Nursing Documentation Variation Across Different Medical Facilities Within an Integrated Healthcare System.

The purpose of this study was to demonstrate nursing documentation variation based on electronic health record design and its relationship with different levels of care by reviewing how various flowsheet measures, within the same electronic health record across an integrated healthcare system, are documented in different types of medical facilities. Flowsheet data with information on patients who were admitted to academic medical centers, community hospitals, and rehabilitation centers were used to calculate the frequency of flowsheet entries documented. We then compared the distinct flowsheet measures documented in five flowsheet templates across the different facilities. We observed that each type of healthcare facility appeared to have distinct clinical care foci and flowsheet measures documented differed within the same template based on facility type. Designing flowsheets tailored to study settings can meet the needs of end users and increase documentation efficiency by reducing time spent on unrelated flowsheet measures. Furthermore, this process can save nurses time for direct patient care.

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma.

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.

RVX-297- a novel BD2 selective inhibitor of BET bromodomains.

Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.

Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low µM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1).

Cas5d processes pre-crRNA and is a member of a larger family of CRISPR RNA endonucleases.

Small RNAs derived from clustered, regularly interspaced, short palindromic repeat (CRISPR) loci in bacteria and archaea are involved in an adaptable and heritable gene-silencing pathway. Resistance to invasive genetic material is conferred by the incorporation of short DNA sequences derived from this material into the genome as CRISPR spacer elements separated by short repeat sequences. Processing of long primary transcripts (pre-crRNAs) containing these repeats by a CRISPR-associated (Cas) RNA endonuclease generates the mature effector RNAs that target foreign nucleic acid for degradation. Here we describe functional studies of a Cas5d ortholog, and high-resolution structural studies of a second Cas5d family member, demonstrating that Cas5d is a sequence-specific RNA endonuclease that cleaves CRISPR repeats and is thus responsible for processing of pre-crRNA. Analysis of the structural homology of Cas5d with the previously characterized Cse3 protein allows us to model the interaction of Cas5d with its RNA substrate and conclude that it is a member of a larger family of CRISPR RNA endonucleases.

Documentation Burden in Nursing and Its Role in Clinician Burnout Syndrome.

OBJECTIVES: The purpose of this study is to understand the relationship between documentation burden and clinician burnout syndrome in nurses working in direct patient care. The Office of the National Coordinator considers documentation burden a high priority problem. However, the presence of documentation burden in nurses working in direct patient care is not well known. Furthermore, the presence of documentation burden has not been linked to the development of clinician burnout syndrome. METHODS: This paper reports that the results of a cross-sectional survey study comprised of three tools: (1) The burden of documentation for nurses and mid-wives survey, (2) the system usability scale, and (3) Maslach's burnout inventory for medical professionals. RESULTS: Documentation burden has a weak to moderate correlation to clinician burnout syndrome. Furthermore, poor usability of the electronic health record (EHR) is also associated with documentation burden and clinician burnout syndrome. CONCLUSION: This study suggests that there is a relationship between documentation burden and clinician burnout syndrome. The correlation of poor usability and domains of clinician burnout syndrome implies the need for more work on improving the usability of EHR for nursing documentation. Further study regarding the presence of documentation burden and its correlation to clinician burnout syndrome should focus on specific areas of nursing to understand the drivers of documentation burden variation within and across specialty domains.

Role of pri-miRNA tertiary structure in miR-17~92 miRNA biogenesis.

MicroRNAs (miRNAs) regulate gene expression in a variety of biological pathways such as development and tumourigenesis. miRNAs are initially expressed as long primary transcripts (pri-miRNAs) that undergo sequential processing by Drosha and then Dicer to yield mature miRNAs. miR-17~92 is a miRNA cluster that encodes 6 miRNAs and while it is essential for development it also has reported oncogenic activity. To date, the role of RNA structure in miRNA biogenesis has only been considered in terms of the secondary structural elements required for processing of pri-miRNAs by Drosha. Here we report that the miR-17~92 cluster has a compact globular tertiary structure where miRNAs internalized within the core of the folded structure are processed less efficiently than miRNAs on the surface of the structure. Increased miR-92 expression resulting from disruption of the compact miR-17~92 structure results in increased repression of integrin α5 mRNA, a known target of miR-92a. In summary, we describe the first example of pri-miRNA structure modulating differential expression of constituent miRNAs.

Design and Synthesis of LM146, a Potent Inhibitor of PB1 with an Improved Selectivity Profile over SMARCA2.

