Structural Competency in Simulation-Based Health Professions Education: A Call to Action and Pragmatic Guide.

SUMMARY STATEMENT: Simulation-based health professions educators can advance diversity, equity, and inclusion by cultivating structural competency, which is the trained ability to discern inequity not only at an individual level, but also at organizational, community, and societal levels. This commentary introduces Metzl and Hansen's Five-Step Model for structural competency and discusses its unique applicability to the metacognitive underpinnings of simulation-based health professions education. We offer a pragmatic guide for simulation-based health professions educators to collaboratively design learning objectives, simulation cases, character sketches, and debriefs in which structural competency is a simulation performance domain, alongside patient management, resource usage, leadership, situational awareness, teamwork, and/or communication. Our overall goal is to promote a paradigm shift in which educators are empowered to partner with patients, colleagues, and communities to recognize, learn about, and challenge the factors driving health inequities; a skill that may be applied to a broad range of health professions education within and outside of simulation.

Use of and attitudes toward tobacco and alcohol among adults in southern Sri Lanka.

The adverse health effects of tobacco and alcohol are well known. Alcohol consumption is increasing in Sri Lanka, but few population studies have been conducted. The objective of this study was to document tobacco and alcohol consumption levels among adults in southern Sri Lanka and to identify the main reasons for using or refraining from alcohol and tobacco products. Tobacco and alcohol use within Sri Lanka is relatively common, particularly among adult males. Reasons given for smoking and drinking frequently relate to social and image-based motivators. Women may be especially susceptible to the influence of peer pressure in social situations. Public health efforts should consider the use of demographic-specific anti-tobacco and anti-alcohol messages, as the motivators driving behavior appear to differ across gender and age groups.

Arsenic trioxide uses caspase-dependent and caspase-independent death pathways in myeloma cells.

Arsenic trioxide (ATO) is emerging as a standard therapy for refractory acute promyelocytic leukemia. Consequently, ATO-based therapies are being investigated in other cancers. We have reported that the combination of ATO and ascorbic acid is an effective strategy in chemoresistant myeloma cell lines and in plasma cells from patients. ATO action is multimodal and appears to involve thiol depletion, increased reactive oxygen species production, loss of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspases. To better define the ATO death pathway, we asked whether caspase activity is required for ATO-mediated cell death. Here we report that ATO exerts cytotoxic effects in myeloma cell lines via both caspase-dependent and caspase-independent pathways. We monitored ATO-induced changes in cell viability, caspase activity, superoxide production, and DeltaPsi(m) in the presence or absence of the caspase inhibitors t-butoxy carbonyl-Asp.fluoromethylketone (BocD.fmk) and Z-Val-Ala-Asp.fluoromethylketone (zVAD.fmk) and the anti-oxidant N-acetylcysteine. Consistent with glutathione levels dictating ATO action, N-acetylcysteine abrogated ATO-induced changes in cell death, caspase activation, free radical production, and loss of DeltaPsi(m) in all the cell lines we tested. Experiments with caspase inhibitors suggested at least two models for ATO death signaling. In 8226/S cells, blockade of caspases had no effect on loss of cell viability, increase in reactive oxygen species production, and minimal effects on the loss of DeltaPsi(m). In contrast, BocD.fmk or zVAD.fmk conferred significant protection from the effects of ATO in U266 cells and MM1.S cells. Chemoresistant variants of 8226/S and MM1.S displayed similar ATO-induced death pathways as their respective parental lines. Studies with myeloma cells from bone marrow biopsies indicated that ATO initiates a caspase-independent pathway in the majority of samples.

Farnesyl transferase inhibitors enhance death receptor signals and induce apoptosis in multiple myeloma cells.

Multiple myeloma is an incurable plasma cell malignancy in which Ras may be constitutively active either via interleukin-6 (IL-6) receptor signaling or by mutation. Inactivation of Ras may be achieved with farnesyl transferase (FTase) inhibitors a class of drugs which have shown promise in clinical trials particularly in patients with acute leukemia. This report investigates the efficacy of two distinct classes of FTase inhibitors in diverse myeloma cell lines and primary isolates. While Ras signaling has traditionally been linked to myeloma cell growth, we found that these compounds also potently triggered cell death. Death induced by perillic acid (PA) was caspase dependent without evidence of death receptor activation. Apoptosis was associated with mitochondrial membrane depolarization and activation of caspase-9 and 3 but proceeded despite over-expression of Bcl-XL a known correlate of relapsed and chemorefractory myeloma. In addition, Fas ligand and TRAIL mediated apoptosis was potentiated in death receptor resistant (U266) and sensitive (RPMI 8226/S) cell lines. Of clinical relevance, the FTase inhibitor R115777 induced cell death in myeloma lines at doses observed in clinical trials. Furthermore, both R115777 and PA induced cell death in primary isolates with relative specificity. Taken together these preclinical data provide evidence that FTase inhibitors may be an effective therapeutic modality for the treatment of multiple myeloma.

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma.

Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3) + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.