Impact of Ethno-racial Factors on Clinical Outcomes and Health Care Utilization in Chronic Pancreatitis.

BACKGROUND: Healthcare disparities adversely affect clinical outcomes in racial and ethnic minorities. Chronic pancreatitis (CP) is a complex disorder, and pressures for time and cost-containment may amplify the disparity for minorities in this condition. This study aimed to assess ethno-racial differences in the clinical outcomes of CP patients cared for at our institution. METHODS: This is a study of CP patients with available ethno-racial information followed at our pancreas center. We reviewed their demographics, comorbidities, clinical outcomes, and resource utilization: pain, frequent flares (≥ 2/year), local complications, psychosocial variables, exocrine, and endocrine insufficiency, imaging, endoscopic procedures, and surgeries. The outcomes underwent logistic regression to ascertain association(s) with covariates and were expressed as odds ratio (95% confidence intervals). RESULTS: Of the 445 CP patients, there were 23 Hispanics, 330 Non-Hispanic Whites, 47 Non-Hispanic Blacks, 16 Asian Americans, and 29 patients from Other/mixed races. Over a median follow-up of 7 years, no significant differences in the pain profile (p = 0.36), neuromodulator use (p = 0.94), and opioid use for intermittent (p = 0.34) and daily pain (p = 0.80) were observed. Frequent flares were associated with Hispanic ethnicity [2.98(1.20-7.36); p = 0.02], despite adjustment for smoking [2.21(1.11-4.41); p = 0.02)] and alcohol [1.88(1.06-3.35); p = 0.03]. Local complications (pseudocysts, mesenteric thrombosis, and biliary obstruction), exocrine and endocrine dysfunction, and healthcare resource utilization (cross-sectional imaging, endoscopic procedures, celiac blocks, or surgeries) were comparable across all ethno-racial groups. CONCLUSIONS: Although no significant differences in clinical outcomes, and health resource utilization were noted across ethno-racial groups, Hispanic ethnicity had significant association with CP flares. This study calls for further investigation of an understudied minority population with CP.

Transcriptomic Profiling of Peripheral B Cells in Antibody Positive Sjogren's Patients Reveals Interferon Signature.

BACKGROUND: Sjögren's disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by lymphocytes and the activation of B lymphocytes with the production of autoantibodies. We aimed to analyze the transcriptome of circulating B cells from patients with SJD and healthy controls to decipher the B-cell-specific contribution to SJD. METHODS: RNA from peripheral blood B cells of five untreated female patients with SjD and positive ANA, positive anti-SSA (both Ro-52 and Ro-60), positive anti-SSB and positive rheumatoid-factor, and five healthy controls was subjected to whole-transcriptome sequencing. A false discovery rate of < 0.1 was applied to define differentially expressed genes (DEG). RESULTS: RNA-sequencing identified 56 up and 23 down DEG. Hierarchal clustering showed a clear separation between the two groups. Ingenuity pathway analysis revealed that these genes may play a role in interferon signaling, chronic mycobacterial infection, and transformation to myeloproliferative disorders. CONCLUSIONS: We found upregulated expression of type-I and type-II interferon (IFN)-induced genes, as well as genes that may contribute to other concomitant conditions, including infections and a higher risk of myeloproliferative disorders. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies.

Withdrawal of bevacizumab is associated with rebound growth of vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis patients.

Background: Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods: This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results: Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions: Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Single-cell RNA sequencing reveals unique monocyte-derived interstitial macrophage subsets during lipopolysaccharide-induced acute lung inflammation.

Interstitial macrophages (IMs) reside in the lung tissue surrounding key structures including airways, vessels, and alveoli. Recent work has described IM heterogeneity during homeostasis, however, there are limited data on IMs during inflammation. We sought to characterize IM origin, subsets, and transcriptomic profiles during homeostasis and lipopolysaccharide (LPS) induced acute lung inflammation. During homeostasis, we used three complementary methods, spectral flow cytometry, single-cell RNA-sequencing, and gene regulatory network enrichment, to demonstrate that IMs can be divided into two core subsets distinguished by surface and transcriptional expression of folate receptor ß (Folr2/FRß). These subsets inhabited distinct niches within the lung interstitium. Within FRß+ IMs we identified a subpopulation marked by coexpression of LYVE1. During acute LPS-induced inflammation, lung IM numbers expand. Lineage tracing revealed IM expansion was due to recruitment of monocyte-derived IMs. At the peak of inflammation, recruited IMs were comprised two unique subsets defined by expression of genes associated with interferon signaling and glycolytic pathways. As recruited IMs matured, they adopted the overall transcriptional state of FRß- resident IMs but retained expression in several origin-specific genes, such as IL-1ß. FRß+ IMs were of near-pure resident origin. Taken together our data show that during LPS-induced inflammation, there are distinct populations of IMs that likely have unique functions. FRΒ+ IMs comprise a stable, resident population, whereas FRß- ΙΜs represent a mixed population of resident and recruited IMs.

Prevalence and risk factors of steatosis and advanced fibrosis using transient elastography in the United States' adolescent population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children and adolescents. AIM: To determine the prevalence and risk factors of steatosis and advanced fibrosis using transient elastography (TE) in the United States' adolescent population. METHODS: Using the National Health and Nutrition Examination Survey 2017-2018, adolescent participants aged 13 to 17 years who underwent TE and controlled attenuation parameter (CAP) were included in this study. Forty-one factors associated with liver steatosis and fibrosis were collected. Univariate and multivariate linear regression analysis were used to identify statistically significant predictors. RESULTS: Seven hundred and forty participants met inclusion criteria. Steatosis (S1-S3), based on CAP, and advanced fibrosis (F3-F4), based on TE, were present in 27% and 2.84% of the study population, respectively. Independent predictors of steatosis grade included log of alanine aminotransferase, insulin resistance, waist-to-height ratio, and body mass index. Independent predictors of fibrosis grade included steatosis grade, non-Hispanic black race, smoking history, and systolic blood pressure. CONCLUSION: This study demonstrated a high prevalence of steatosis in the United States' adolescent population. Almost 3% of United States' adolescents had advanced fibrosis. These findings are concerning because a younger age of onset of NAFLD can lead to an earlier development of severe disease, including steatohepatitis, cirrhosis, and liver decompensation.

A 16-Year-Old Boy With Cough and Fever in the Era of COVID-19.

A 16-year-old white boy with a history of chronic lung disease of prematurity, cough-variant asthma, and incidental lung nodules presented to the emergency center in spring 2020 with acute onset dry cough, shortness of breath, and fever. An initial history, gathered from his mother because of the patient's respiratory distress, revealed no recent travel. However, his mother is a health care worker at a hospital, and sick contacts included ongoing contact with a friend with cold-like symptoms. He had a variety of animals at home, including a dog, cats, fish, rodents, and reptiles. He had a history of vaping tobacco products >6 months ago. Fever and respiratory symptoms were associated with fatigue, chest tightness, abdominal pain, and myalgias. On examination, he was ill appearing and had tachycardia, tachypnea, borderline hypoxia with an oxygen saturation of 91% on room air, diminished breath sounds at the lung bases, and unremarkable abdominal examination results. A chest radiograph was consistent with the lung examination, revealing bilateral lower lobe hazy infiltrates. He showed initial improvement for 48 hours with antibiotics, intravenous fluid resuscitation, oxygen via nasal cannula, albuterol, and prednisone. Subsequently, he worsened with persistent high fever, increasing respiratory distress with pulmonary findings, and severe persistent epigastric pain, which added a layer of diagnostic complexity. As this patient's clinical course evolved and further history became available, pulmonary medicine and infectious diseases services were consulted to guide diagnostic evaluation and treatment of this patient early in the era of coronavirus disease 2019.

Protein tyrosine phosphatase-α amplifies transforming growth factor-ß-dependent profibrotic signaling in lung fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal, fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-ß (TGF-ß), are central to its pathogenesis. Protein tyrosine phosphatase-α (PTPα) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTPα (Ptpra-/-) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-ß signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTPα controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from patients with IPF revealed that PTPα was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTPα promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles (Ptpraf/f). These mice were crossed with Dermo1-Cre or with Sftpc-CreERT2 mice to delete Ptpra in mesenchymal cells and alveolar type II cells, respectively. Dermo1-Cre/Ptpraf/f mice were protected from bleomycin-induced pulmonary fibrosis, whereas Sftpc-CreERT2/Ptpraf/f mice developed pulmonary fibrosis equivalent to controls. Both canonical and noncanonical TGF-ß signaling and downstream TGF-ß-induced fibrogenic responses were attenuated in isolated Ptpra-/- compared with wild-type fibroblasts. Furthermore, TGF-ß-induced tyrosine phosphorylation of TGF-ß type II receptor and of PTPα were attenuated in Ptpra-/- compared with wild-type fibroblasts. The phenotype of cells genetically deficient in PTPα was recapitulated with the use of a Src inhibitor. These findings suggest that PTPα amplifies profibrotic TGF-ß-dependent pathway signaling in lung fibroblasts.

