High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression.

The collecting duct endothelin-1 (ET-1), endothelin B (ETB) receptor, and nitric oxide synthase-1 (NOS1) pathways are critical for regulation of fluid-electrolyte balance and blood pressure control during high-salt feeding. ET-1, ETB receptor, and NOS1 are highly expressed in the inner medullary collecting duct (IMCD) and vasa recta, suggesting that there may be cross talk or paracrine signaling between the vasa recta and IMCD. The purpose of this study was to test the hypothesis that endothelial cell-derived ET-1 (paracrine) and collecting duct-derived ET-1 (autocrine) promote IMCD nitric oxide (NO) production through activation of the ETB receptor during high-salt feeding. We determined that after 7 days of a high-salt diet (HS7), there was a shift to 100% ETB expression in IMCDs, as well as a twofold increase in nitrite production (a metabolite of NO), and this increase could be prevented by acute inhibition of the ETB receptor. ETB receptor blockade or NOS1 inhibition also prevented the ET-1-dependent decrease in ion transport from primary IMCDs, as determined by transepithelial resistance. IMCD were also isolated from vascular endothelial ET-1 knockout mice (VEETKO), collecting duct ET-1 KO (CDET-1KO), and flox controls. Nitrite production by IMCD from VEETKO and flox mice was similarly increased twofold with HS7. However, IMCD NO production from CDET-1KO mice was significantly blunted with HS7 compared with flox control. Taken together, these data indicate that during high-salt feeding, the autocrine actions of ET-1 via upregulation of the ETB receptor are critical for IMCD NO production, facilitating inhibition of ion reabsorption.

You Are Not Alone: PARISH NURSES BRIDGE CHALLENGES FOR FAMILY CAREGIVERS.

In 2015, there were 43.5 million informal, unpaid caregivers in the United States. Caregivers reported a moderate to high level of burden of care, including performing medical and nursing tasks they were not trained to do. A study of family caregiver experiences with parish/faith community nurses reveals four key ways parish nurses support caregivers and offers important implications for parish nurse preparation and practice.

Theory-based behavior change intervention to increase uptake of risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 pathogenic variant: The PREVENT randomized controlled trial.

OBJECTIVE: To evaluate the effect of a theory-based behavioral intervention delivered by genetic counselors on the uptake of risk-reducing salpingo-oophorectomy (RRSO) at 12 and 24 months by women with a BRCA1 or BRCA2 pathogenic variant (PV) compared to women who received usual care. METHODS: In this two-arm, multi-site randomized controlled trial participants were randomized to receive a theoretically-guided behavioral telephone intervention or usual care. Outcome data were collected at 12 and 24 months. Participants in the usual care arm were offered the intervention after 12 months. RESULTS: Data on 107 participants were included in the analysis. There was no significant difference in the proportion of women who had a RRSO by 1 year (28.6%- intervention; 22.9%- usual care (p = 0.54)). At 1 year, women who received the intervention had significantly lower mean decisional conflict (pinteraction <0.001) and a higher mean knowledge score at one-year compared to usual care (pinteraction <0.001). At 2 years, 53.9% of participants in the intervention arm had RRSO compared to 32.6% in usual care (p = 0.05). CONCLUSIONS: A theory-based behavioral intervention delivered by genetic counselors to women with a BRCA PV who chose not to have the recommended RRSO was effective at reducing decisional conflict and increasing knowledge in women with a BRCA1 or BRCA2 PV.

Pan-histone deacetylase inhibitor panobinostat depletes CXCR4 levels and signaling and exerts synergistic antimyeloid activity in combination with CXCR4 antagonists.

Stromal cell derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 are involved in the directional homing to the bone marrow niches and in peripheral mobilization of normal and transformed hematopoietic stem and myeloid progenitor cells. Elevated CXCR4 expression confers poor prognosis, whereas inhibition of CXCR4 signaling overcomes stroma-mediated chemoresistance in acute myeloid leukemia (AML). Here, we demonstrate that treatment with the pan-histone deacetylase inhibitor panobinostat (PS) depleted the mRNA and protein levels of CXCR4 in the cultured and primary AML cells. PS-induced acetylation of the heat shock protein (hsp) 90 reduced the chaperone association between CXCR4 and hsp90, directing CXCR4 to degradation by the 20S proteasome. PS treatment also depleted G protein-coupled receptor kinase 3, as well as attenuated the phosphorylation of AKT and ERK1/2 in AML cells, which was not affected by cotreatment with CXCL12. Compared with each agent alone, cotreatment with PS and CXCR4 antagonist AMD3100 or FC-131 synergistically induced apoptosis of cultured and primary AML cells. PS and FC-131 exerted more lethal effects on primary AML versus normal CD34(+) bone marrow progenitor cells. These findings support the rationale to test the in vivo efficacy of PS in enhancing the lethal effects of CXCR4 antagonists against AML cells.

