Faculty Bibliography

Background mRNA-2752 is a first-in-class mRNA-based therapeutic agent encoding T cell co-stimulator OX40L, and proinflammatory cytokines IL-23 and IL-36g. Preclinical data demonstrated activity in a range of tumor microenvironments (TMEs), including immune checkpoint inhibitor (CPI)- refractory cancer models, and synergy when combined with alpha-PDL1 antibodies. Data from the dose escalation phase of the study was previously reported and the recommended mRNA- 2752 dose for expansion (RDE) was up to 8mg ITu. Methods We evaluated the safety and efficacy of ITu mRNA- 2752 administered as monotherapy (Arm A; previously reported ASCO 2020) and in combination with the PD-L1 inhibitor durvalumab (Arm B) in patients (pts) with tumors that were palpable or accessible with image guidance. Here we report preliminary data for the expansion cohorts in TNBC, CPI-refractory melanoma, and HNSCC. Biomarker analyses included IHC/F-IHC of immune status markers and whole transcriptome assessments of paired tumor biopsies. Protein quantification of IL-23, IL-36g and other pro-inflammatory cytokines were performed in plasma and tumors. Results As of 01JUL 2022, 88 pts were treated, 69 in Arm B with mRNA-2752 dosed by tumor size ranging from 0.25-8 mg. The most common treatment related adverse events occurring in >= 10% of pts in Arm B included grade 1/2 injection site erythema/pain/swelling, fever, chills, fatigue, nausea, and flushing. Grade 3 events included injection site pain/erythema, and fever. There were no grade 4/5 related events. Objective responses were observed in immune refractory tumors by RECIST and iRECIST, including a confirmed PR in a PD-L1 low TNBC and confirmed iCR in an immune checkpoint- refractory melanoma pt, respectively. Biomarker analyses of plasma and tumor show mRNA-2752 treatment was associated with elevated pro-inflammatory cytokines, including IL- 23, IL-36g, IFNgamma, and TNFalpha. F-IHC of paired tumor biopsies showed increase in proliferating CD8+ T cells. Transcriptional profiling of the TME demonstrates a pronounced immune response including dendritic cell recruitment and T cell activation, which remained elevated in longitudinal samples. The greatest increases in immune response and markers of cytolytic activity were observed in pts deriving clinical benefit. Conclusions ITu mRNA-2752 + IV durvalumab is safe, tolerable, and shows preliminary efficacy in immune refractory tumors, including TNBC and melanoma. Biomarker analyses indicate mRNA-2752 drives cytokine responses. Consistent with the expected mechanism of action, a productive and sustained inflammatory response is observed in the TME in response to treatment, including signatures of increased innate and adaptive immune cell abundance and effector response

Objectives/UNASSIGNED:The objective was to bridge the relative educational gap for newly matched emergency medicine preinterns between Match Day and the start of internship by implementing an Accreditation Council for Graduate Medical Education Milestone (ACGME)-based virtual case curriculum over the social media platform Slack. Methods/UNASSIGNED:We designed a Milestone-based curriculum of 10 emergency department clinical cases and used Slack to implement it. An instructor was appointed for each participating institution to lead the discussion and encourage collaboration among preinterns. Pre- and postcurriculum surveys utilized 20 statements adapted from the eight applicable Milestones to measure the evolution of preintern self-reported perceived preparedness (PP) as well as actual clinical knowledge (CK) performance on a case-based examination. Results/UNASSIGNED:A total of 11 institutions collaborated and 151 preinterns were contacted, 127 of whom participated. After participating in the Slack intern curriculum (SIC), preinterns reported significant improvements in PP regarding multiple Milestone topics. They also showed improved CK regarding the airway management Milestone based on examination performance. Conclusions/UNASSIGNED:Implementation of our SIC may ease the difficult transition between medical school and internship for emergency medicine preinterns. Residency leadership and medical school faculty will benefit from knowledge of preintern PP, specifically of their perceived strengths and weaknesses, because this information can guide curricular focus at the end of medical school and beginning of internship. Limitations of this study include variable participation and a high attrition rate. Further studies will address the utility of such a virtual curriculum for preinterns and for rotating medical students who have been displaced from clinical rotations during the novel coronavirus pandemic.

Background/UNASSIGNED:There is little evidence guiding equipment handling during emergency endotracheal intubations (EEI). Available evidence and current practice are either outdated, anecdotal or focused on difficult-not emergency-intubation. In this study, we describe and evaluate our equipment handling unit: the AIR-BOX. Methods/UNASSIGNED:This is a proof-of-concept, prospective, randomised simulation trial. A convenience sample of 50 airway course participants voluntarily underwent randomisation: 21 to the AIR-BOX group, 14 to the intubation box group, and 15 to the crash cart group. The volunteers were asked to intubate a manikin using the equipment from the storage unit of their randomisation. Outcome measures included time-to-readiness, time-to-intubation, first-pass success, and subjective operator experience. Results/UNASSIGNED:The mean time-to-readiness was 67.2 s with the AIR-BOX, 84.6 s with the intubation box, and 115 s with the crash cart. The mean time-to-intubation was 105 s with the AIR-BOX, 127 s with the intubation box and 167 s with the crash cart. A statistically significant difference was achieved between the AIR-BOX and the crash cart. No statistically significant difference was found between the three groups with regard to first-pass success or the time between intubation readiness and intubation. Conclusions/UNASSIGNED:This study supports the AIR-BOX as a viable tool that can improve and simplify access to emergency intubating equipment. It also opens doors for multiple future innovations that can positively impact equipment handling practices. Future studies can focus on assessing whether applying the AIR-BOX will yield a clinically significant impact on patient outcomes.