Members of the ErbB subfamily of receptor tyrosine kinases are critical regulators of normal mammary gland development, and alterations in their signaling have been associated with breast tumorigenesis. ErbB4 expression in breast carcinomas predicts improved patient survival and inversely correlates with tumor grade, metastasis and disease recurrence. When examined in the context of the breast cancer molecular subtypes, ErbB4 expression is rarely expressed in the triple-negative tumor subtype, which is associated with poor prognosis. Recently, our lab discovered a genomic context for the loss of ErbB4 expression in metastatic, refractory triple-negative breast cancer (TNBC) samples by next generation sequencing technology. The goal of this study was to examine the effects of ErbB4 overexpression on the growth and migration of TNBC cell lines. A GFP-containing construct was used to overexpress ErbB4 in the ErbB4-negative TNBC cell lines BT-20, BT-549 and MDA-MB-468. An empty vector construct was used as the control. Expression was confirmed by western blot and fluorescence microscopy to detect expression of ErbB4 or GFP respectively. Cell motility and growth was assessed with a transwell migration assay and a sulforhodamine B assay to measure cell density, respectively. Our data indicates that overexpression of ErbB4 resulted in no significant difference in the migration of BT-549 or MDA-MB-468 cells but resulted in a slight increase in the migration of BT-20 cells. ErbB4 had a growth inhibitory effect on BT-549 and BT-20 cells but showed no difference in the growth of MDA-MB-468 cells. This data suggests that multiple ErbB4-mediated mechanisms occur to alter the growth of TNBC cells. Although the translational significance of ErbB4 loss may be in its ability to predict outcome in patients with TNBC, more work is needed to elucidate the molecular mechanisms mediating its function.

Endoscopic retrograde cholangiopancreatography (ERCP) is a technically difficult procedure that requires extensive training to achieve competency. The study was undertaken to assess retrospectively whether advanced ERCP training made a difference in the competency of a physician who was performing ERCPs for eleven years before taking an extra year of advanced training in ERCP. The physician did not get any ERCP experience during the two-year formal fellowship between 1995-97, and learned ERCPs from colleagues post formal GIfellowship for four years after which he was given privileges to independently perform ERCPs. Data were collected on 172 and 213 patients who underwent ERCP before and after the training year respectively. Chi-square test was utilized to analyze the data. Baseline characteristics including height, weight, race and indications for ERCP were similar in the two groups. The results of the study showed that rates of biliary cannulation increased from the Pre-ERCP fellowship rate of 83% to 93% (Chi- Square = 9.06, p = 0.0026) and a reduction in postprocedure pancreatitis from 8.1% to 2.7% (Chi- Square = 4.56, p = 0.0327). Data in this study indicate that extra training in ERCP improves outcomes of ERCP in a single operator’s experience.

Type 2 diabetes (T2D) continues to be a growing public health concern and will be the seventh leading cause of death by 2030.  Education programs have shown to be moderately effective in disease management, but there are little known about interactive patient‐centered diabetes programs.  This study implemented a single‐group pretest‐posttest quasi‐experimental design including a three‐session novel patient‐centered diabetes education program at the Phoenix Veterans Affairs Medical Center using the model originally developed by Esden and Nichols.  Measurements were obtained using validated and reliable instruments from Michigan Diabetes Research Training Center (MDRTC), which included the Brief Diabetes Knowledge Test (BDKT) and Diabetes Empowerment Scale (DES), and a participant satisfaction survey.  Results showed participants’ knowledge of diabetes was higher at three months follow up (M = 17; SD = 4.64) than at baseline/pretest (M = 13.8; SD = 2.95) with a 23 percent change in knowledge scores from baseline 95% CI [0.24,6.16], with corrected Cohen’s dunbiased = 0.66 (i.e., medium effect).  There was very good pre‐test reliability for the DES subscales: “managing the psychosocial aspects of diabetes” (0.93), “assessing dissatisfaction and readiness to change (0.83), “setting and achieving goals” (0.88).  Despite moderate effects in these 3 subscales, there were no statistically significant differences in posttest scores.  In conclusion, Esden and Nichol’s model was successfully replicated in the VA Heath Care setting, and future work with a larger sample size and matched control is needed to further validate the results found in this study. 

Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK- Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-B dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.

Cancer‐related fatigue (CRF) is a well‐documented symptom among gynecologic oncology patients. However, there is little known about the etiology, and treatment options are currently suboptimal. While the lack of knowledge surrounding the intricacies of CRF impedes effective care, there is arguably a more serious barrier to delivering adequate treatment. Fatigue symptoms are highly underreported to physicians making it impossible to offer treatment to a large subsection of patients. This study will focus specifically on gynecologic oncology patients, a population with a staggering prevalence of CRF. The purpose of this study is to identify clinical, psychosocial, and lifestyle characteristics that may be associated with the underreporting of fatigue specifically in gynecologic oncology patients. The design of this study is a cross‐sectional survey. 89 subjects were recruited from three outpatient sites. Inclusion criteria included: (a) women age ≥18 years old with a known ovarian, uterine, cervical, vaginal, vulvar, or primary peritoneal cancer; (b) Currently attending physician’s office hours and/or undergoing chemotherapy at one of the above listed centers. This study will focus specifically on the reporting of CRF in gynecologic oncology patients. Results showed that barriers to reporting fatigue were significantly correlated with the chemotherapy cycle a patient was undergoing. Additionally, the date of last treatment, a patient’s weight, and the cancer stage was associated with higher levels of underreporting in this population. The prevalence of cancer related fatigue is staggering; however, there is limited research as to why patients are underreporting such a significant symptom to their health care team. With the knowledge from this study, screening for fatigue can become more efficient by targeting women in specific chemotherapy cycles. Practitioners can also use this data to identify patients with high‐risk characteristics that might contribute to their unwillingness to discuss fatigue symptoms.

Histopathologic examination of the tumor microenvironment demonstrates the presence of a vast repertoire of infiltrating lymphocytes and antigen presenting cells (APC’s). Recent studies establish a strong correlation between the tumor microenvironment cell composition and prognostic value in terms of cell type, location and ratio, referred to as a tumor’s immunoscore. More specifically, the relationship between T regulatory (Treg) cell to T effector (Teff) cell percentage predominates as a mechanism of tumor immune evasion. Further investigation of the factors influencing the development of Treg and Teff cells is therefore warranted. Gammainterferon‐inducible lysosomal thiol reductase (GILT) acts to influence antigenic processing and presentation by MHC class II cells, ultimately impacting lymphocyte development. Evaluation of the role of GILT expression in MHC class II+ APC’s with respect to Treg and Teff cell development in primary melanoma lesions, to our knowledge, has not been reported. Therefore our investigation focuses on elucidating a plausible relationship between GILT presence and Treg to Teff cell ratio. The aim of our study is to examine a possible association between GILT expression in APC’s and Treg:Teff cell ratio. We hypothesized GILT expression in melanoma cells would result in a decreased Treg to Teff ratio or an enhanced T cell‐mediated response. Our study included 17 de‐identified primary melanoma specimens previously stained and scored for Treg, Teff, CD8, MHC class II and GILT. Scoring was performed through identification of four areas per specimen with highest Treg and Teff cell density. These four areas were then averaged with ± standard deviation (SD). With use of landmark association, these four areas were identified and scored for MHC class II and GILT in APC’s and tumor cells with consideration to presence/absence, intensity and frequency of staining. Statistical significance was not reached relative to our hypothesized relationship of a decreased Treg to Teff cell ratio in the presence of GILT+ MHC class II. Similarly, we did not reach statistical significance when comparing individual cell types to GILT, MHC class II and GILT + MHC class. In our study, we were unable reach statistical significance relative to our proposed correlation between MHC class II and GILT presence leading to a decreased Treg to Teff cell ratio or enhanced T‐cell mediated immune response. A major limitation of our study included the small sample size leading to a probable type II error, prompting the need for further investigation of the factors influencing the Treg to Teff cell ratio within the melanoma tumor microenvironment on a larger scale.