PB1 is a bromodomain-containing protein hypothesized to act as the nucleosome-recognition subunit of the PBAF complex. Although PB1 is a key component of the PBAF chromatin remodeling complex, its exact role has not been elucidated due to the lack of potent and selective inhibitors. Chemical probes that target specific bromodomains within the complex would constitute highly valuable tools to characterize the function and therapeutic pertinence of PB1 and of each of its bromodomains. Here, we report the design and synthesis of lead compound LM146, which displays strong stabilization of the second and fifth bromodomains of PB1 as shown by DSF. LM146 does not interact with bromodomains outside of sub-family VIII and binds to PB1(2), PB1(5), and SMARCA2B with K D values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5) over SMARCA2.

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program.

PURPOSE: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. EXPERIMENTAL DESIGN: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. RESULTS: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. CONCLUSIONS: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

The Burden and Burnout in Documenting Patient Care: An Integrative Literature Review.

The implementation of the electronic health record (EHR) across the globe has increased significantly in the last decade. Motivations for this trend include patient safety, regulatory requirements, and healthcare cost containment. However, the impact of regulatory requirements and new EHRs on clinicians has increased the incidence of documentation burden and may lead to burnout syndrome. It is important to understand the extent of documentation burden and potential solutions such as EHR user-interface redesign and the use of scribes to assist healthcare providers across the world.

Analysis of Nursing Clinical Decision Support Requests and Strategic Plan in a Large Academic Health System.

OBJECTIVES: To understand requests for nursing Clinical Decision Support (CDS) interventions at a large integrated health system undergoing vendor-based EHR implementation. In addition, to establish a process to guide both short-term implementation and long-term strategic goals to meet nursing CDS needs. MATERIALS AND METHODS: We conducted an environmental scan to understand current state of nursing CDS over three months. The environmental scan consisted of a literature review and an analysis of CDS requests received from across our health system. We identified existing high priority CDS and paper-based tools used in nursing practice at our health system that guide decision-making. RESULTS: A total of 46 nursing CDS requests were received. Fifty-six percent (n=26) were specific to a clinical specialty; 22 percent (n=10) were focused on facilitating clinical consults in the inpatient setting. "Risk Assessments/Risk Reduction/Promotion of Healthy Habits" (n=23) was the most requested High Priority Category received for nursing CDS. A continuum of types of nursing CDS needs emerged using the Data-Information-Knowledge-Wisdom Conceptual Framework: 1) facilitating data capture, 2) meeting information needs, 3) guiding knowledge-based decision making, and 4) exposing analytics for wisdom-based clinical interpretation by the nurse. CONCLUSION: Identifying and prioritizing paper-based tools that can be modified into electronic CDS is a challenge. CDS strategy is an evolving process that relies on close collaboration and engagement with clinical sites for short-term implementation and should be incorporated into a long-term strategic plan that can be optimized and achieved overtime. The Data-Information-Knowledge-Wisdom Conceptual Framework in conjunction with the High Priority Categories established may be a useful tool to guide a strategic approach for meeting short-term nursing CDS needs and aligning with the organizational strategic plan.

Prioritization and Refinement of Clinical Data Elements within EHR Systems.

Standardization of clinical data element (CDE) definitions is foundational to track, interpret, and analyze patient states, populations, and costs across providers, settings and time - critical activities to achieve the Triple Aim: improving the experience of care, improving the health of populations, and reducing per capita healthcare costs. We defined and implemented two analytical methods to prioritize and refine CDE definitions within electronic health records (EHRs), taking into account resource restrictions to carry out the analysis and configuration changes: 1) analysis of downstream data needs to identify high priority clinical topics, and 2) gap analysis of EHR CDEs when compared to reference models for the same clinical topics. We present use cases for six clinical topics. Pain Assessment and Skin Alteration Assessment were topics with the highest regulatory and non-regulatory downstream data needs and with significant gaps across documention artifacts in our system, confirming that these topics should be refined first.

A Decade of Experience in Creating and Maintaining Data Elements for Structured Clinical Documentation in EHRs.

Structured clinical documentation is an important component of electronic health records (EHRs) and plays an important role in clinical care, administrative functions, and research activities. Clinical data elements serve as basic building blocks for composing the templates used for generating clinical documents (such as notes and forms). We present our experience in creating and maintaining data elements for three different EHRs (one home-grown and two commercial systems) across different clinical settings, using flowsheet data elements as examples in our case studies. We identified basic but important challenges (including naming convention, links to standard terminologies, and versioning and change management) and possible solutions to address them. We also discussed more complicated challenges regarding governance, documentation vs. structured data capture, pre-coordination vs. post-coordination, reference information models, as well as monitoring, communication and training.

