Driving stroke quality improvement at scale in EDs across a nationwide network of hospitals: strategies and interventions.

OBJECTIVES: Reducing the treatment time while increasing the proportion of eligible stroke patients who receive intravenous tissue plasminogen activator (tPA) has been a priority for many quality improvement efforts. Recent studies have primarily focused on identifying interventions that reduce door-to-needle (DTN) time, while comparatively little has been done to determine whether these interventions also improve tPA rates. METHODS: In order to investigate interventions related to process improvements, an electronic dashboard serving as a stroke performance tool was implemented to store and retrieve patient outcome data. These data were used to study the efficacy of interventions designed to facilitate triage of stroke patients in the ED, and determine the individual interventions associated with the most significant improvements in the fraction of patients receiving tPA and in reducing the DTN time. Stroke performance data from the dashboard collected over a 2-year period (2015-2017) from 89 US hospitals were analysed with respect to interventions implemented by individual facilities, as verified by a hospital survey. RESULTS: A statistically significant association was found between increases in the fraction of patients receiving tPA and reductions in DTN time over the study period. These improvements in outcomes were most strongly associated with process interventions that allocate stroke-specific physical and human resources in the ED, most notably a designated emergency room space for stroke, and with workflows that decrease the time to key checkpoints for determining a patient's eligibility for tPA. CONCLUSIONS: Data from the stroke performance tool was leveraged to identify the programmes and process interventions that lead to improved patient outcomes and allow EDs to better prioritise process interventions and resources.

Feeding the Soul via Creation of a Suborganization to Promote a Sense of Community.

Pharmacy faculty commonly report feeling stressed, overwhelmed, exhausted, and burnt out. Women may be disproportionally impacted by personal and professional demands. The purpose of this commentary is to describe one mechanism for creating a suborganization (Circle) that establishes a supportive community to combat burnout and promote professional fulfillment. This commentary is a description of one American Academy of Colleges of Pharmacy (AACP) Women Faculty Special Interest Group (SIG) Circle. The authors describe how one Circle sought to enhance the well-being of its members through the various domains of the Stanford Model of Professional Fulfillment, including personal resilience, workplace efficiency, and creating a culture of well-being. Circles and similar frameworks may be effective tools for combatting burnout, improving fulfillment, and promoting wellness and well-being among women and other groups of faculty.

Design and implementation of a pilot student wellness program at a school of pharmacy.

BACKGROUND AND PURPOSE: In response to concerns about student stress and well-being, a volunteer wellness task force was formed to promote a culture of wellness at the school of pharmacy (SOP). The purpose of this paper is to describe the development and implementation of this pilot wellness program. EDUCATIONAL ACTIVITY AND SETTING: A task force was formed to design and implement a pilot wellness program for pharmacy students. Interventions included: orientation to wellness program, sessions on nutrition and mindfulness, in-class brain breaks, and promotion of on-campus resources. Student wellness was assessed at baseline with a questionnaire including sociodemographic data, perceived stress levels using the Perceived Stress Scale (PSS-10), wellness practices, and use of wellness resources. Program feedback was obtained using a post-questionnaire to identify student perceptions and preferences for wellness activities. FINDINGS: Pharmacy year one through three students (n = 166) were included in the pilot wellness program, with 92.2% and 88.8% completing the baseline and post-questionnaires, respectively. There were notable changes in wellness practices compared to baseline including an increase in weekly exercise and sleeping >4 hours a night. There was greatest use of and satisfaction with 5- to 10-min in-class wellness breaks. The mean student PSS-10 baseline score was 20.14 while the post-implementation mean score was 19.62. SUMMARY: This study demonstrates the potential for implementing a faculty-driven wellness program despite limited resources. The design, implementation, and lessons learned from this pilot program may serve as a practical framework for institutions seeking to promote student wellness.

Implementation of an Opioid Overdose and Naloxone Distribution Training in a Pharmacist Laboratory Course.