MicroRNA-126-3p Inhibits Angiogenic Function of Human Lung Microvascular Endothelial Cells via LAT1 (L-Type Amino Acid Transporter 1)-Mediated mTOR (Mammalian Target of Rapamycin) Signaling.

OBJECTIVE: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. CONCLUSIONS: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

Younger age is associated with greater early neurocognitive decline postcardiopulmonary bypass.

Objective: To examine the effect of aging on postoperative neurocognitive decline (NCD) in cardiac surgery patients. Methods: Patients undergoing coronary artery bypass graft or open aortic valve replacement were administered the Repeatable Battery for the Assessment of Neuropsychological Status at preoperative, postoperative day (POD) 4, and 1 month. Blood samples were collected at preoperative, 6 hours postoperative, and POD 4. Plasma interleukin (IL)-6, tumor necrosis factor-α, and C-reactive protein (CRP) levels were quantified. Quality of life was measured with the 12-Item Short Form Health Survey. Data were analyzed using paired ratio and unpaired t tests with Welch's correction, and linear regression for cytokine levels. Results: NCD occurred in 15 patients (N = 33, 45.5%). Dichotomized at age extremes (<60 years; ≥75 years), youngest patients had greater preoperative scores (P = .02) with lower scores by POD 4 (P = .03). There was no NCD in the oldest patients, and scores were not different between age groups on POD 4 (P = .08). Regression at 1 month showed NCD scores again declined by age (n = 15), with younger scores returning toward baseline (P = .008). Regression analyses showed decline by age at 6 hours postoperative and POD 4 in plasma CRP levels (P = .05 6 hours, P = .02 POD 4). Dichotomizing IL-6 levels by age (<70 years, ≥70 years) demonstrated that levels were greater in younger versus older patients at 6 hours postoperative (P = .03), but not on POD 4. Conclusions: Younger patients tend to have better cognitive scores before surgery but scores at POD 4 are similar to those of older patients, with this trend disappearing at 1 month. IL-6 and CRP upregulation is greater in younger patients, suggesting that a robust perioperative inflammatory response may be associated with reduction in neurocognitive function, and this may be greater in younger versus older patients.

Skeletal muscle microvasculature response to ß-adrenergic stimuli is diminished with cardiac surgery.

BACKGROUND: Cardiac surgery and cardiopulmonary bypass are associated with alterations in blood pressure in the perioperative period, which, if uncontrolled, can result in end organ damage or dysfunction. Microvessels, significant contributors to blood pressure, both in the myocardium and peripheral skeletal muscle, have diminished responsiveness to major mediators of vascular tone, including thromboxane and serotonin after cardiopulmonary bypass. Responsiveness of these vessels to ß-adrenergic stimulation, a major mediator of vascular tone, has not yet been studied. In this report, we investigated the role of ß-adrenergic receptors in vascular tone regulation in human skeletal muscle microvessels before and after ß-adrenergic stimulation. METHODS: Skeletal muscle microvessels were isolated from patients undergoing cardiac surgery before and after cardiopulmonary bypass. Vessels were exposed in an ex vivo model to the ß-adrenergic agonist isoproterenol, or the direct adenylyl cyclase activator, forskolin, and the selective ß-receptor antagonist ICI18.551 hydrochloride plus isoproterenol. Immunofluorescence of ß receptors and Western blotting were also performed. RESULTS: Microvessels showed diminished responsiveness to isoproterenol (10-6 to 10-4M) after cardiopulmonary bypass (n = 8/group, P = .01). Pretreatment with the selective ß-2 blocker ICI18.551 (10-6M) prevented isoproterenol-induced microvascular relaxation (P = .001). Forskolin-induced relaxation response was also significantly diminished after cardiopulmonary bypass (n = 4/group, P < .05 versus before cardiopulmonary bypass). No significant changes in the total protein expression of ß-1, ß-2, and ß-3 receptors were detected by western blotting or immunofluorescence. CONCLUSION: Microvessels isolated from human skeletal muscle show diminished responsiveness to isoproterenol and its downstream activator forskolin after cardiopulmonary bypass, suggesting there is an alteration in ß-adrenergic receptor responsive in adenylate cyclase. The relaxation response to isoproterenol was via activation ß-2 receptors without changes in ß-adrenergic receptor abundance.

