Nurse Executives Impacting the Human Experience in Health Care.

The human experience in health care over the past 2 and one-half years has been unprecedented. Impacted by the COVID-19 pandemic, march on the United States Capitol, economic crisis, social injustice, and growing concerns regarding structural racism-our health system is under siege. Executive nurse leaders find themselves at the crossroads of motivating colleagues to provide excellence in nursing and patient care while confronting both a current and future shortage of registered nurses. Over 30 nurse leaders from around the globe meet and strategize on creating a preferred future for health care. The purpose of this article is to describe The Beryl Institute, the formation of the nurse executive council, the work of its members, and a collective call to action.

Cultivating a Culture:: Implementing Methods to Embrace Diversity and Inclusion.

Anne Arundel Medical Center, Annapolis, Maryland, was the recipient of this year's American Organization for Nursing Leadership's Prism Award, which recognizes an organization with advanced diversity efforts. The medical center, part of Luminis Health, added diversity as a core organizational value in 2009, making efforts to provide care to diverse populations and support an inclusive work environment for staff. Through strategic initiatives and community partnerships that target recruiting efforts, the organization has created a culture in which difficult conversations about differences are supported and encouraged. Additionally, targeted hiring initiatives have increased diversity among hospital leadership. Diversity and inclusion initiatives focus on creating a culture that welcomes and supports everyone, regardless race, ethnicity, or sexual orientation/identity.

Engaging Employees in Well-Being: Moving From the Triple Aim to the Quadruple Aim.

Anne Arundel Medical Center has been on a 3-year journey to improve employee well-being with the assumption that employee well-being and employee engagement are interconnected. Improvements in employee well-being will result in increased employee engagement and will be a pivotal driver to assist the health system meet its goals. Historically, Anne Arundel Medical Center successfully differentiated itself in the market by being the region's high-quality, low-cost provider of health services delivered through intense collaboration with patients and families. The financial, quality, and patient satisfaction results are in the top percentiles nationwide. However, as the pace of change accelerates and the organization faces increased pressure to improve outcomes, keeping employees from becoming burned out and disengaged becomes an increasing concern. The WellBeing framework was developed on the basis of the work of Tom Rath and Jim Harter as the model to support Anne Arundel's WellBeing work. The efforts around well-being are comprehensive and impact all aspects of how work is conducted. Employee well-being has been elevated to an equal third prong along with providing high-quality low-cost care in a patient-centered environment. This focus on leading an employee WellBeing Program has resulted in improved engagement scores at Anne Arundel Medical Center.

MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus.

OBJECTIVE: We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus. MATERIALS AND METHODS: Systemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes. RESULTS: After induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15). CONCLUSIONS: MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.

Assessment of pathology instruction in U.S. Dental hygiene educational programs.

PURPOSE: To assess the instruction of pathology content in entry-level and advanced practitioner dental hygiene educational programs and the program directors' perceptions whether their graduates are adequately prepared to meet the increasingly complex medical and oral health needs of the public. METHODS: A 28-question survey of instructional content and perceptions was developed and distributed using Qualtrics® software to the 340 directors of entry-level and advanced practitioner dental hygiene programs in the US. Respondents rated their level of agreement to a series of statements regarding their perceptions of graduates' preparation to perform particular dental hygiene services associated with pathology. Descriptive statistics for all 28 categorical survey questions were calculated and presented as the frequency (percentage). RESULTS: Of the 340 directors surveyed, 130 (38%) responded. Most entry-level respondents (53%) agreed or strongly agreed (29%) that their graduates were adequately prepared to meet the complex medical and oral health needs of the public, while all respondents of advanced practitioner programs strongly agreed. More respondents strongly agreed to statements related to clinical instruction than to didactic courses. While 64% of respondents agreed that their graduates were prepared to practice unsupervised, if it were legally allowed, 21% were ambivalent. The extent of pathology instruction in entry-level programs varied, but most used traditional formats of instruction, educational resources and assessments of educational outcomes. Advanced practitioner programs emphasized histological and clinical examination of oral lesions and patient case studies. CONCLUSION: Strengthening pathology instruction would ensure that future generations of dental hygienists would be adequately prepared to treat medically compromised patients.

Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma.

Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies.

Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1-MMP) controls melanoma cell proliferation.

Notch1 is an evolutionarily conserved signaling molecule required for stem cell maintenance that is inappropriately reactivated in several cancers. We have previously shown that melanomas reactivate Notch1 and require its function for growth and survival. However, no Notch1-activating mutations have been observed in melanoma, suggesting the involvement of other activating mechanisms. Notch1 activation requires two cleavage steps: first by a protease and then by γ-secretase, which releases the active intracellular domain (Notch1(NIC)). Interestingly, although ADAM10 and -17 are generally accepted as the proteases responsible of Notch1 cleavage, here we show that MT1-MMP, a membrane-tethered matrix metalloproteinase involved in the pathogenesis of a number of tumors, is a novel protease required for the cleavage of Notch1 in melanoma cells. We find that active Notch1 and MT1-MMP expression correlate significantly in over 70% of melanoma tumors and 80% of melanoma cell lines, whereas such correlation does not exist between Notch1(NIC) and ADAM10 or -17. Modulation of MT1-MMP expression in melanoma cells affects Notch1 cleavage, whereas MT1-MMP expression in ADAM10/17 double knock-out fibroblasts restores the processing of Notch1, indicating that MT1-MMP is sufficient to promote Notch1 activation independently of the canonical proteases. Importantly, we find that MT1-MMP interacts with Notch1 at the cell membrane, supporting a potential direct cleavage mechanism of MT1-MMP on Notch1, and that MT1-MMP-dependent activation of Notch1 sustains melanoma cell growth. Together, the data highlight a novel mechanism of activation of Notch1 in melanoma cells and identify Notch1 as a new MT1-MMP substrate that plays important biological roles in melanoma.

An innovative professional practice model: adaptation of Carper's patterns of knowing, patterns of research, and Aristotle's intellectual virtues.

Professional practice models have emerged as the way hospital-based nursing expresses its consensus-derived philosophy. Magnet recognition influences this practice, while extant nursing theories continue the quest to bridge scholarship with practice. The innovative model presented in this article is an adaptation of Carper's patterns of knowing into a nursing meta-language of science, ethics, art, and advocacy. In this model, boundaries of the patterns of knowing blur and synchronous movement of values, patterns of research, and Aristotelian intellectual virtues blend. Patient and nurse in an intersubjective relationship share the end of human flourishing as the patient's narrative evolves and shared meaning of the ultimate good is actualized.

An ERBB3/ERBB2 oncogenic unit plays a key role in NRG1 signaling and melanoma cell growth and survival.

We recently identified neuregulin-1 (NRG1) as a novel target of Notch1 required in Notch-dependent melanoma growth. ERBB3 and ERBB4, tyrosine kinase receptors specifically activated by NRG1, have been shown to be either elevated in melanoma cell lines and tumors or to be mutated in 20% of melanomas, respectively. While these data support key roles of NRG1 and its receptors in the pathogenesis of melanoma, whether ERBB3 and ERBB4 display redundant or exclusive functions is not known. Here, we show that ERBB3 and ERBB4 inhibition results in distinct outcomes. ERBB3 inhibition ablates the cellular responses to NRG1, results in AKT inactivation and leads to cell growth arrest and apoptotic cell death. In contrast, ERBB4 knockdown mildly affects cell growth, has no effects on cell survival and, importantly, does not alter the responses to NRG1. Finally, we identified ERBB2 as a key coreceptor in NRG1-dependent ERBB3 signaling. ERBB2 forms a complex with ERBB3, and its inhibition recapitulates the phenotypes observed upon ERBB3 ablation. We propose that an NRG1-ERBB3-ERBB2 signaling unit operates in melanoma cells where it promotes growth and survival.

