A new methodological framework for hazard detection models in health information technology systems.

The adoption of health information technology (HIT) has facilitated efforts to increase the quality and efficiency of health care services and decrease health care overhead while simultaneously generating massive amounts of digital information stored in electronic health records (EHRs). However, due to patient safety issues resulting from the use of HIT systems, there is an emerging need to develop and implement hazard detection tools to identify and mitigate risks to patients. This paper presents a new methodological framework to develop hazard detection models and to demonstrate its capability by using the US Department of Veterans Affairs' (VA) Corporate Data Warehouse, the data repository for the VA's EHR. The overall purpose of the framework is to provide structure for research and communication about research results. One objective is to decrease the communication barriers between interdisciplinary research stakeholders and to provide structure for detecting hazards and risks to patient safety introduced by HIT systems through errors in the collection, transmission, use, and processing of data in the EHR, as well as potential programming or configuration errors in these HIT systems. A nine-stage framework was created, which comprises programs about feature extraction, detector development, and detector optimization, as well as a support environment for evaluating detector models. The framework forms the foundation for developing hazard detection tools and the foundation for adapting methods to particular HIT systems.

Real-Time Automated Hazard Detection Framework for Health Information Technology Systems.

An increase in the reliability of Health Information Technology (HIT) will facilitate institutional trust and credibility of the systems. In this paper, we present an end-to-end framework for improving the reliability and performance of HIT systems. Specifically, we describe the system model, present some of the methods that drive the model, and discuss an initial implementation of two of the proposed methods using data from the Veterans Affairs HIT and Corporate Data Warehouse systems. The contributions of this paper, thus, include (1) the design of a system model for monitoring and detecting hazards in HIT systems, (2) a data-driven approach for analysing the health care data warehouse, (3) analytical methods for characterising and analysing failures in HIT systems, and (4) a tool architecture for generating and reporting hazards in HIT systems. Our goal is to work towards an automated system that will help identify opportunities for improvements in HIT systems.

aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation.

The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation.

The lifelong self-renewal of the epidermis is driven by a progenitor cell population with high proliferative potential. To date, the upstream signals that determine this potential have remained largely elusive. Here, we find that insulin and insulin-like growth factor receptors (IR and IGF-1R) determine epidermal proliferative potential and cooperatively regulate interfollicular epidermal morphogenesis in a cell autonomous manner. Epidermal deletion of either IR or IGF-1R or both in mice progressively decreased epidermal thickness without affecting differentiation or apoptosis. Proliferation was temporarily reduced at E17.5 in the absence of IGF-1R but not IR. In contrast, clonogenic capacity was impaired in both IR- and IGF-1R-deficient primary keratinocytes, concomitant with an in vivo loss of keratin 15. Together with a reduction in label-retaining cells in the interfollicular epidermis, this suggests that IR/IGF-1R regulate progenitor cells. The expression of dominant active Rac rescued clonogenic potential of IR/IGF-1R-negative keratinocytes and reversed epidermal thinning in vivo. Our results identify the small GTPase Rac as a key target of epidermal IR/IGF-1R signalling crucial for proliferative potential and interfollicular morphogenesis.

Nutrient sensing by the early mouse embryo: hexosamine biosynthesis and glucose signaling during preimplantation development.

Although mouse oocytes and cleavage-stage embryos are unable to utilize glucose as a metabolic fuel, they have a specific requirement for a short exposure to glucose prior to compaction. The reason for this requirement has been unclear. In this study we confirm that cleavage-stage exposure to glucose is required for blastocyst formation and show that the absence of glucose between 18-64 h after hCG causes an irreversible decrease in cellular proliferation and an increase in apoptosis. More importantly, this glucose signals to activate expression of Slc2a3 transcript and SLC2A3 protein, a facilitative glucose transporter (previously known as GLUT3) associated with developmental competence and increased glucose uptake used to fuel blastocyst formation. Glucosamine could substitute for glucose in these roles, suggesting that hexosamine biosynthesis may be a nutrient-sensing mechanism involved in metabolic differentiation. Inhibition of the rate-limiting enzyme in this pathway, glutamine-fructose-6-phosphate amidotransferase (GFPT), inhibited expression of the SLC2A3 transporter protein and blastocyst formation. Glucosamine, a substrate that enters this pathway downstream of GFPT, was able to overcome this inhibition and support SLC2A3 expression. These data suggest that early embryos rely on hexosamine biosynthesis as a glucose-sensing pathway to initiate metabolic differentiation.

