Introduction: Timely administration of corticosteroids improves asthma care in the pediatric emergency department (ED). Using the Model for Improvement, we aimed to decrease time to delivery of corticosteroids in patients presenting to the ED with an acute asthma exacerbation. Methods: This is a single-center, prospective, multidisciplinary quality improvement (QI) project targeting ED patients 1−18 years of age with an acute asthma exacerbation. We collected 5 months of baseline data from the arrival time of an ED patient with an asthma exacerbation with a Modified Pulmonary Index Score ≥5 to the time of administration of corticosteroids. A quality improvement project was launched in October 2017 involving multiple Plan-Do-Study-Act ramps. Improvement interventions continued for 9 months through June 2018, including reeducation of residents and nurses in the ED asthma order set and nursing treatment protocols, respectively, and changes to the electronic health record. Data were tacked for 15 additional months until September 2019. To promote the use of the nursing treatment protocol, we utilized real-time improvement feedback and continuing nursing education. Results: The mean percentage of patients receiving steroids within 60 minutes of arrival improved from 59.3% to 84.3% over the first 5 months. The mean time to the administration of steroids within 60 minutes of arrival improved from 71.4 to 48.1 minutes. There was no increase in ED return rates. Conclusions: Our project improved the percentage of patients with acute asthma exacerbations receiving steroids within 60 minutes of ED arrival and mean time to administration of steroids. We sustained improvement for 18 months after the implementation of our QI interventions.
BACKGROUND: Patient satisfaction measures have important implications for physicians. Patient bias against non-White physicians may impact physician satisfaction ratings, but this has not been widely studied. OBJECTIVE: To assess differences in patient satisfaction by physician race/ethnicity. DESIGN: A cross-sectional observational study. PARTICIPANTS: Patients seeking care on a large nationwide direct to consumer telemedicine platform between July 2016 and July 2018 and their physicians. MAIN MEASURES: Patient satisfaction was ascertained immediately following the encounter on scales of 1 to 5 stars and scored two ways: (1) top-box satisfaction (5 stars versus fewer) and ( 2) dissatisfaction (2 or fewer stars versus 3 or more). To approximate the information patients would use to make assumptions about physician race/ethnicity, four reviewers classified physicians into categories based on physician name and photo. These included White American, Black American, South Asian, Middle Eastern, Hispanic, and East Asian. Mixed effects logistic regression was used to assess differences in patient top-box satisfaction and patient dissatisfaction by physician race/ethnicity, controlling for patient characteristics, prescription receipt, physician specialty, and whether the physician trained in the USA versus internationally. KEY RESULTS: The sample included 119,016 encounters with 390 physicians. Sixty percent were White American, 14% South Asian, 7% Black American, 7% Hispanic, 6% Middle Eastern, and 6% East Asian. Encounters with South Asian physicians (aOR 0.70; 95% CI 0.54-0.91) and East Asian physicians (aOR 0.72; 95% CI 0.53-0.99) were significantly less likely than those with White American physicians to result in top-box satisfaction. Compared to encounters with White American physicians, those with Black American physicians (aOR 1.72; 95% CI 1.12-2.64), South Asian physicians (aOR 1.77; 95% CI 1.23-2.56), and East Asian physicians (aOR 2.10; 95% CI 1.38-3.20) were more likely to result in patient dissatisfaction. CONCLUSIONS: In our study, patients reported lower satisfaction with some groups of non-White American physicians, which may have implications for their compensation, professional reputation, and job satisfaction.
Background BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. Methods Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. Results Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/− myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. Conclusion BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.
BACKGROUND: Treating hypertension is important but physicians often do not intensify blood pressure (BP) treatment in the setting of pain. OBJECTIVE: To identify whether reporting pain is associated with (1) elevated BP at the same visit, (2) medication intensification, and (3) elevated BP at the subsequent visit. DESIGN: Retrospective cohort SETTING: Integrated health system PARTICIPANTS: Adults seen in primary care EXPOSURE: Pain status based on numerical scale: mild (1-3), moderate (4-6), or severe (≥ 7). MAIN MEASURES: We defined elevated BP as ≥ 140/ 80 mmHg and medication intensification as increasing the dose or adding a new antihypertensive medication. Multilevel regression models were used to find the association between pain and ( 1) elevated BP at the index visit;(2) medication intensification at the index visit; and (3) elevated BP at the subsequent visit. Models adjusted for demographics, chronic conditions, and clustering within physician. In the third model, we adjusted for initial systolic BP as well. KEY RESULTS: Our population included 56,322 patients; 3155 (6%) reported mild pain, 5050 (9%) reported moderate pain, and 4647 (8%) reported severe pain at the index visit. Compared with no pain, the adjusted odds ratios of elevated BP were 1.38 (95% CI: 1.28-1.48) for severe pain, 1.06 (95% CI: 0.99-1.14) for moderate pain, and 1.02 (95% CI: 0.93-1.12) for mild pain. Adjusted odds ratios of medication intensification at the index visit were 0.65 (95% CI: 0.54-0.80) for mild pain, 0.61 (95% CI: 0.52-0.72) for moderate pain, and 0.55 (95% CI: 0.47-0.64) for severe pain. Among patients with elevated BP at the index visit, reporting pain at the index visit was not associated with elevated BP at the subsequent visit. CONCLUSIONS: When patients reported pain, physicians were less likely to intensify antihypertensive treatment; nevertheless, patients reporting pain were not more likely to have elevated BP at the subsequent visit.