Thrombospondin-1 expression in melanoma is blocked by methylation and targeted reversal by 5-Aza-deoxycytidine suppresses angiogenesis.

BACKGROUND: Reversibility of aberrant methylation via pharmacological means is an attractive target for therapies through epigenetic reprogramming. To establish that pharmacologic reversal of methylation could result in functional inhibition of angiogenesis, we undertook in vitro and in vivo studies of thrombospondin-1 (TSP1), a known inhibitor of angiogenesis. TSP1 is methylated in several malignancies, and can inhibit angiogenesis in melanoma xenografts. We analyzed effects of 5-Aza-deoxycytidine (5-Aza-dC) on melanoma cells in vitro to confirm reversal of promoter hypermethylation and restoration of TSP1 expression. We then investigated the effects of TSP1 expression on new blood vessel formation and tumor growth in vivo. Finally, to determine potential for clinical translation, the methylation status of TSP1 promoter regions of nevi and melanoma tissues was investigated. RESULTS: 5-Aza-dC reduced DNA (cytosine-5)-methyltransferase 1 (DNMT1) protein, reversed promoter hypermethylation, and restored TSP1 expression in five melanoma cell lines, while having no effect on TSP1 protein levels in normal human melanocytes. In in vivo neovascularization studies, mice were implanted with melanoma cells (A375) either untreated or treated with 5Aza-dC. Vessels at tumor sites were counted by an observer blinded to treatments and the number of tumor vessels was significantly decreased at pretreated tumor sites. This difference occurred before a significant difference in tumor volumes was seen, yet in further studies the average tumor volume in mice treated in vivo with 5-Aza-dC was decreased by 55% compared to untreated controls. Knockdown of TSP1 expression with shRNA enhanced tumor-induced angiogenesis by 68%. Analyses of promoter methylation status of TSP1 in tumors derived from untreated and treated mice identified 67% of tumors from untreated and 17% of tumors from treated mice with partial methylation consistent with the methylation specific PCR analysis of A375 cells. Examination of methylation patterns in the promoter of TSP1 and comparison of aberrantly methylated TSP1 in melanoma with non-malignant nevi identified a significantly higher frequency of promoter methylation in tumor samples from melanoma patients. CONCLUSIONS: Pharmacological reversal of methylation silenced TSP1 had functional biological consequences in enhancing angiogenesis inhibition and inducing antitumor effects to decrease murine melanoma growth. Angiogenesis inhibition is an additional mechanism by which epigenetic modulators can have antitumor effects.

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects.

Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-α2b in vitro and in mice, two Phase I trials of SSG/IFN-α2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-α2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNα-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-α2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN-α2b. Representative ISGs in peripheral blood were induced after IFN-α2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-α2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-α2b with or without chemotherapy.

Gene regulatory and clinical effects of interferon ß in patients with metastatic melanoma: a phase II trial.

Interferon (IFN)-ß in preclinical studies, compared to IFN-α2, bound with higher affinity to its receptor, induced to higher levels of IFN-stimulated gene products, induced more apoptosis in melanoma cells, and had antitumor effects against melanoma. A maximally tolerated dose of 12 × 10(6) international units/m(2) after 2 weeks subcutaneously daily with dose escalation to 18 × 10(6) international units/m(2) was thus used in a phase II trial of IFN-ß1a in cutaneous metastatic melanoma (n = 17) and uveal melanoma (n = 4). It resulted in expected but reversible drug-related severe (grade 3) adverse events in 13/21 patients; anorexia and fatigue were mostly of mild or moderate severity and infrequently needed dose reduction. Although a single patient had a sustained regression, overall IFN-ß1a did not have clinical benefit (response rate <10%; median progression-free survival 1.8 months). Effective and potent induction in peripheral blood cells and into serum of products of IFN-stimulated genes such as the pro-apoptotic cytokine, TRAIL, and the immunomodulatory and anti-angiogenic chemokines, CXCL10 and CCL8, confirmed gene regulatory actions. To probe further anti-angiogenic mechanisms, both VEGF-A and CXCL-5 were assessed; compared to before treatment, both proteins decreased. Continued improvements in understanding of antitumor mechanisms will enhance usefulness of IFNs for nodal or distant metastases from melanoma.

