Disruptive Effects of the Coronavirus – Errors of Commission and of Omission?

It is increasingly evident that the coronavirus disease, COVID-19, is more than a health problem; it is and will continue to adversely affect work and workplaces, education, families and social engagements, political and environmental dimensions, and financial indicators. Apart from its health ramifications, the crisis is revealing serious challenges in the global supply chain. Those difficulties are, at least in part, consequences of unwise, short-sighted business decisions made over the course of decades to outsource and downsize

Our Wicked Problem

The Coronavirus is more than a health problem. It is a “wicked” problem disrupting work, education, travel, politics, financial indicators, and more. This label came about in 1973 to help describe a special class of situations that are volatile, uncertain and ambiguous, often difficult to recognize, and difficult or impossible to solve because of incomplete, contradictory, and changing requirements. There is no clear problem definition due to interdependencies so the problem cannot be fully understood until after the solution comes about

Rethinking Executive Education: A Program for Responding to Sudden Disruptions Caused by Dynamic Complexity

Lately, many social systems (i.e., countries, organizations and projects) are experiencing adverse situations that are characterized as “dynamic complexity.” These situations usually co-produce disruptions in the day-to-day operations as a result of which many social systems become partially extinct. We posit this is because these situations are not clearly recognized by those who are empowered to deal with them. In this paper we propose a new and updated approach to executive education that takes into account the prevalence of dynamic complexity caused by massive changes in the nature of the internal and external environments of a system. We argue that the educational requirements necessary to prepare leaders who have the cognitive capacity to steer through the “perfect storm,” are very different from leading in simple and stable contexts. We suggest that this proficiency emerges from the interaction of relevant skills, accessed experience, knowledge and understanding of the situation, practical wisdom and sound judgment, and relevant personality attributes. We present a model with a multi-layered approach to executive education which addresses how the ability to rapidly assimilate, sort through, and comprehend vast amounts of data/information in order to make the right decisions depends on approaches to learning, knowledge of critical concepts, particularly systems thinking as a mindset/filter, and knowledge of enabling IT

Designing a Strategic Plan for the Jefferson Center for Interprofessional Practice and Education (JCIPE)

https://jdc.jefferson.edu/jscpsposters/1007/thumbnail.jp

Collaborative SCA Survival Project: Cardiac Arrest Survival is a Mess

Systems diagnoses have been effectively used to understand many complex organizational systems within healthcare, government, military, and global corporate enterprises. Systems methodologies have been effectively used to change the direction and improve the outcomes of complex organizational systems. We feel that framing cardiac arrest survival as a systems problem and applying a systems methodology is innovative, practical, and essential if we are to make significant and sustainable impact

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.

Purpose Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and methods Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL

Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding 2 biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies replicated the subgroups, with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and the need for a patient-selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients exhibited an enrichment in response rate and progression-free survival of 44% and 6.2 months vs 19% and 1.6 months for classifier-negative patients (hazard ratio, 0.49; 95% confidence interval, 0.280-0.86; P = .0096). The classifier was not prognostic for rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and nontumor composition and has potential utility to enrich for clinical response to immunomodulatory agents, including avadomide

Strategic Plan: 2018 and Forward - Jefferson Center for Interprofessional Practice & Education

Founded in 2007, the Jefferson Center for Interprofessional Practice and Education (JCIPE) is one of the premier interprofessional education centers in the U.S. Our center is dedicated to improving interprofessional care (IPC) through implementing and evaluating patient-centered education throughout the Thomas Jefferson University curriculum. We offer robust trainings and educational opportunities, provide innovative teaching models and evidence-based practices to help support emerging priorities in healthcare. To coincide with our 10-year anniversary and the transition to new leadership, we engaged the Jefferson Doctor of Management program in Strategic Leadership (DSL) to help us to reimagine and rethink our interests and needs in the increasingly complex and changing environment. With their facilitation we drew on the experience of more than 120 JCIPE stakeholders including co-directors, staff advisors, faculty, deans, student learners, community leaders, health mentors, and patients. We adopted a system-thinking framework and applied interactive design planning methodology to create the design for an ideal center for interprofessional care. From this prototype, we created our new strategic plan, business model, and roadmap. We believe our design experience and deep understanding of IPC will lead us to an even more prominent role as a model of excellence for interprofessional and professional practice and education

Towards the development of a simulator for investigating the impact of people management practices on retail performance

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mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer