Unusual Neuroimaging in a Case of Rapidly Progressive Juvenile-Onset Krabbe Disease.

Krabbe disease is a progressive neurologic disorder caused by deficiency of the lysosomal enzyme galactocerebrosidase. The disease commonly has an early-infantile onset, but can have late-infantile, juvenile, or adult-onset phenotypes. Classic computed tomography (CT) and magnetic resonance imaging (MRI) findings in Krabbe have been well described. We report a patient, ultimately diagnosed with juvenile-onset Krabbe, who presented with atypical CT imaging and rapid disease progression. Our patient was a previously healthy and developmentally appropriate female who presented at 3 years 4 months of age with ataxia and motor regression that had progressed over the course of 6 weeks without an identifiable catalyst. CT, performed in the emergency setting, demonstrated extensive white matter hyperdensity. Subsequent MRI showed T2 hyperintensity of the white matter corresponding to the areas of hyperdensity on the CT, as well as enhancement of multiple cranial nerves bilaterally, suggestive of Krabbe disease. Enzymatic testing demonstrated low galactocerebrosidase activity and molecular testing of GALC revealed compound heterozygosity for 2 known pathogenic mutations, consistent with a diagnosis of Krabbe Disease. This included the common 30-kb deletion and a known pathogenic mutation associated with juvenile/adult-onset disease. Our patient's diffuse hyperdensity on CT offers a new radiographic finding to include in the repertoire of Krabbe imaging, and thus aide in the diagnostic evaluation. The rapidity of progression our patient demonstrated is additionally unique and should be considered in the identification of juvenile Krabbe as well as the complicated decision-making process regarding potential treatments.

Developing a Center for Education Research and Scholarship in a Department of Pediatrics.

This article was migrated. The article was marked as recommended. Background The skills needed to engage in scholarship in medical education are not part of the training that all physicians acquire. To build skills and promote scholarship, we developed a Center for Education Research and Scholarship (CERS) in the Department of Pediatrics at the University of Colorado. In this paper, we offer recommendations for others who seek to establish departmental-level efforts to support education. Approach and Lessons Learned CERS provides an "education home" for those interested in education scholarship, supplementing campus-wide efforts such as an Academy of Medical Educators. Mentorship from two experienced leaders in medical education provided a foundation for other faculty in the department and helped to build scholarship efforts more broadly. Through a weekly meeting and an annual departmental retreat, CERS provides opportunities for community among educators, faculty development in the skills needed to engage in education research, and a forum for generating ideas and planning projects. Essential resources for success include at least one leader with expertise in educational research, an administrative and/or research assistant, and some funding for faculty time and initiation of projects. Mentors with experience in education research and scholarship are also needed, although a group of mentors quickly grows as more individuals engage. Results Benefits to the department include peer-reviewed presentations and publications in medical education, with regional, national, and international recognition. Faculty members can focus on medical education as a key component of their careers, and the quality of education programs is enhanced. Conclusions While it takes time to fully develop a departmental center for education scholarship, it is possible to start small and grow. One or two leaders in education with vision can begin the effort and engage others, and the faculty will begin to experience the satisfaction of collaborative projects in education, successful innovation, and dissemination of scholarship.

If You Build It, Will They Come? A Hard Lesson for Enthusiastic Medical Educators Developing a New Curriculum.

BACKGROUND: Primary care forms a critical part of pediatricians' practices, yet the most effective ways to teach primary care during residency are not known. OBJECTIVE: We established a new primary care curriculum based on Malcolm Knowles' theory of andragogy, with brief clinical content that is easily accessible and available in different formats. METHODS: We used Kern's model to create a curriculum. In 2013, we implemented weekly e-mails with links to materials on our learning management system, including moderators' curricular content, resident-developed quizzes, and podcasts. After 3 years, we evaluated the curriculum with resident focus groups, retrospective pre-/post-resident surveys, faculty feedback, a review of materials accessed, and resident attendance. RESULTS: From content analysis of focus groups we learned that residents found the curriculum beneficial, but it was not always possible to do the pre-work. The resident survey, with a response rate of 87% (71 of 82), showed that residents perceived improvement in 37 primary care clinical skills, with differences from 0.64 to 1.46 for scales 1-5 (P < .001 for all). Faculty feedback was positive regarding curriculum organization and structure, but patient care often precluded devoting time to discussing the curriculum. In other ways, our results were disappointing: 51% of residents did not access the curriculum materials, 51% did not open their e-mails, only 37% completed any of the quizzes, and they attended a weekly conference 46% of the time. CONCLUSIONS: Although residents accessed the curriculum less than expected, their self-assessments reflect perceptions of improvement in their clinical skills after implementation.