Reducing heart failure hospital readmissions from skilled nursing facilities.

PURPOSE/OBJECTIVES: Readmission rates for heart failure patients are a Center for Medicare & Medicaid and Joint Commission core measure. At this urban Midwestern medical center, the 6-month baseline skilled nursing facility (SNF) readmission rate was 30%. Nurse case management implemented a process to decrease the rate for this population. Follow-up phone calls were in place for patients discharged to home, but a gap remained in those discharged to SNFs. Nurse case management developed a follow-up phone call process within 48 hours of discharge to the registered nurse/licensed practical nurse in the SNFs to verify that: 1. Daily morning weights were ordered. 2. Parameters to contact primary care provider if weight gain was greater than 3 pounds per day or 5 pounds per week. 3. 2 gram sodium restricted diet was ordered. 4. Appropriate diuretic was ordered and reconciled. 5. Follow-up provider visits were made, for patient to be seen within 3 to 5 days following discharge. PRIMARY PRACTICE SETTING: Acute inpatient care settings. FINDINGS/CONCLUSIONS: The phone calls resulted in improved continuity of care and clarification of discharge orders. The opportunity for question-and-answer time between the hospital and the SNF nurse provided just-intime education; relationships have also been strengthened. Recent data show that the current readmission rate averages 11.32% (a decrease from 30%). This nurse case management­driven process of follow-up phone calls between the hospital and SNF staff to reduce readmission rates in heart failure patients resulted in improved continuity of care and clarification of discharge orders. IMPLICATIONS FOR CM PRACTICE: This simple, innovative process allowed for improved continuity of care and partnerships between inpatient hospitalization and the SNF, thereby reduced transcription errors and improved patient health outcomes. Enhanced communication between providers allowed for a significant reduction in readmissions from SNFs to the hospital.

Nurse and physician preferences for end-of-life care for trauma patients.

BACKGROUND: End-of-life care for trauma patients requires unique practice guidelines because it is fraught with difficulties not encountered in end-of-life care for terminally ill patients. The purpose of this project was to analyze survey information from nurses and physicians regarding preferences for end-of-life care in trauma that would inform best-practice guidelines. METHODS: A survey was sent via the US Postal Service to a convenience sample of trauma professionals, including physicians, nurses, and emergency medical technicians. Questions were designed to provide information on difficult issues related to death and dying from trauma. The general public was also surveyed, and all results were used to develop a best-practice model for end-of-life care. RESULTS: Seven hundred seventy-four trauma professionals returned the survey for a response rate of 51%. This included 460 nurses and 181 physicians. Some salient findings include: (1) If a loved one required resuscitation in the emergency department, more nurses (78.4%) than physicians (38.7%) prefer to be in the treatment room rather than in the waiting room; (2) similar percentages of nurses (97.7%) and physicians (99.4%) agree that life-sustaining treatment should be withdrawn in cases in whom there is no hope of recovery; and (3) a larger percentage of nurses (58.8%) than physicians (20.6%) believe that patients have the right to demand care that physicians think is medically futile. CONCLUSIONS: Nurses and physicians agree on some issues about end-of-life care in trauma but disagree on others. Education and discourse among trauma professionals are needed to bring understanding to the issues.

Surges of electroencephalogram activity at the time of death: a case series.