Morbidity and mortality of coagulase-negative staphylococcal sepsis in very-low-birth-weight infants.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are the most common cause of late-onset sepsis in the neonatal intensive care unit (NICU) and usually require vancomycin treatment. Our objective was to determine whether CoNS are associated with neonatal morbidity and mortality. METHODS: This was a retrospective cohort study of very-low-birth-weight (VLBW, ≤ 1500 g) infants from 1989 to 2015. Exclusion criteria were major congenital anomaly or death within 72 h. CoNS was considered a pathogen if recovered from ≥ 2 cultures, or 1 culture if treated for ≥ 5 days and signs of sepsis were present. Logistic regression was used to examine factors associated with morbidity and mortality. RESULTS: Of 2242 VLBW infants, 285 (12.7%) had late-onset sepsis. CoNS (125, 44%), Staphylococcus aureus (52, 18%), and Escherichia coli (36, 13%) were the most commonly recovered organisms. In multivariate analysis, CoNS sepsis was not associated with mortality [OR 0.6 (95% CI 0.2-2.6)), but sepsis with other organisms was [OR 4.5 (95% CI 2.6-8.0)]. CoNS sepsis was associated with longer hospitalization but not risk for bronchopulmonary dysplasia, intraventricular hemorrhage, or retinopathy of prematurity. CONCLUSION: CoNS sepsis was not associated with mortality or morbidities other than length of stay. These findings support vancomycin-reduction strategies in the NICU.

The impact of social support and partner relationship dynamics on engagement in HIV care and antiretroviral treatment adherence among MSM in Latin America.

In Latin America (LA), HIV prevalence among MSM is estimated at thirty times greater than in the general male population. Little is known about the role of social support or disclosure status in relation to the HIV care continuum among LA MSM. Using multivariable logistic generalized estimation equations, we assessed the impact of social support satisfaction and disclosure status on engagement in HIV care, ART initiation, and ART adherence with data from an online, multinational sample of HIV infected MSM in Latin America (N = 2,350). 80.0% were engaged in HIV care, 71% initiated ART, and among those, 37% reported missing at least one dose in the past month. In multivariable models, compared to being very satisfied with social support, being somewhat satisfied (aOR = 0.73, 95% CI 0.56, 0.95) or somewhat dissatisfied (aOR = 0.83, 95% CI 0.70, 0.98) were associated with reduced odds of reporting 100% ART adherence. Disclosure of status was associated with a greater odds of HIV care engagement (OR = 1.63, 95% CI 1.28, 2.07) and ART initiation (OR = 1.55, 95% CI 1.30, 1.84). Greater satisfaction with social support and comfort disclosing HIV status to these sources were associated with improved engagement in HIV care and greater initiation of ART among MSM in LA.

Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass.

BACKGROUND: Diabetic patients are associated with impaired peripheral microvascular function after cardiopulmonary bypass (CPB) and cardiac surgery. We hypothesized that upregulation of the inducible cyclooxygenase 2 (COX-2) contributes to altered microvascular reactivity of peripheral arterioles in diabetic patients undergoing CPB and cardiac surgery. METHODS: Skeletal muscle samples of nondiabetic (ND) patients and patients with diabetes mellitus (DM; n = 8 per group) undergoing cardiac surgery were harvested before and after CPB. The protein expression/localization of COX-2 was assayed by Western blotting and immunohistochemistry. Peripheral arterioles were dissected from the harvested skeletal muscle tissue samples, the isolated arterioles (80-180 µm) were cannulated and pressurized, and changes in diameter were measured with video microscopy. In-vitro relaxation responses of precontracted arterioles were examined in the presence of the endothelium-dependent vasodilator bradykinin (10-10 to 10-6M) and in the presence or absence of the selective COX-2 inhibitor NS398 (10-5M). RESULTS: The post-CPB protein levels of the inducible COX-2 were significantly increased compared with pre-CPB values in both the ND and DM groups (P < 0.05), whereas, this increase was higher in DM than that of ND (P < 0.05). In the DM arterioles, not the ND vessels, bradykinin-induced relaxation response was inhibited in the presence of the specific COX-2 inhibitor NS398 at baseline (P < 0.05). After CPB, bradykinin-induced relaxation response of the ND and DM arterioles was inhibited in the presence of the specific COX-2 inhibitor NS398, but this effect was more pronounced in the diabetic patients (P < 0.05). CONCLUSIONS: Diabetes and CPB are associated with upregulation in COX-2 expression/activation in human peripheral microvasculature. This alteration may lead to altered peripheral microvascular reactivity in diabetic patients undergoing cardiac surgery.