Right Care for Children: Top Five Do's and Don'ts.

Underuse and overuse of medical interventions, failure to use interventions known to be effective, and provision of tests or interventions in which benefits do not exceed harms are types of low-value care. The Lown Institute's Right Care Alliance Children's Health Council identified five "do" recommendations that highlight underuse and five "don't" recommendations that highlight overuse in children's health care. The five "do" recommendations include: do provide access to long-acting reversible contraception for adolescents, do use nonpharmacologic interventions first for treatment of attention-deficit/hyperactivity disorder, do discuss quality of life for children with complex medical conditions using a shared decision-making model and access resources such as palliative care subspecialists, do promote childhood literacy development by providing free, age-appropriate books in clinical settings, and do screen for socioeconomic status of the patient and family and provide access to community health and wellness resources. The five "don't" recommendations include: don't routinely prescribe antibiotics in children two to 12 years of age with a middle ear infection, don't perform computed tomography of the head for children with minor head trauma, don't use albuterol in children with bronchiolitis, don't routinely screen for hyperlipidemia in children and adolescents, and don't routinely perform preparticipation sports evaluations. These 10 examples of underuse and overuse were identified with the intent of improving health care value and promoting "Right Care."

School Health: Pediatric Primary Care Curriculum.

Introduction: Pediatric residents encounter issues related to school health (SH) throughout their training, particularly in their continuity clinics, and often serve as liaisons between a patient's medical home and school environment. However, there is currently a paucity of formal education on SH for pediatric residents to prepare them for this role. Methods: We created a 3-hour interactive learning conference that was delivered to four groups of six to eight pediatric residents during their intern year by a multidisciplinary team. Our curriculum focused on understanding the differences between individualized educational plans (IEPs), individualized health plans (IHPs), and 504 plans; the IEP process; and communication with schools. Residents were given pre- and postdidactic surveys, completed reflective writings, and participated in feedback sessions. Results: Twenty-seven pediatric interns completed the curriculum; 85% and 74% had improved knowledge of IEP/504/IHP and SH personnel, respectively. Eighty-five percent reported feeling comfortable with family conversations about accommodations postcurriculum versus 0% precurriculum. The majority of interns found the curriculum to be valuable to their clinic performance. Discussion: Our curriculum offers a unique multidisciplinary approach to teaching and can be easily integrated into other residency programs, even with limited protected didactic time.

Acute Otitis Media Curriculum.

INTRODUCTION: Studies have shown that clinicians do a poor job of diagnosing middle ear infections, and an inaccurate diagnosis may result in inappropriate treatment, such as overuse of antibiotics. Antibiotic overuse is known to lead to increased bacterial resistance and puts patients at risk of deleterious side effects, including allergic reactions, vomiting, diarrhea, and rash. In this curriculum, we teach three important topics for achieving a successful middle ear exam and diagnosis of pathology. METHODS: The topics covered during the session are middle ear examination techniques, diagnosis of middle ear pathology and criteria for diagnosing acute otitis media, and treatment of acute otitis media. Each topic has a 30-minute lesson plan with broad goals, specific and measurable learning objectives, interactive learning activities, and assessment measures. Teaching activities include a mix of knowledge, skill, and attitude activities. Assessment measures aim at the highest level of Miller's pyramid of assessment when possible. Also included is a scholarship map that relates how this learning activity can fit into the assessment of learners at the program level by linking learning objectives with pediatric developmental milestones. RESULTS: The interactive nature of these lessons has been very well received by learners, and pediatric residents have had a self-perceived increase in skills. DISCUSSION: This curriculum provides a standardized approach to teaching the middle ear exam structured by educational rubrics and allows for accurate assessment of learners.

Urinary Tract Infections: Pediatric Primary Care Curriculum Podcast.

INTRODUCTION: Demands on residents' time during training make it difficult for them to engage consistently with a primary care curriculum. In response to this, the emergency medicine and critical care fields have successfully utilized podcasting to the point where a recent study showed US emergency medicine residents ranked podcasts as the best use of their time for extracurricular education. METHODS: We produced a 30-minute podcast on urinary tract infections from a primary care perspective, based on descriptors from Entrustable Professional Activity 4, "Manage acute common illnesses in the ambulatory setting." A moderator, a primary care pediatrician, and a pediatric nephrologist used a loose script of salient points, allowing for a natural evolution of the dialogue. The podcast was distributed to residents via email, along with a 7-question survey. RESULTS: The survey was completed by 50 out of 84 residents. Ninety-two percent listened to all or part of the podcast, 98% found it educational, 93% enjoyed listening, and 74% felt more confident identifying and managing patients with possible urinary tract infections after listening. Ninety-six percent felt podcasts were a good alternative method for delivering this curriculum. One comment read, "This was great! It makes the information more accessible so that I can listen while working out or driving or just laying on the couch." DISCUSSION: Based on this success, we are producing additional podcasts and will strive to keep them under 20 minutes, provide key summary points at the end, and improve ease of access by utilizing an RSS (rich site summary) feed.