Neuroleptic medications are commonly administered in the emergency department but are known to induce extrapyramidal symptoms (EPS) in some patients; typically dystonia and akathisia. This systematic review will examine if adjunctive medications are efficacious when given in conjunction with neuroleptic medications to prevent these extrapyramidal symptoms. The Central, DARE, LILACS, PubMed, CINAHL, and OVID databases were searched for relevant articles between January 2014 and February 2016. Inclusion criteria required the article to be a randomized controlled trial; administer an anticholinergic medication given concurrently or just prior to treatment with medications with known extrapyramidal side effects; and be published in English. The initial search strategy yielded 1222 prospective articles of which 1208 were excluded by title and/or abstract. Fourteen articles were retrieved in full text and independently reviewed by each author. Seven 7 RCTs representing 645 patients were determined to be appropriate for analysis. Meta‐analysis of 5 studies found a significant effect (OR 0.4 with 95% CI 0.23‐0.71) for utilizing anticholinergic adjunct medications in the prevention of EPS for 60 minutes after administration. No reduction was found (OR 1.14 with 95% CI 0.01‐164) in EPS after 60 minutes in meta‐analysis of 2 studies with opposing results. Adjunctive anticholinergic medication was effective in reducing symptoms of dystonia (OR 0.13 with 95% CI 0.04‐0.43) but not in reducing symptoms of akathisia (OR 0.74 with 95% CI 0.27‐1.98). This systematic review found that anticholinergic adjuvant anticholinergic treatment reduced EPS induced by antipsychotic medications during 60 minutes after administration, with the greatest reduction in dystonic symptoms.

BACKGROUND: In order to improve the quality and efficacy of healthcare while reducing the overall cost to deliver that healthcare, it has become increasingly important to manage utilization of services for populations of patients. Healthcare systems are aggressively working to identify patients at risk for hospital readmissions. Although readmission rates have been studied before, parameters for identifying patients at risk for readmission appear to vary depending the patient population. We will examine existing Electronic Health Record (EHR) data at Banner Health to establish what parameters are clinical indicators for readmission risk. Three conditions were identified by the CMS to have high and costly readmissions rates; heart failure (HF), acute myocardial infarction (AMI), and pneumonia. This study will focus on attempting to determine the primary predictive variables for these three conditions in order to have maximum impact on cost savings. METHODS: A literature review was done and 68 possible risk variables were identified. Of these, 30 of the variables were identifiable within the EHR system. Inclusion criteria for individual patient records are that they had an index admission secondary to AMI, heart failure, or pneumonia and that they had a subsequent readmission within 30 days of the index admission. Pediatric populations were not studied since they have unique factors for readmission that are not generalizable. Logistics regression was applied to all data including data with missing data rows. This allowed all coefficients to be interpreted for significance. This model was termed the full model. Variables that were determined to be insignificant were subsequently removed to create a new reduced model. Chi square testing was then done to compare the reduced model to the full model to determine if any significant differences existed between the two. RESULTS: Several variables were determined to be the significant predictors of readmission. The final reduced model had 19 predictors. When analyzed using ROC analysis, the area under the curve (AUC) was 0.64. CONCLUSION: Several variables were identified that could be significant contributors to readmission risk. The final model had an AUC on it ROC of 0.64 suggesting that it would only have poor to moderate clinical value for predicting readmission.