Diabetes Upregulation of Cyclooxygenase 2 Contributes to Altered Coronary Reactivity After Cardiac Surgery.

BACKGROUND: We hypothesized that upregulation of inducible cyclooxygenase 2 (COX-2) contributes to altered coronary arteriolar reactivity early after cardioplegic arrest and cardiopulmonary bypass (CP/CPB) in patients with diabetes mellitus who are undergoing cardiac surgery. METHODS: The right atrial tissue samples of nondiabetes (ND), controlled diabetes (CDM), and uncontrolled diabetes (UDM) patients undergoing cardiac surgery were harvested before and after CP/CPB. Coronary arterioles (80 to 150 µm) were dissected from the harvested atrial tissue samples, cannulated, and pressurized. The changes in diameter were measured with video microscopy. The protein expression and localization of COX-1 and COX-2 were assayed by Western blot and immunohistochemistry. RESULTS: In the diabetes arterioles, bradykinin-induced relaxation response was inhibited by the selective COX-2 inhibitor NS398 at baseline (p < 0.05). This effect was more pronounced in UDM arterioles than CDM (p < 0.05). After CP/CPB, bradykinin-induced responses in all groups were inhibited by NS398, but this effect was more pronounced in the UDM patients (p < 0.05). The intensities of COX-2 staining of coronary arterioles and COX-2 protein levels in myocardium were higher in diabetes than nondiabetes at baseline (p < 0.05). The post-CP/CPB protein levels of the inducible COX-2 were significantly increased compared with pre-CP/CPB values in all groups (p < 0.05), whereas this increase was higher with diabetes than with ND (p < 0.05). Furthermore, these effects were more profound in UDM than CDM (p < 0.05). CONCLUSIONS: Diabetes and CP/CPB are associated with upregulation in COX-2 expression in human coronary vasculature. Upregulation of COX-2 expression may contribute to bradykinin-induced coronary arteriolar relaxation in diabetic patients undergoing cardiac surgery.

Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567es as well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV-driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, both in vitro and in vivoCancer Res; 77(9); 2439-52. ©2017 AACR.

Acceptability and Reliability of a Novel Palliative Care Screening Tool Among Emergency Department Providers.

BACKGROUND: The Palliative Care and Rapid Emergency Screening (P-CaRES) Project is an initiative intended to improve access to palliative care (PC) among emergency department (ED) patients with life-limiting illness by facilitating early referral for inpatient PC consultations. In the previous two phases of this project, we derived and validated a novel PC screening tool. This paper reports on the third and final preimplementation phase. OBJECTIVES: Examine the acceptability of the P-CaRES tool among PC and ED providers as well as test its reliability on case vignettes. Compare variations in reliability and acceptability of the tool based on ED providers' roles (attendings, residents, and nurses) and lengths of experience. METHODS: A two-part electronic survey was distributed to ED providers at multiple sites across the United States. We tested the reliability of the tool in the first part of the survey, through a series of case vignettes. A criterion standard of correct responses was first defined by consensus input from expert PC physicians' interpretations of the vignettes. The experts' input was validated using the Gwet's AC1 coefficient for inter-rater reliability. ED providers were then presented with the case vignettes and asked to use the P-CaRES tool to correctly identify which patients had unmet PC needs. ED provider responses were compared both against the criterion standard and against different subsets of respondents (divided both by role and by level of experience). The second part of the survey assessed acceptability of the P-CaRES tool among ED providers using responses to questions from a modified Ottawa Acceptability of Decision Rules Instrument, based on a 1-5 Likert rating scale. Descriptive statistics were used to report all outcomes. RESULTS: In total, 213 ED providers employed in three different regions across the country responded to the survey (39.4%) and 185 (86.9%) of those completed it. The majority of providers felt that the tool would be useful in their practice (80.5%), agreed that the tool was clear and unambiguous (87.1%), thought that use of the tool would likely benefit patients (87.5%), and thought that it would result in improved use of resources to help severely ill patients (83.6%). Over three-quarters of ED providers (78.5%) also self-reported that they refer patients with unmet PC needs less than 10% of the time, and only 10.8% of respondents believed that they are already utilizing an effective strategy to screen or refer patients to PC. Applying our P-CaRES tool to case vignettes, ED providers generated PC referrals in concordance with PC experts over 88.7% of the time (95% confidence interval = 86.4% to 90.6%), with an overall sensitivity of more than 90%. These results varied minimally regardless of the respondent's role in the ED or their level of experience. CONCLUSION: Screening by emergency medicine providers for unmet PC needs using a brief, novel, content-validated screening tool is acceptable and is also reliable when applied to case vignettes-regardless of provider role or experience. Clinical trial and further study are warranted and are currently under way.