Building health information technology capacity: they may come but will they use it?

Medical errors remain a major safety problem more than a decade after the Institute of Medicine reported 98 000 related deaths occur yearly in US hospitals. Medication errors account for one-third of these errors. Although medication reconciliation is an accepted care standard for patient safety, little evidence is available to make practice recommendations for primary care. The purpose of this study was to evaluate the effectiveness of using secure e-mail alerts within the reconciliation process on patient medication safety in clinics where electronic and personal health records are used. A nonexperimental, descriptive design with a convenience sample of 62 patients from two Veterans Health Administration clinics was used. Patients received secure e-mail instructing them to review their online medication list, update it based on home medications, and bring it to the appointment for discussion with their provider. A retrospective chart review was conducted examining changes made to medication lists in the electronic record after reconciliation. Data revealed the organization's adoption of secure e-mail did not guarantee its meaningful use by providers and patients, a clear barrier to implementing technology as an adjunct to care in context of complex clinical processes such as medication reconciliation. Lessons learned from the project's implementation are discussed.

Revision of a Parental Stress Scale for use on a pediatric general care unit.

The purpose of this descriptive correlational study was to test and evaluate the psychometric properties of a revised Parental Stressor Scale: Pediatric Intensive Care Unit (PSS:PICU) for use on a pediatric general care unit (PSS:GCU). The sample consisted of 403 parents of hospitalized children in a large military Mid-Atlantic medical center. Reliability and validity were assessed by examining the modified scale using factor analysis, Cronbach's alpha, item analysis, and concurrent validity. Factor analysis supported the subscales on the PSS:PICU. Internal consistency of the PSS:GCU produced a Cronbach's alpha of 0.92 for the total scale similar to the PSS:PICU scale, with the reliabilities for the subscales ranging from 0.70 to 0.92. Significant correlations were found between the total scores of the PSS:GCU and the Family Inventory of Life Events (FILE), a measure of general life stress. The results of psychometric testing suggest that the PSS:GCU is a reliable and valid scale to measure parental stress in general pediatric care units.

Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells.

The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primary AML cells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34(+) bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells.

Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells.

The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.

Managing DNP projects in student/faculty groups to facilitate learning with large cohorts.

Despite the initial intent of the 2004 American Association of Colleges of Nursing (AACN) position statement to move all advanced nursing practice education to the doctoral level, many schools remain at the master's degree level. Many schools successfully transitioned their programs but struggled with adequate resources for the growing number of students and the faculty, staff, and preceptor workload associated with the Doctor of Nursing Practice (DNP) project courses. The AACN 2015 taskforce made many recommendations related to quality of DNP projects, but there is little in the literature on best operational practices. The goal of this paper is to describe how one school modified the DNP project courses from a traditional chair and committee driven format to a class driven format with multiple smaller sections to successfully manage large numbers of DNP students across nine specialties. Specifically, a new model with its successes and challenges is described as well as details regarding finances, course coordination, project advisors, project team, annual offerings and grouping of students.

Lessons Learned Using Logic Models to Design and Guide DNP Projects.

BACKGROUND: A final culminating project that is derived from a practice immersion experience is a critical part of a doctor of nursing practice (DNP) program. PROBLEM: Many schools use well-designed quality improvement (QI) projects to meet this requirement, but there is no consensus on which QI methods and tools are the most effective for DNP students to demonstrate before graduation. APPROACH: One Mid-Atlantic public university began using QI process models, one of which was a logic model, to guide their DNP projects. This led to subsequent changes in the curriculum, faculty preparation, and practice partner responsibilities. OUTCOME: Many benefits and challenges were identified during the logic model implementation that may benefit other schools seeking to increase consistency and rigor. Although the learning process for students and faculty may be challenging, the outcomes included improved project conceptualization, clarity, concision, and feasibility of goal attainment. CONCLUSIONS: Use of logic models expands DNP students' skills to develop and implement a successful project and supports clinical scholarship.