Objective/Hypothesis: The United States does not universally produce optimal levels of healthcare delivery, however, there are pockets throughout the country where organizations have utilized innovative strategies to produce high-value healthcare (better outcomes at lower costs). Our project aimed to identify factors that result in, or impede, the delivery of high-value healthcare. We hypothesized that there are common factors assisting or inhibiting organizations from producing high-value healthcare. Methods: We performed an analysis of innovative delivery models utilized at 10 different healthcare organizations throughout the country. The analysis included a literature search pertinent to each innovation we selected, a telephone interview with executives at the organization, integration of information we obtained into a pre-established template, a follow-up questionnaire, and finally an integration of new data from the questionnaire. Results: 10 different enablers were found to be common among the organizations. These included: shared vision, provider leadership, front-line empowerment, defined population, patient centeredness, co-creation with customer, information technology, culture of learning, presence of a willing payer, and a clear business case. The organizations ranked provider leadership and shared vision to be the two most important enablers. Three common barriers to success were found among the organizations and included government regulations, provider culture, and reimbursement. Provider culture was assessed as the most important barrier to overcome in the follow up questionnaire. Significance: The United States spends more overall and more per capita than any other country on healthcare, yet we are ranked 37th in the world for healthcare performance on average.1 Moreover, there is significant variability in mortality rates, access, safety, and patient satisfaction throughout the country.2 The information from this study provides a better understanding of how effective organizations are producing higher value healthcare and may act as a roadmap for organizations actively looking to produce better outcomes while lowering their costs.

PURPOSE: Contrast-induced nephropathy (CIN) has been recognized as a potential adverse outcome in patients receiving contrast dye for CT evaluation for over 50 years. Despite the time and resources dedicated to better identifying at-risk patients and implementing preventative measures, contrast induced nephropathy continues to be a significant cause of hospital acquired renal insufficiency. This study was aimed to evaluate the incidence and factors associated with contrast-induced nephropathy in the trauma patient population. MATERIALS AND METHODS: A retrospective institutional review of 563 patients admitted to the trauma service at St. Joseph’s Hospital and Medical Center were evaluated. Data were recorded for each patient including demographics, injury severity score (ISS), clinical prediction score (CPS), laboratory values on admission, 24, 48 and 72 hours including hematocrit, blood urea nitrogen, creatinine and eGFR, IV fluid volume given, contrast volume given, systolic blood pressure (SBP), urine output (UOP), intensive care unit length of stay (ICU LoS) and total hospital length of stay (tot LoS). Contrast induced nephropathy was considered to be present if the patient received contrast material for CT scan and 24-48 hour creatinine increased by an absolute value of 0.5mg/dl or if there was a 25% increase in 24-48 hour creatinine when compared to admission creatinine. Contrast volumes given to each patient before CT scan were determined by the Department of Radiology. RESULTS: As seen in table 1 results of univariate analysis demonstrate the following significant data: CIN vs age (p 0.004), CIN vs ISS (p <0.000), CIN vs CPS (p <0.000), CIN vs ICU length of stay (p 0.006), CIN vs total length of stay (p 0.002), CIN vs SBP (p <0.000), CIN vs IVF volume given in the 2nd 24 hours (p <0.000) and CIN vs IVF volume given in the first 48hrs (p <0.000). Data from multivariate analysis demonstrate the following significant data: CIN vs CPS (p <0.000, CI 1.92E-2 – 3.93E-2), CIN vs SBP (p 0.003 CI 8.61E-4 – 4.41E-3) and CIN vs IVF vol 2nd 24 hours (p 0.001, CI 1.47E-5 – 5.91E-5). The mean data for patients who did and did not develop CIN respectively were CPS: 9.09 and 3.12, SBP 84mmHg and 99mmHg, and IVF vol 2nd 24 hrs 2504ml and 5931ml CONCLUSION: Contrast induced nephropathy continues to be a significant problem in many hospital populations including trauma patients. Certain patient groups including those with higher CPS, hypotension or receiving decreased IV fluids may benefit from aggressive mindfulness of the risk of contrast induced kidney injury and continued investigation is needed to better identify trauma patients at increased risk.