Pain Documentation: Validation of a Reference Model.

Over the last decade, interoperability of the Electronic Health Record (EHR) is becoming more of a reality. However, inconsistencies in documentation such as pain are considered a barrier to obtaining this goal. In order to be able to remedy this issue, it is necessary to validate reference models that have been created based upon requirements defined by Health Level 7 (HL7), Logical Names and Codes (LOINC) and the Intermountain Clinical Element Model using external published sources and guidelines. Using pain as an example of complex and inconsistent documentation, it was found that the reference model based upon these standards is valid because the data elements identified are broad and can meet the needs of each sub-domain within the primary domain of pain.

A Practical Approach to Governance and Optimization of Structured Data Elements.

Definition and configuration of clinical content in an enterprise-wide electronic health record (EHR) implementation is highly complex. Sharing of data definitions across applications within an EHR implementation project may be constrained by practical limitations, including time, tools, and expertise. However, maintaining rigor in an approach to data governance is important for sustainability and consistency. With this understanding, we have defined a practical approach for governance of structured data elements to optimize data definitions given limited resources. This approach includes a 10 step process: 1) identification of clinical topics, 2) creation of draft reference models for clinical topics, 3) scoring of downstream data needs for clinical topics, 4) prioritization of clinical topics, 5) validation of reference models for clinical topics, and 6) calculation of gap analyses of EHR compared against reference model, 7) communication of validated reference models across project members, 8) requested revisions to EHR based on gap analysis, 9) evaluation of usage of reference models across project, and 10) Monitoring for new evidence requiring revisions to reference model.

RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.

Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.

Recognition and maturation of effector RNAs in a CRISPR interference pathway.

In bacteria and archaea, small RNAs derived from clustered, regularly interspaced, short palindromic repeat (CRISPR) loci are involved in an adaptable and heritable gene-silencing pathway. Resistance to phage infection is conferred by the incorporation of short invading DNA sequences into the genome as CRISPR spacer elements separated by short repeat sequences. Processing of long primary transcripts (pre-crRNAs) containing these repeats by an RNA endonuclease generates the mature effector RNAs that interfere with phage gene expression. Here we describe structural and functional analyses of the Thermus thermophilus CRISPR Cse3 endonuclease. High-resolution X-ray structures of Cse3 bound to repeat RNAs model both the pre- and post-cleavage complexes associated with processing the pre-crRNA. These structures establish the molecular basis of a specific CRISPR RNA recognition and suggest the mechanism for generation of effector RNAs responsible for gene silencing.

Structural elucidation of a PRP8 core domain from the heart of the spliceosome.

The spliceosome is a complex ribonucleoprotein (RNP) particle containing five RNAs and more than 100 associated proteins. One of these proteins, PRP8, has been shown to interact directly with the splice sites and branch region of precursor-mRNAs (pre-mRNAs) and spliceosomal RNAs associated with catalysis of the two steps of splicing. The 1.85-A X-ray structure of the core of PRP8 domain IV, implicated in key spliceosomal interactions, reveals a bipartite structure that includes the presence of an RNase H fold linked to a five-helix assembly. Analysis of mutant yeast alleles and cross-linking results in the context of this structure, coupled with RNA binding studies, suggests that domain IV forms a surface that interacts directly with the RNA structures at the catalytic core of the spliceosome.

FRET analysis of in vivo dimerization by RNA-editing enzymes.

Members of the ADAR (adenosine deaminase that acts on RNA) enzyme family catalyze the hydrolytic deamination of adenosine to inosine within double-stranded RNAs, a poorly understood process that is critical to mammalian development. We have performed fluorescence resonance energy transfer experiments in mammalian cells transfected with fluorophore-bearing ADAR1 and ADAR2 fusion proteins to investigate the relationship between these proteins. These studies conclusively demonstrate the homodimerization of ADAR1 and ADAR2 and also show that ADAR1 and ADAR2 form heterodimers in human cells. RNase treatment of cells expressing these fusion proteins changes their localization but does not affect dimerization. Taken together these results suggest that homo- and heterodimerization are important for the activity of ADAR family members in vivo and that these associations are RNA independent.