potential feelings of shame, guilt, and embracing our loss of privilege, allow necessary, but challenging, personal growth to occur. Finally, dismantling the racist structures that exist within medicine, moving us beyond individual interventions, will address the systemic nature of racism in medicine. Everyone can find a starting place within this guide, as simple, consistent actions foster change in our spheres of influence; and the ripple effect of these changes will impact attitudes and behaviours broadly.

Il est plus que jamais nécessaire de s'attaquer activement au racisme dans les facultés de médecine. Une des stratégies qu'on peut adopter à cette fin est celle de l'allié, désignée en anglais par le terme allyship. Il s'agit de la pratique du désapprentissage et de la réévaluation, par laquelle une personne en position de privilège et de pouvoir s'efforce d'agir en solidarité avec un groupe marginalisé. Cet article vise à proposer aux enseignants et aux responsables des conseils pratiques sur la façon d'agir en alliés, notamment en offrant les informations nécessaires à une compréhension générale de la problématique en toile de fond, ainsi que des outils importants pour promouvoir activement l'équité et la diversité. Nous partageons également des stratégies pour encourager l'inclusivité afin de représenter plus fidèlement les populations auxquelles nous offrons nos services. Grâce à une démarche à six volets (être, savoir, ressentir, faire, promouvoir et agir), nous pouvons donner aux personnes les moyens de devenir des alliées dans la lutte contre le racisme de façon générale et dans l'enseignement médical en particulier. La création d'espaces psychologiquement sûrs, la sensibilisation aux vécus complexes et à leur influence sur le présent des individus, la reconnaissance du racisme et le plaidoyer pour le changement contribuent à une prise de conscience qui permet d'orienter le dialogue. La croissance personnelle, aussi difficile que nécessaire, passe par la reconnaissance des sentiments de honte et de culpabilité et par la renonciation au privilège. Enfin, le démantèlement des structures racistes présentes dans le monde médical permettra de s'attaquer à la nature systémique du racisme dans le milieu de la santé, au-delà des interventions au cas par cas. Tout un chacun trouvera un point de départ dans ce guide, car ce sont les actions simples et cohérentes qui favorisent le changement dans les sphères d'influence; l'effet d'entraînement que produisent les actions individuelles se traduira par un changement général des mentalités et des comportements.

Persistent Aortic Stiffness and Left Ventricular Hypertrophy in Children of Diabetic Mothers.

BACKGROUND: Fetuses of diabetic mothers develop left ventricular (LV) hypertrophy and are at increased long-term risk of cardiovascular disease. In our previous longitudinal study from midgestation to late infancy we showed persistence of LV hypertrophy and increased aortic stiffness compared with infants of healthy mothers, the latter of which correlated with third trimester maternal hemoglobin A1c. In the present study, we reexamined the same cohort in early childhood to determine if these cardiovascular abnormalities persisted. METHODS: Height, weight, and right arm blood pressure were recorded. A full functional and structural echocardiogram was performed with offline analysis of LV posterior wall and interventricular septal diastolic thickness (IVSd), systolic and diastolic function, and aortic pulse wave velocity. Vascular reactivity was assessed using digital thermal monitoring. Participants also completed a physical activity questionnaire. RESULTS: Twenty-five children of diabetic mothers (CDMs) and 20 children from healthy pregnancies (mean age, 5.6 ± 1.7 and 5.3 ± 1.3 years, respectively; P = not significant) were assessed. Compared with controls, IVSd z score was increased in CDMs (1.2 ± 0.6 vs 0.5 ± 0.3, respectively; P = 0.006), with one-fifth having a z score of more than +2.0. Aortic pulse wave velocity was increased in CDMs (3.2 ± 0.6 m/s vs 2.2 ± 0.4 m/s; P = 0.001), and correlated with IVSd z score (R 2 = 0.81; P = 0.001) and third trimester maternal A1c (R 2 = 0.65; P < 0.0001). Body surface area, height, weight, blood pressure, vascular reactivity, and physical activity scores did not differ between groups. Our longitudinal analysis showed that individuals with greater IVSd, and aortic stiffness in utero, early and late infancy also tended to have greater measures in early childhood (P < 0.001 and P < 0.0001, respectively). CONCLUSIONS: CDMs show persistently increased interventricular septal thickness and aortic stiffness in early childhood.