Cinderella no longer: alpha-catenin steps out of cadherin's shadow.

To date, alpha-catenin has been best understood as an important cytoplasmic component of the classical cadherin complex responsible for cell-cell adhesion. By virtue of its capacity to bind F-actin, alpha-catenin was commonly envisaged to support cadherin function by coupling the adhesion receptor to the actin cytoskeleton. But is alpha-catenin solely the cadherin's handmaiden? A range of recent developments suggest, instead, that its biological activity is much more complex than previously appreciated. Evidence from cellular systems and model organisms demonstrates a clear, often dramatic, role for alpha-catenin in tissue organization and morphogenesis. The morphogenetic impact of alpha-catenin reflects its capacity to mediate functional cooperation between cadherins and the actin cytoskeleton, but is not confined to this. alpha-catenin has a role in regulating cell proliferation and cadherin-independent pools of alpha-catenin may contribute to its functional impact.

Ena/VASP proteins can regulate distinct modes of actin organization at cadherin-adhesive contacts.

Functional interactions between classical cadherins and the actin cytoskeleton involve diverse actin activities, including filament nucleation, cross-linking, and bundling. In this report, we explored the capacity of Ena/VASP proteins to regulate the actin cytoskeleton at cadherin-adhesive contacts. We extended the observation that Ena/vasodilator-stimulated phosphoprotein (VASP) proteins localize at cell-cell contacts to demonstrate that E-cadherin homophilic ligation is sufficient to recruit Mena to adhesion sites. Ena/VASP activity was necessary both for F-actin accumulation and assembly at cell-cell contacts. Moreover, we identified two distinct pools of Mena within individual homophilic adhesions that cells made when they adhered to cadherin-coated substrata. These Mena pools localized with Arp2/3-driven cellular protrusions as well as at the tips of cadherin-based actin bundles. Importantly, Ena/VASP activity was necessary for both modes of actin activity to be expressed. Moreover, selective depletion of Ena/VASP proteins from the tips of cadherin-based bundles perturbed the bundles without affecting the protrusive F-actin pool. We propose that Ena/VASP proteins may serve as higher order regulators of the cytoskeleton at cadherin contacts through their ability to modulate distinct modes of actin organization at those contacts.

Arp2/3 activity is necessary for efficient formation of E-cadherin adhesive contacts.

Classical cadherin adhesion molecules are fundamental determinants of cell-cell recognition that function in cooperation with the actin cytoskeleton. Productive cadherin-based cell recognition is characterized by a distinct morphological process of contact zone extension, where limited initial points of adhesion are progressively expanded into broad zones of contact. We recently demonstrated that E-cadherin ligation recruits the Arp2/3 actin nucleator complex to the plasma membrane in regions where cell contacts are undergoing protrusion and extension. This suggested that Arp2/3 might generate the protrusive forces necessary for cell surfaces to extend upon one another during contact assembly. We tested this hypothesis in mammalian cells by exogenously expressing the CA region of N-WASP. This fragment, which potently inhibits Arp2/3-mediated actin assembly in vitro, also effectively reduced actin assembly at cadherin adhesive contacts. Blocking Arp2/3 activity by this strategy profoundly reduced the ability of cells to extend cadherin adhesive contacts but did not affect cell adhesiveness. These findings demonstrate that Arp2/3 activity is necessary for cells to efficiently extend and assemble cadherin-based adhesive contacts.