Biliary cancer (BC), or cholangiocarcinoma originates from the malignant transformation of epithelial cells in the bile ducts. This deadly cancer is typically refractory to standard therapies and has a 3 year survival rate of only 10%. Therefore, novel treatment strategies are desparately needed against this malignancy. One important feature of BC cells is their ability to secrete interleukin-6 (IL-6) in an autocrine manner. This characteristic affords them an opportunity to activate numerous pro-oncogenic signaling pathways including MAPK, and STAT3 within the tumor cell, while simultaneously promoting immunologic changes in patients with advanced disease. We hypothesized that inhibitors of Signal-Transducer and Activator of Transcription-3 (STAT3) pathway may elicit a dual effect by promoting apoptosis of human BC cell lines, and limiting the secretion of immunosuppressive cytokines from these cells. A panel of human BC cell lines with various genotypic profiles was utilized, and all demonstrated secretion of IL-6 (range 5149-68pg/mL) and had constitutively phosphorylated STAT3 as determined by western blot. Similar to positive control conditions with IL-6 + GM-CSF (10 ng/mL each), exposure of human peripheral blood mononuclear cells to 5% or 10% BC culture supernatants induced in vitro differentiation into myeloid derived suppressor cells (MDSC). These data indicate that BC cells have robust activation of the IL-6/STAT3 signaling axis, and that culture supernatants contain factors capable of promoting expansion of immune suppressive cell subsets. A novel small molecule inhibitor FLLL100, could directly inhibit Tyr705 phosphorylation within the SH2 domain of STAT3, and induce apoptosis in the BC cell lines regardless of genotypic profile. Both growth inhibitory (by MTT assay) and pro-apoptotic effects (by Annexin V/PI staining) were observed within 24-48 hours of drug exposure at micromolar concentrations. Apoptosis was confirmed after drug exposure by assessment of PARP cleavage by immunoblot. Exposure of BC cell lines to FLLL100 resulted in significantly reduced secretion of immunomodulatory cytokines including IL-6 (p<0.05) and GM-CSF (p<0.05) in culture supernatants. Together, these data indicate that the IL-6/STAT3 signaling axis plays a role in human BC survival and that targeting this pathway can limit immune suppressive factors derived from BC cell lines. Citation Format: Jennifer Yang, Kaitlin Keenan, Thomas Mace, Tanios Bekaii-Saab, James Fuchs, Eric Schwartz, Chenglong Li, Jiayuh Lin, Pui-Kai Li, Gregory Lesinski. STAT3 inhibitors elicit direct anti-tumor effects against human biliary caner cell lines and limit release of immune suppressive cytokines in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4073. doi:10.1158/1538-7445.AM2014-4073
Biliary cancer (BC), or cholangiocarcinoma, is derived from the malignant transformation of epithelial cells in the bile ducts. The disease usually presents at advanced stages and is almost uniformly deadly. Current therapeutic regimens have limited efficacy for treatment of BC, thus the need for developing novel and effective targeted strategies is a priority. This malignancy is characterized by deregulated PI3 kinase/Akt signaling, upregulated mitogen-activated protein kinase (MAPK) pathway and an autocrine IL-6/STAT3 signal transduction feedback loop, which can also drive immunosuppression. A recent report showed clinical responses for BC patients receiving the MEK inhibitor AZD244, which promoted more extensive pre-clinical studies to validate the effect of MEK inhibition and importance of this pathway in BC. In the present study, MEK162, a MEK inhibitor, was used to assess the growth inhibitory, pro-apoptotic, and immunomodulatory effects in BC. In vitro studies in a panel of human BC cell lines (HuCCT1, HuH28, MzCha1) revealed that MEK162 significantly inhibited cell growth and induced apoptosis in a concentration-dependent manner in all three cell lines. Immunoblot data confirmed decreased phosphorylated ERK (pERK) in the HuCCT1 BC cell line following a 24 hour treatment with MEK162. MEK inhibition was also associated with clinically-relevant immunomodulatory effects. First, culture supernatants from human BC cells displayed significant reductions in IL-6 protein by ELISA after treatment with MEK162 at varying concentrations. Second, MEK162 inhibited