Survey of Nursing Faculty Preparation for Guiding DNP Quality Improvement Projects.

BACKGROUND: Quality improvement (QI) projects comprise the majority of University of Maryland School of Nursing (UMSON) Doctor of Nursing Practice (DNP) projects. METHODS: An online survey was completed by 51% (n = 38) of faculty, who teach or mentor DNP students, and was analyzed using quantitative and descriptive methods. RESULTS: Faculty were somewhat or not familiar with developing a QI charter 68.4%, human error theory and error proofing 63.2%, driver diagrams 60.5%, characteristics of high-reliability organizations 60.5%, and Standards for Quality Improvement Reporting Excellence (SQUIRE) guidelines 55.3%. The faculty were most interested in learning more about (n = 97 responses) were human error theory and error proofing (28.9%), SQUIRE guidelines (26.3%), statistical process control (21.1%), and implementation strategies and tactics (21.1%). The most commonly identified challenges included identifying QI projects (24%), project time constraints (16%), keeping up-to-date on QI concepts, methods, and tools (12%), and balancing professional workload (10%). CONCLUSIONS: Gaps in self-reported QI knowledge indicate there is a need for further development of DNP and PhD prepared faculty at the UMSON.

Incidental findings from cancer next generation sequencing panels.

Next-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

Finding a balance: health promotion challenges of military women.

In this study, we explored what may determine, or predict, United States military women's health promotion behaviors. Using a descriptive correlational design grounded in Pender's Health Promotion model, 491 military women completed instruments measuring their demographic variables, perception of health, definition of health, self-efficacy, and interpersonal influences to determine the significant factors affecting participation in health promotion activities. The outcome indicated that self-efficacy and interpersonal influences were the most influential in determining health promotion. This research illuminates some of the challenges working women face in meeting health promotion activities and how best to support their ability to participate in healthy behaviors.

Impact of Electronic Reminders on Student Grades and Attitudes in Online Courses.

BACKGROUND: Reminders guide students in meeting course expectations for submitting assignments. PROBLEM: Variables linked to the effective use of reminders are unclear. The purpose of this study was to evaluate the impact on student grades and attitudes of using routine reminders for assignments in an online course. APPROACH: Students enrolled in online graduate and undergraduate nursing courses were emailed weekly reminders for discussion board assignments. Students received reminders for half of the semester and served as their own control to evaluate the impact of reminders on grades. OUTCOMES: There was no significant impact of reminders on grades or overall attitude. However, when undergraduate and graduate students were compared on individual questions on an attitude toward reminders' scale, undergraduate students reported that reminders were necessary, had a positive impact on their grades, and should be included in all courses. CONCLUSIONS: Reminders should be routinely used in undergraduate online courses.

Structuring Doctor of Nursing Practice project courses to facilitate success and ensure rigor.

There is currently a lack of consensus on the best format for Doctor of Nursing Practice project deliverables. In this article the project course history, current format, and evaluation methods are described for a Doctor of Nursing Practice program during the transition from a sole post-master's option to one that also admitted post-baccalaureate students. The project course format shifted focus from one in which students independently implemented multiple types of projects under the direction of a chairperson and committee to one in which students carried out projects utilizing quality improvement methods and tools under the mentorship of a project faculty advisor and clinical site representative. The integration of quality improvement models is exemplified through course objectives and assignments. Lessons learned through this transition are provided in the hope that the work may benefit other nursing schools with similar programs.

Cellular levels of p120 catenin function as a set point for cadherin expression levels in microvascular endothelial cells.

