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Introduction: Multidisciplinary clinics in academic settings are often inefficient and can lead to lengthy clinic visits for patients and staff. Aim: We aimed to use quality improvement (QI) methodology and a multidisciplinary approach to optimize outpatient comprehensive haemophilia clinic flow. Methods: At baseline, a multidisciplinary QI team created a key driver diagram to identify drivers of haemophilia clinic flow. Identified drivers included patient needs/scheduling, provider flow and laboratory/research requirements. From December 2016 to August 2017, value stream mapping (VSM) was used to identify barriers to clinic flow, and plan–do–study–act cycles were used to address these barriers. Interventions included (a) standardizing the order in which providers saw patients to enable time‐sensitive laboratories, (b) improving HTC team meeting functionality, (c) optimizing a visual management board and implementing a flow coordinator, (d) initiating a team huddle prior to clinic start and (e) modifying the clinic appointment template. Timely laboratory draw was used as a surrogate marker of clinic flow, and VSM utilization percentage was used as an objective measure of efficiency. Results: We did not demonstrate a statistically significant improvement in timed laboratory draws; however, clinic utilization percentage increased by 30%, which resulted in adding point‐of‐care musculoskeletal ultrasound services without lengthening clinic duration. Conclusion: Quality improvement methodology is an effective means of improving clinic utilization in a multidisciplinary clinic. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Established guidelines from the American Academy of Pediatrics for the care of patients with Down syndrome are often not followed. Our goal was to integrate aspects of the guidelines into the electronic health record (EHR) to improve guideline adherence throughout a child's life span. METHODS: Two methods of EHR integration with age-based logic were created and implemented in June 2016: (1) a best-practice advisory that prompts an order for referral to genetics; and (2) a health maintenance record that tracks completion of complete blood cell count and/or hemoglobin testing, thyrotropin testing, echocardiogram, and sleep study. Retrospective chart review of patients with Down syndrome and visits to locations with EHR integration (NICUs, primary care centers, and genetics clinics) assessed adherence to the components of EHR integration; the impact was analyzed through statistical process control charts. RESULTS: From July 2015 to October 2017, 235 patients with Down syndrome (ages 0 to 32 years) had 466 visits to the EHR integration locations. Baseline adherence for individual components ranged from 51% (sleep study and hemoglobin testing) to 94% (echocardiogram). EHR integration was associated with a shift in adherence to all select recommendations from 61.6% to 77.3% (P < .001) including: genetic counseling, complete blood cell count and/or hemoglobin testing, thyrotropin testing, echocardiogram, and sleep study. CONCLUSIONS: Integrating specific aspects of Down syndrome care into the EHR can improve adherence to guideline recommendations that span the life of a child. Future quality improvement should be focused on older children and adults with Down syndrome. [ABSTRACT FROM AUTHOR]

Objective The Apgar score has been shown to have utility in predicting mortality in the extremely preterm infant in delivery hospital populations, where most mortality occurs within 12 hours of birth. We tested the hypothesis that the 5 minute Apgar score would remain associated with mortality in extremely preterm infants after transfer from the delivery hospital to an all referral neonatal intensive care unit at an average age of 10 days. Study Design A retrospective analysis of 454 infants born at < 27 weeks gestation. Results The median Apgar score was 3 at 1 minute (interquartile range [IQR] 2-6) and 6 at 5 minutes (IQR 4-7). The Apgar score increased from 1 to 5 minutes by 2.0 ±1.7 (p < 0.001). In logistic regression modeling, an Apgar score of < 5 at 5 minutes was associated with an increased mortality (odds ratio 1.76 [95% confidence interval 1.06-2.94], p < 0.05), but not morbidities. Conclusion Infants born at < 27 weeks gestation admitted to an all referral children's hospital at a mean age of 10 days with a 5 minute Apgar < 5 are at an increased risk of mortality. Our findings continue to support the importance of the Apgar score given at delivery even in the extremely preterm infant referred to a nondelivery children's hospital. [ABSTRACT FROM AUTHOR]

Defects in cardiac valve morphogenesis and septation of the heart chambers constitute some of the most common human congenital abnormalities. Some of these defects originate from errors in atrioventricular (AV) endocardial cushion development. Although this process is being extensively studied in mouse and chick, the zebrafish system presents several advantages over these models, including the ability to carry out forward genetic screens and study vertebrate gene function at the single cell level. In this paper, we analyze the cellular and subcellular architecture of the zebrafish heart during stages of AV cushion and valve development and gain an unprecedented level of resolution into this process. We find that endocardial cells in the AV canal differentiate morphologically before the onset of epithelial to mesenchymal transformation, thereby defining a previously unappreciated step during AV valve formation. We use a combination of novel transgenic lines and fluorescent immunohistochemistry to analyze further the role of various genetic (Notch and Calcineurin signaling) and epigenetic (heart function) pathways in this process. In addition, from a large-scale forward genetic screen we identified 55 mutants, defining 48 different genes, that exhibit defects in discrete stages of AV cushion development. This collection of mutants provides a unique set of tools to further our understanding of the genetic basis of cell behavior and differentiation during AV valve development. [ABSTRACT FROM AUTHOR]