Objective. To describe the instructional design, implementation, and evaluation of an opioid overdose response program (ORP) and opioid overdose education and naloxone distribution (OEND) training program to third-year pharmacy (P3) students. Methods. Using the 5-E learning cycle during a three-hour laboratory session, the authors developed an OEND training program. The training began with an engagement exercise encompassing validated pre-Opioid Overdose Knowledge Scale (OOKS) and pre-Opioid Overdose Attitudes Scale (OOAS) assessments. Directly after, students moved to the exploration phase of the program, which consisted of two stations with placebo naloxone products. There, instructors explained key content related to OEND. Students applied what was learned during the elaboration by completing two cases: using group-based point-by-point counseling as well as a scenario with a simulation patient manikin. The class ended with an evaluation exercise that involved completing post-OOKS and post-OOAS. Results. Fifty-six students participated in the ORP certification and OEND training. Significant increases in total scores were seen on the pre- and post-assessment. Additionally, significant increases in student confidence in providing overdose response counseling and dispensing naloxone were observed. Students rated all the learning activities as very effective. Conclusion. Use of the 5-E learning cycle as an educational design method to structure active-learning activities was effective in increasing students' knowledge and improving their attitudes toward and confidence in providing overdose response.

HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases.

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4-31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery.

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.

Tocilizumab for severe COVID-19 related illness - A community academic medical center experience.

The SARS-CoV-2 virus responsible for the COVID-19 pandemic can result in severe or fatal disease in a subset of infected patients. While the pathogenesis of severe COVID-19 disease has yet to be fully elucidated, an overexuberant and harmful immune response to the SARS-CoV-2 virus may be a pivotal aspect of critical illness in this patient population. The inflammatory cytokine, IL-6, has been found to be consistently elevated in severely ill COVID-19 patients, prompting speculation that IL-6 is an important driver of the pathologic process. The inappropriately elevated levels of inflammatory cytokines in COVID-19 patients is similar to cytokine release syndrome (CRS) observed in cell therapy patients. We sought to describe outcomes in a series of severely ill patients with COVID-19 CRS following treatment with anti-IL-6/IL-6-Receptor (anti-IL-6/IL-6-R) therapy, including tocilizumab or siltuximab. At our academic community medical center, we formed a multi-disciplinary committee for selecting severely ill COVID-19 patients for therapy with anti-IL-6 or IL-6-R agents. Key selection criteria included evidence of hyperinflammation, most notably elevated levels of C-reactive protein (CRP) and ferritin, and an increasing oxygen requirement. By the data cutoff point, we treated 31 patients with anti-IL-6/IL-6-R agents including 12 who had already been intubated. Overall, 27 (87%) patients are alive and 24 (77%) have been discharged from the hospital. Clinical responses to anti-IL-6/IL-6-R therapy were accompanied by significant decreases in temperature, oxygen requirement, CRP, IL-6, and IL-10 levels. Based on these data, we believe anti-IL-6/IL-6-R therapy can be effective in managing early CRS related to COVID-19 disease. Further study of anti-IL-6/IL-6-R therapy alone and in combination with other classes of therapeutics is warranted and trials are underway.

Ethanolic Echinacea purpurea Extracts Contain a Mixture of Cytokine-Suppressive and Cytokine-Inducing Compounds, Including Some That Originate from Endophytic Bacteria.

Echinacea preparations, which are used for the prevention and treatment of upper respiratory infections, account for 10% of the dietary supplement market in the U.S., with sales totaling more than $100 million annually. In an attempt to shed light on Echinacea's mechanism of action, we evaluated the effects of a 75% ethanolic root extract of Echinacea purpurea, prepared in accord with industry methods, on cytokine and chemokine production from RAW 264.7 macrophage-like cells. We found that the extract displayed dual activities; the extract could itself stimulate production of the cytokine TNF-α, and also suppress production of TNF-α in response to stimulation with exogenous LPS. Liquid:liquid partitioning followed by normal-phase flash chromatography resulted in separation of the stimulatory and inhibitory activities into different fractions, confirming the complex nature of this extract. We also studied the role of alkylamides in the suppressive activity of this E. purpurea extract. Our fractionation method concentrated the alkylamides into a single fraction, which suppressed production of TNF-α, CCL3, and CCL5; however fractions that did not contain detectable alkylamides also displayed similar suppressive effects. Alkylamides, therefore, likely contribute to the suppressive activity of the extract but are not solely responsible for that activity. From the fractions without detectable alkylamides, we purified xanthienopyran, a compound not previously known to be a constituent of the Echinacea genus. Xanthienopyran suppressed production of TNF-α suggesting that it may contribute to the suppressive activity of the crude ethanolic extract. Finally, we show that ethanolic extracts prepared from E. purpurea plants grown under sterile conditions and from sterilized seeds, do not contain LPS and do not stimulate macrophage production of TNF-α, supporting the hypothesis that the macrophage-stimulating activity in E. purpurea extracts can originate from endophytic bacteria. Together, our findings indicate that ethanolic E. purpurea extracts contain multiple constituents that differentially regulate cytokine production by macrophages.