The mechanisms by which catenins regulate cadherin function are not fully understood, and the precise function of p120 catenin (p120ctn) has remained particularly elusive. In microvascular endothelial cells, p120ctn colocalized extensively with cell surface VE-cadherin, but failed to colocalize with VE-cadherin that had entered intracellular degradative compartments. To test the possibility that p120ctn binding to VE-cadherin regulates VE-cadherin internalization, a series of approaches were undertaken to manipulate p120ctn availability to endogenous VE-cadherin. Expression of VE-cadherin mutants that competed for p120ctn binding triggered the degradation of endogenous VE-cadherin. Similarly, reducing levels of p120ctn using siRNA caused a dramatic and dose-related reduction in cellular levels of VE-cadherin. In contrast, overexpression of p120ctn increased VE-cadherin cell surface levels and inhibited entry of cell surface VE-cadherin into degradative compartments. These results demonstrate that cellular levels of p120ctn function as a set point mechanism that regulates cadherin expression levels, and that a major function of p120ctn is to control cadherin internalization and degradation.

Reducing the risks of wound consultation: adding digital images to verbal reports.

PURPOSE: The purpose of this study was to examine the impact of digital images on the assessment and recommendations of a WOC nurse who was providing remote nurse-to-nurse consultations on home care patients with wounds. METHODS: In a descriptive comparative study, data were collected by home care nurses from a sample of 43 adult patients with a total of 89 wounds with various etiologies. To determine whether or not the addition of a digital photograph influenced the WOC nurse's assessment and recommendations, the WOC nurse first completed a wound assessment and recommendation form based on a verbal report from the home care nurse. The WOC nurse then accessed digital images of the wounds and made any indicated modifications to the original assessment and management plan, providing a rationale for any changes. Comparisons were made between the assessment completed by the home care nurse and the WOC nurse's assessment and between the WOC nurse's assessment and recommendations based only on a verbal report and his or her assessment and recommendations based on the combination of a verbal report and a digital photograph. RESULTS: Although there was a high percentage of agreement between the wound assessments completed by the home care nurse and those completed by the WOC nurse, areas of disagreement often impacted on the overall assessment. The agreement rates between the WOC nurse's assessment and recommendations based only on a verbal report versus those based on a combination of verbal report and digital photographs were as follows: total agreement (26/89 = 29.2%), trivial disagreement (11/89 = 12.4%), and clinically relevant disagreement (52/89 = 58.4%). CONCLUSIONS: WOC nurses who provide remote nurse-to-nurse consultations without directly visualizing the patients' wounds through digital images are at risk for under-or overtreating patients' wounds. Digital images also provide an opportunity for the WOC nurse to mentor home care nurses in wound assessment and care.

p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin.

VE-cadherin is an adhesion molecule critical to vascular barrier function and angiogenesis. VE-cadherin expression levels are regulated by p120 catenin, which prevents lysosomal degradation of cadherins by unknown mechanisms. To test whether the VE-cadherin cytoplasmic domain mediates endocytosis, and to elucidate the nature of the endocytic machinery involved, the VE-cadherin tail was fused to the interleukin (IL)-2 receptor (IL-2R) extracellular domain. Internalization assays demonstrated that the VE-cadherin tail dramatically increased endocytosis of the IL-2R in a clathrin-dependent manner. Interestingly, p120 inhibited VE-cadherin endocytosis via a mechanism that required direct interactions between p120 and the VE-cadherin cytoplasmic tail. However, p120 did not inhibit transferrin internalization, demonstrating that p120 selectively regulates cadherin internalization rather than globally inhibiting clathrin-dependent endocytosis. Finally, cell surface labeling experiments in cells expressing green fluorescent protein-tagged p120 indicated that the VE-cadherin-p120 complex dissociates upon internalization. These results support a model in which the VE-cadherin tail mediates interactions with clathrin-dependent endocytic machinery, and this endocytic processing is inhibited by p120 binding to the cadherin tail. These findings suggest a novel mechanism by which a cytoplasmic binding partner for a transmembrane receptor can serve as a selective plasma membrane retention signal, thereby modulating the availability of the protein for endo-lysosomal processing.

Addressing challenges in nursing education through a clinical instruction model based on a hybrid, inquiry-based learning framework.

This article describes an innovative hybrid, inquiry-based learning clinical instruction model used in accelerated baccalaureate nursing programs at three university nursing schools in the Washington DC metropolitan area. The authors describe student and faculty roles and offer examples of grading criteria. Nurse faculty and students from the three schools of nursing regard the clinical instruction model as a valuable teaching-learning approach that strengthens the relationship between theory and practice, prepares students to think critically and act effectively, and grooms students and faculty for a lifetime of learning in a changing world.