INTRODUCTION: Les fœtus des mères diabétiques présentent une hypertrophie du ventricule gauche (VG) et sont exposés à un risque accru à long terme de souffrir d'une maladie cardiovasculaire. Dans notre étude longitudinale précédente qui portait sur la période mi-gestationnelle à la fin de la première enfance, nous avons montré la persistance de l'hypertrophie du VG et l'augmentation de la rigidité aortique par rapport aux bébés des mères bien portantes, qui sont en corrélation avec le troisième trimestre de l'hémoglobine A1c maternelle. Dans la présente étude, nous avons réexaminé la même cohorte au début de la seconde enfance pour déterminer si ces anomalies cardiovasculaires persistaient. MÉTHODES: Nous avons enregistré la taille, le poids et la pression artérielle au bras droit. Nous avons réalisé une échocardiographie complète pour évaluer l'état fonctionnel et structurel par analyse hors ligne de la paroi postérieure du VG et de l'épaisseur du septum interventriculaire en diastole (SIVd), la fonction systolique et diastolique, et la vitesse de l'onde de pouls aortique. Nous avons évalué la réactivité vasculaire à l'aide de la surveillance thermique numérique. Les participants ont également rempli un questionnaire sur l'activité physique. RÉSULTATS: Vingt-cinq enfants issus de mères diabétiques (EMD) et 20 enfants de mères bien portantes (âge moyen, 5,6 ± 1,7 et 5,3 ± 1,3 ans, respectivement ; P = non significatif) ont fait l'objet d'une évaluation. Comparativement aux témoins, les EMD avaient un score z du SIVd plus élevé (1,2 ± 0,6 vs 0,5 ± 0,3, respectivement ; P = 0,006), et un cinquième de ces enfants avaient un score z de plus de +2,0. La vitesse de l'onde de pouls aortique était plus élevée chez les EMD (3,2 ± 0,6 m/s vs 2,2 ± 0,4 m/s ; P = 0,001), et était en corrélation avec le score z du SIVd (R 2 = 0,81 ; P = 0,001) et le troisième trimestre de l'A1c maternelle (R 2 = 0,65 ; P < 0,0001). Les scores de la surface corporelle, la taille, le poids, la pression artérielle, la réactivité vasculaire et l'activité physique ne différaient pas entre les groupes. Notre étude longitudinale a montré que les individus qui avaient une plus grande SIVd et une rigidité aortique in utero, au début et à la fin de la première enfance, avaient également tendance à avoir des mesures plus grandes au début de la seconde enfance (P < 0,001 et P < 0,0001, respectivement). CONCLUSIONS: Les EMD montrent une persistance de l'augmentation de l'épaisseur du septum interventriculaire et de l'augmentation de la rigidité aortique au début de la seconde enfance.

Medical education advances and innovations: A silver lining during the COVID-19 pandemic.

The COVID-19 pandemic has disrupted healthcare processes substantially including medical education, necessitating several changes along the spectrum of medical training. While this crisis presents major challenges to medical education, it is also an immense opportunity for innovation. In this commentary, Canadian medical students cast a spotlight on four domains of Canadian medical education which have seen substantial changes during the COVID-19 pandemic: medical school admissions, pre-clerkship content delivery, virtual care and telemedicine curricula, and the residency matching process. Using the 10 recommendations noted in the Association of Faculties of Medicine of Canada (AFMC) 2010 Future of Medical Education in Canada report as a guiding framework, we discuss why these changes represent key steps forward that should be preserved in medical education beyond the pandemic, and advocate for a continuous quality improvement approach to evaluate and implement these innovations.

La pandémie COVID-19 a considérablement perturbé les processus de soins de santé, y compris l'éducation médicale, ce qui a nécessité plusieurs changements dans le spectre de la formation médicale. Si cette crise pose des défis majeurs en éducation médicale, elle constitue également une immense opportunité d'innovation. Dans ce commentaire, les étudiants en médecine canadiens mettent en lumière quatre domaines de l'éducation médicale canadienne qui ont connu des changements substantiels durant la pandémie COVID-19 : les admissions dans les facultés de médecine, enseignement des cours au pré-externat, les cursus de soins virtuels et de télémédecine, et le processus de jumelage des résidents. En utilisant les 10 recommandations mentionnées dans le rapport 2010 sur l'avenir de l'enseignement médical au Canada de l'Association des facultés de médecine du Canada (AFMC) comme cadre d'orientation, nous expliquons pourquoi ces changements représentent des étapes clés qui devraient être préservées en éducation médicale au-delà de la pandémie, et nous préconisons une approche d'amélioration continue de la qualité pour évaluer et mettre en œuvre ces innovations.

Intrauterine exposure to chronic hypoxia in the rat leads to progressive diastolic function and increased aortic stiffness from early postnatal developmental stages.

AIM: We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages. METHODS: Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2 ) from embryonic day E15-21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro-sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively. RESULTS: Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p < .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1-2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E'/A' tissue velocities compared to controls (p < .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p < .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p < .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4. CONCLUSION: Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages.

Fluorescent Hexose Conjugates Establish Stringent Stereochemical Requirement by GLUT5 for Recognition and Transport of Monosaccharides.

The specificity characteristics of transporters can be exploited for the development of novel diagnostic therapeutic probes. The facilitated hexose transporter family (GLUTs) has a distinct set of preferences for monosaccharide substrates, and while some are expressed ubiquitously (e.g., GLUT1), others are quite tissue specific (e.g., GLUT5, which is overexpressed in some breast cancer tissues). While these differences have enabled the development of new molecular probes based upon hexose- and tissue-selective uptake, substrate design for compounds targeting these GLUT transporters has been encumbered by a limited understanding of the molecular interactions at play in hexose binding and transport. Four new fluorescently labeled hexose derivatives have been prepared, and their transport characteristics were examined in two breast cancer cell lines expressing mainly GLUTs 1, 2, and 5. Our results demonstrate, for the first time, a stringent stereochemical requirement for recognition and transport by GLUT5. 6-NBDF, in which all substituents are in the d-fructose configuration, is taken up rapidly into both cell lines via GLUT5. On the other hand, inversion of a single stereocenter at C-3 (6-NBDP), C-4 (6-NBDT), or C-5 (6-NDBS) results in selective transport via GLUT1. An in silico docking study employing the recently published GLUT5 crystal structure confirms this stereochemical dependence. This work provides insight into hexose-GLUT interactions at the molecular level and will facilitate structure-based design of novel substrates targeting individual members of the GLUT family and forms the basis of new cancer imaging or therapeutic agents.