In silico identification of potential therapeutic targets in the TGF-ß signal transduction pathway.

The transforming growth factor-ß (TGF-ß) superfamily of cytokines controls fundamental cellular processes, such as proliferation, motility, differentiation, and apoptosis. This fundamental role is emphasized by the widespread presence of mutations of the core components of the TGF-ß signal transduction pathway in a number of human diseases. Therefore, there is an increasing interest in the development of therapies to specifically target this pathway. Here we develop a computational approach to identify potential intervention points that are capable of restoring the normal signaling dynamics to the mutated system while maintaining the behavior of normal cells substantially unperturbed. We apply this approach explicitly to the TGF-ß pathway to study the signaling dynamics of mutated and normal cells treated with inhibitory drugs and identify the processes in the pathway that are most susceptible to therapeutic intervention.

Computational modelling of Smad-mediated negative feedback and crosstalk in the TGF-ß superfamily network.

The transforming growth factor-ß (TGF-ß) signal transduction pathway controls many cellular processes, including differentiation, proliferation and apoptosis. It plays a fundamental role during development and it is dysregulated in many diseases. The factors that control the dynamics of the pathway, however, are not fully elucidated yet and so far computational approaches have been very limited in capturing the distinct types of behaviour observed under different cellular backgrounds and conditions into a single-model description. Here, we develop a detailed computational model for TGF-ß signalling that incorporates elements of previous models together with crosstalking between Smad1/5/8 and Smad2/3 channels through a negative feedback loop dependent on Smad7. The resulting model accurately reproduces the diverse behaviour of experimental datasets for human keratinocytes, bovine aortic endothelial cells and mouse mesenchymal cells, capturing the dynamics of activation and nucleocytoplasmic shuttling of both R-Smad channels. The analysis of the model dynamics and its system properties revealed Smad7-mediated crosstalking between Smad1/5/8 and Smad2/3 channels as a major determinant in shaping the distinct responses to single and multiple ligand stimulation for different cell types.

Characterization of negative feedback network motifs in the TGF-ß signaling pathway.

The transforming growth factor-ß (TGF-ß) superfamily of cytokines plays a fundamental role in a wide variety of cellular processes, including growth, differentiation, apoptosis, and tissue homeostasis [corrected]. Its relevance is emphasized by the mutations of its core components that are associated with diverse human diseases, such as cancer and cardiovascular pathologies. A prominent regulator of the pathway is Smad7, which attenuates the signal and controls its duration in a cell-type-dependent manner through a negative feedback loop. Here, we characterize all the potential Smad7-mediated negative feedback network motifs and investigate their effects on the signaling dynamics upon stimulation with TGF-ß and bone morphogenetic protein (BMP) ligands. The results show that the specific negative feedback implementation is a key determinant of both the response of the system to single and multiple ligands of the TGF-ß superfamily and its robustness and sensitivity to parameter perturbations.

A synthetic biology approach to self-regulatory recombinant protein production in Escherichia coli.

BACKGROUND: Recombinant protein production is a process of great industrial interest, with products that range from pharmaceuticals to biofuels. Since high level production of recombinant protein imposes significant stress in the host organism, several methods have been developed over the years to optimize protein production. So far, these trial-and-error techniques have proved laborious and sensitive to process parameters, while there has been no attempt to address the problem by applying Synthetic Biology principles and methods, such as integration of standardized parts in novel synthetic circuits. RESULTS: We present a novel self-regulatory protein production system that couples the control of recombinant protein production with a stress-induced, negative feedback mechanism. The synthetic circuit allows the down-regulation of recombinant protein expression through a stress-induced promoter. We used E. coli as the host organism, since it is widely used in recombinant processes. Our results show that the introduction of the self-regulatory circuit increases the soluble/insoluble ratio of recombinant protein at the expense of total protein yield. To further elucidate the dynamics of the system, we developed a computational model that is in agreement with the observed experimental data, and provides insight on the interplay between protein solubility and yield. CONCLUSION: Our work introduces the idea of a self-regulatory circuit for recombinant protein products, and paves the way for processes with reduced external control or monitoring needs. It demonstrates that the library of standard biological parts serves as a valuable resource for initial synthetic blocks that needs to be further refined to be successfully applied in practical problems of biotechnological significance. Finally, the development of a predictive model in conjunction with experimental validation facilitates a better understanding of the underlying dynamics and can be used as a guide to experimental design.