in vitro generation of human myeloid derived suppressor cells from peripheral blood mononuclear cells cultured with IL-6 and GM-CSF. Finally, in vivo studies in athymic mice bearing HuCCT1 xenografts showed that daily oral administration of MEK162 (30 mg/kg in 1% (w/v) carboxymethylcellulose, 0.5% (v/v) Tween 80) was well-tolerated and resulted in significant growth inhibition as compared to vehicle-treated controls (p < 0.0001). Immunohistochemical analysis of tumor xenografts revealed significant decreases in both Ki67 and pERK staining in the MEK162-treated mice as compared to controls (p = 0.0163 and 0.0132,respectively). Together, these data suggest that MEK inhibition represents a promising therapeutic approach with potential for direct antitumor activity and immunomodulation in BC. Citation Format: Jennifer Yang, Thomas A. Mace, Gergory S. Young, Patrice A. Lee, Kaitlin E. Keenan, Zheng Che, Tonios Bekaii-saab, Gregory B. Lesinski. MEK162, an allosteric MEK inhibitor promotes apoptosis and in vivo antitumor activity against human biliary cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 934. doi:10.1158/1538-7445.AM2013-934
Cholangiocarcinoma (CC) responds poorly to chemo- and immunotherapy and is nearly always fatal within one year. In recent years we have gained important insight into the signaling pathways that drive this cancer. These cancers are characterized by deregulated mitogen-activated protein kinase (MAPK), PI3 kinase/Akt and a dependence on the IL-6 axis of signal transduction. Importantly, we previously reported clinical responses for CC patients receiving single agent MEK inhibitors, indicating these agents have activity in this disease. We hypothesized that dual targeting of these pathways in CC using MEK162 and buparlisib would lead to potent antitumor and immunomodulatory activity, possibly circumventing resistance to single agent MEK162. In a panel of n = 7 human CC cell lines with diverse genetic profiles, constitutive phosphorylation of ERK (7/7) and Akt (2/7) was observed. Human CC cell lines displayed variable sensitivity to the growth inhibitory and pro-apoptotic effects of single agent MEK162 or buparlisib. CC cell lines with basal AKT phosphorylation (WITT, Mz-Cha-1) showed greater sensitivity to growth inhibition by buparlisib (IC50 10-20 μM), as compared to CC lines lacking pAKT (HuCCT1, HuH28, IC50 > 20μM). Immunoblot analysis confirmed decreased phosphorylated ERK (pERK) in the HuCCT1 and SNU-478 CC cell lines following treatment with MEK162. Culture supernatants from four separate human CC cell lines displayed significant reductions in IL-6, VEGF, and GM CSF in a concentration-dependent manner after treatment with MEK162. Immunomodulatory effects of MEK162 were also evident, independent of its tumor-intrinsic effects upon CC cell lines. Namely, it significantly reduced IL 6/GM-CSF driven MDSC differentiation (HLA-DRlo CD11b+ CD33+) from healthy normal donor PBMC in vitro. These observations were not due to cytotoxic activity as treatment with MEK162 for 72 hours did not reduce viability of bulk human PBMCs. Finally, to evaluate the effect of this treatment combination, in vivo studies were conducted in athymic mice bearing Mz-Cha1 or SNU-478 xenografts. Tumor bearing mice received daily oral administration of MEK162 (30 mg/kg), buparlisib (25 mg/kg), or both agents combined. Vehicle treated animals served as negative controls. Inhibition of tumor growth was observed following administration of single agent MEK162 or buparlisib as compared to control animals. This effect was further enhanced in the combination treated animals. Body weight of animals indicated this regimen was well-tolerated. Together, these data suggest that dual PI3K and MEK inhibition can target CC with varying genotypes and represents a promising therapeutic regimen with potential for direct antitumor activity and immunomodulation in CC. Citation Format: Jennifer Yang, Omar Elnaggar, Thomas Mace, Matthew Farren, Gregory Young, Patrice Lee, Kaitlin Keenan, Zheng Che, Jacob Kaufman, Denis Guttridge, David Carbone, Cynthia Timmers, Tanios Bekaii-Saab, Gregory Lesinski. Combined inhibition of MEK and PI3K elicits anti-tumor activity in human cholangiocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2656. doi:10.1158/1538-7445.AM2015-2656
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