Changing organizational culture: using the CEO cancer gold standard policy initiatives to promote health and wellness at a school of public health.

BACKGROUND: Worksite wellness initiatives for health promotion and health education have demonstrated effectiveness in improving employee health and wellness. We examined the effects of a multifaceted health promotion campaign on organizational capacity to meet requirements to become CEO Cancer Gold Standard Accredited. METHODS: We conducted an online survey to assess perceived organizational values and support for the five CEO Cancer Gold Standard Pillars for cancer prevention: tobacco cessation; physical activity; nutrition; cancer screening and early detection; and accessing information on cancer clinical trials. Baseline and follow-up surveys were sent 6-months apart to faculty, staff, and students at a school of public health to test the impact of a multifaceted health promotion campaign on perceived organizational change. Descriptive analyses were used to characterize percent improvement. Multivariate logistic regression analyses were used to control for participants' university status. RESULTS: The current organizational culture highly supported tobacco cessation at both time points. Significant improvements (p < .05) from baseline to follow-up were observed for questions measuring organizational values for 'prevention, screening, and early detection of cancer' and 'accessing cancer treatment and clinical trials'. CONCLUSIONS: Health promotion and education efforts using multiple approaches were effective to improve perceived organizational values and support for cancer prevention and early detection, and increase access to information about cancer clinical trials. Future studies are needed to examine broader impacts of implementing worksite health promotion initiatives.

Content Validation of a Novel Screening Tool to Identify Emergency Department Patients With Significant Palliative Care Needs.

BACKGROUND: The emergency department (ED) is increasingly used by patients with life-limiting illness. These patients are frequently admitted to the hospital, where they suffer from poorly controlled symptoms and are often subjected to marginally effective therapies. Palliative care (PC) has emerged as the specialty that cares for patients with advanced illness. PC has been shown to reduce symptoms, improve quality of life, and decrease resource utilization. Unfortunately, most patients who could benefit from PC are never identified. At present, there exists no validated screening tool to identify significant unmet PC needs among ED patients with life-limiting illness. OBJECTIVES: The objective was to develop a simple, content-valid screening tool for use by ED providers to identify ED patients with significant PC needs. A positive screen would result in an inpatient PC consultation. METHODS: An initial screening tool was developed based on a critical review of the literature. Content validity was determined by a two-round modified Delphi technique using a panel of PC experts. The expert panel reviewed the items of the tool for accuracy and necessity using a Likert scale and provided narrative feedback. Expert's responses were aggregated and analyzed to revise the tool until consensus was achieved. Greater than 80% agreement, as well as meeting Lawshe's critical values, was required to achieve consensus. RESULTS: Fifteen experts completed two rounds of surveys to reach consensus on the content validity of the tool. Three screening items were accepted with minimal revisions. The remaining items were revised, condensed, or eliminated. The final tool contains 13 items divided into three steps: 1) presence of a life-limiting illness, 2) unmet PC needs, and 3) hospital admission. The majority of panelists (86%) endorsed adoption of the final screening tool. CONCLUSIONS: Use of a modified Delphi technique resulted in the creation of a content-validated screening tool for identification of ED patients with significant unmet PC needs. Further validation testing of the instrument is warranted.