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih−/−) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk−/−) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk−/− embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfks11 variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease. Cardiac anomolies can result from very early defects in heart development. In zebrafish, such defects have been shown to be caused by a new gene called cardiofunk. [ABSTRACT FROM AUTHOR]

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih-/- ) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk-/- ) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk-/- embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfks11 variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Safety I error elimination concepts are focused on retrospectively investigating what went wrong and redesigning system processes and individual behaviors to prevent similar future occurrences. The Safety II approach recognizes complex systems and unpredictable circumstances, mandating flexibility and resilience within systems and among individuals to avoid errors. We hypothesized that in our high-complexity and high-risk PICU, Safety II concepts contribute to its remarkably low adverse drug event rate. Our goal was to identify how this microsystem enacts Safety II. METHODS: We conducted multidisciplinary focus group sessions with PICU members using nonleading, open-ended questions to elicit free-form conversation regarding how safety occurs in their unit. Qualitatively analyzing transcripts identified system characteristics and behaviors potentially contributing to low adverse drug event rates in PICU. Researchers skilled in qualitative methodologies coded transcripts to identify key domains and common themes. RESULTS: Four domains were identified: (1) individual characteristics, (2) relationships and interactions, (3) structural and environmental characteristics, and (4) innovation approaches. The themes identified in the first 3 domains are typically associated with Safety I and adapted for Safety II. Themes in the last domain (innovation approaches) were specific to Safety II, which were layered on Safety I to improve results under unusual situations. CONCLUSIONS: Safety II behavior in this unit was based on strong Safety I behaviors adapted to the Safety II environment plus innovation behaviors specific to Safety II situations. We believe these behaviors can be taught and learned. We intend to spread these concepts throughout the organization. [ABSTRACT FROM AUTHOR]

Mutations in cardiac actin (ACTC) have been associated with different cardiac abnormalities in humans, including dilated cardiomyopathy and septal defects. However, it is still poorly understood how altered ACTC structure affects cardiovascular physiology and results in the development of distinct congenital disorders. A zebrafish mutant (s434 mutation) was identified that displays blood regurgitation in a dilated heart and lacks endocardial cushion (EC) formation. We identified the mutation as a single nucleotide change in the alpha-cardiac actin 1a gene (actc1a), resulting in a Y169S amino acid substitution. This mutation is located at the W-loop of actin, which has been implicated in nucleotide sensing. Consequently, s434 mutants show loss of polymerized cardiac actin. An analogous mutation in yeast actin results in rapid depolymerization of F-actin into fragments that cannot reanneal. This polymerization defect can be partially rescued by phalloidin treatment, which stabilizes F-actin. In addition, actc1a mutants show defects in cardiac contractility and altered blood flow within the heart tube. This leads to downregulation or mislocalization of EC-specific gene expression and results in the absence of EC development. Our study underscores the importance of the W-loop for actin functionality and will help us to understand the structural and physiological consequences of ACTC mutations in human congenital disorders. [ABSTRACT FROM AUTHOR]

CULLIN 2 (CUL2) is a component of the ElonginB/C-CUL2- RBX-1-Von Hippel-Lindau (VHL) tumor suppressor complex that ubiquitinates and degrades hypoxia-inducible factor a (HIFα). HIFα is a transcription factor that mediates the expression of hypoxia-sensitive genes, including vascular endothelial growth factor (VEGF), which in turn regulates vasculogenesis. Whereas CUL2 participates in the degradation of HIFα, the potential role of CUL2 in the regulation of other cellular processes is less well established. In the present study, suppression of CUL2 expression by Cu12 siRNA inhibited HIFα transcriptional activation of the VEGF gene in vitro, indicating that CUL2 plays a role distinct from its known function in HIFα degradation. Because ARNT heterodimerizes with HIFα, we assessed whether CUL2 influenced ARNT expression. Cul2 siRNA inhibited the expression of endogenous ARNT. Ectopically expressed ARNT reversed the inhibition of HIF activity by Cu12 siRNA in the VEGF promoter, suggesting that CUL2 regulates HIF activation through ARNT. In 786-O cells lacking VHL, Cu12 siRNA suppressed the expression of both ARNT and VEGF, indicating that CUL2 regulates HIF activity independently of VHL. In transgenic zebrafish expressing GFP driven by the Elk promoter (a known HIF target), zCul2 morpholino blocked embryonic vasculogenesis in a manner similar to that caused by inhibition of VEGF-A. In the zebrafish embryos, zCul2 lnhibited the expression of CUL2, VEGF, and Flk-GFP protein, indicating that CUL2 is required for expression of other vasculogenic HIF targets. Taken together, CUL2 is required for normal vasculo-genesis, at least in part mediated by its regulation of HIF-mediated transcription. [ABSTRACT FROM AUTHOR]