Abstract Level of consciousness at the end of life in critically ill patients is poorly characterized. We report a case series of seven patients who were neurologically intact before the decision to withdraw care due to extensive systemic critical illness. As part of our end-of-life care protocol, bispectral index (BIS) monitor (Aspect Medical Systems, Newton, MA) or SEDline (Hospira, Lake Forest, IL) monitoring devices are placed on each patient to ensure adequate comfort. Both monitoring systems use an integer-based system (BIS or PSI, respectively) to reflect the level of consciousness/effect of anesthesia. In each case, loss of blood pressure, as monitored by indwelling arterial line, was followed by a decline is BIS/PSI activity followed by a transient spike in BIS/PSI activity that approached levels normally associated with consciousness. This spike in electroencephalogram (EEG) activity had short duration and the activity then declined to a level of activity associated with burst suppression. In one case of a patient who had a SEDLine device, we were able to capture and analyze the raw EEG signal, and confirm that the EEG waveform was not artifact, and in fact a high frequency waveform was present during the spike activity. We speculate that this level of BIS/SEDline activity is related to the cellular loss of membrane polarization due to hypoxemia. We further speculate that since this increase in electrical activity occurred when there was no discernable blood pressure, patients who suffer "near death" experiences may be recalling the aggregate memory of the synaptic activity associated with this terminal but potentially reversible hypoxemia.

Trauma death: views of the public and trauma professionals on death and dying from injuries.

OBJECTIVES: To determine the values and preferences of the general public and trauma professionals regarding end-of-life care due to injury so as to inform practice guidelines. DESIGN, SETTING, AND PARTICIPANTS: Surveys of the general public sampled by random-digit dialing between June 6, 2005, and July 5, 2005, and of a convenience sample of trauma professionals during fall 2005 in the United States were conducted regarding preferences for care in the prehospital, emergency, and critical care settings. MAIN OUTCOME MEASURES: Responses to the survey questions. RESULTS: Most of the public and trauma professionals would prefer palliative care when doctors determine that aggressive critical care would not be beneficial in saving their lives. During resuscitation of an injured loved one, 51.9% of the public and 62.7% of the professionals would prefer to be in the emergency department treatment room. Most of the public believes that patients should have the right to demand care not recommended by their physicians. Most of both groups trust a doctor's decision to withdraw treatment when futility is determined. More of the public (57.4%) than the professionals (19.5%) believe that divine intervention could save a person when physicians believe treatment is futile. Other findings suggest further important insights. CONCLUSIONS: The results pose challenges that will require societal discourse to determine the best practice. Resolutions will need to be included in educational curricula and incorporated into practice to ensure that dying trauma victims and their families receive quality end-of-life care.

Proteasome inhibitors in the clinical setting: benefits and strategies to overcome multiple myeloma resistance to proteasome inhibitors.

The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341), a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and other malignancies.

Short communication: phase I clinical and gene modulatory evaluation of tamoxifen and IFN-alpha2b.

Preclinical studies had determined that tamoxifen and interferon-alpha2b (IFN-alpha2b) synergistically inhibited growth of both estrogen-receptor positive and negative murine tumor xenografts and had combined antiangiogenic effects and that tamoxifen potentiated IFN-stimulated gene (ISG) expression. A phase I trial in 26 patients was conducted using the combination to define tolerance and potentiation of ISG expression. IFN- alpha2b at a dose of 3 x 10(6) units/m(2) daily was given subcutaneously (s.c.), and tamoxifen was initiated as a loading dose of 150 mg/m(2) and then 60 mg/m(2) twice daily on day 8. At this initial dose, reduction of dose of IFN- alpha2b was required in 4 of 11 patients, primarily because of fatigue. Another group of patients was treated with an identical tamoxifen dose but with IFN-alpha2b reduced to 2 x 10(6)/m(2) U; this was better tolerated. As the projected serum tamoxifen level to reduplicate preclinical effects was 300 mg/m(2), dose escalation in a third cohort was undertaken; it had to be discontinued secondary to grade III or IV toxicity in 2 of 2 patients. Increases in products of transcriptionally regulated ISGs, beta (2)-microglobulin, neopterin, and ISG15 were assessed. All ISGs increased after IFN-alpha2b, but only ISG15 had a further significant rise after initiation of tamoxifen. Because at doses not limited by unacceptable toxicities, no marked potentiation of ISGs by tamoxifen could be identified, clinical evaluation of the combination was terminated.