Implementing a telemedicine curriculum for internal medicine residents during a pandemic: the Cleveland Clinic experience.

Telemedicine training was not a substantial element of most residency programmes prior to the COVID-19 pandemic. Social distancing measures changed this. The Cleveland Clinic Internal Medicine Residency Programme (IMRP) is one of the largest programmes in the USA, which made the task of implementing a telemedicine curriculum more complex. Here we describe our experience implementing an effective, expedited telemedicine curriculum for our ambulatory resident clinics. This study was started in April 2020 when we implemented a resident-led curriculum and training programme for providing ambulatory telemedicine care. The curriculum was finalised in less than 5 weeks. It entailed introducing a formal training programme for residents, creating a resource guide for different video communication tools and training preceptors to safely supervise care in this new paradigm. Residents were surveyed before the curriculum to assess prior experience with telemedicine, and then afterward to assess the curriculum's effectiveness. We also created a mini-CEX assessment for residents to solicit feedback on their performance during virtual appointments. Over 2000 virtual visits were performed by residents in a span of 10 weeks. Of 148 residents, 38% responded to the pre-participation survey. A majority had no prior telemedicine experience and expressed only slight comfort with the modality. Through collaboration with experienced residents and faculty, we expeditiously deployed an enhancement to our ambulatory care curriculum to teach residents how to provide virtual care and help faculty with supervision. We share our insights on this experience for other residency programmes to use.

The COVID-19 pandemic as a catalyst for medical education innovation: A learner's perspective.

The COVID-19 pandemic has been transformative for healthcare and medical education. Physician trainees and the education system that serves them adapted quickly so that trainees could finish the academic year on time and advance to the next phase of training without compromising clinical competency or public safety. Systemic changes have had the most significant impact on telemedicine training, virtual learning, secure testing, and the interview process for residency and fellowship training positions. Trainees are now getting regular, supervised practice experience with telemedicine. Some secure testing is being done remotely, without jeopardizing examination test items or trainee assessment. Attending physicians are experimenting with novel ways to engage learners with video for virtual rounds to keep the rounding team safe. Finally, the interview process for medical school, residency, and fellowship programs, which has traditionally been an expensive and travel-laden process, has been made completely virtual for the first time ever. These changes have disadvantages, including a lack of social connection, potential distraction when learning remotely, and limited contact with a potential training program when interviewing by video. This perspective paper, written by a senior internal medicine resident, details his firsthand experience with these changes during the pandemic. It also looks forward to how the current changes will likely change medical education permanently and for the better.

Teaching residents how to break bad news: piloting a resident-led curriculum and feedback task force as a proof-of-concept study.

Background: Breaking bad news (BBN) is a critically important skill set for residents. Limited formal supervision and unpredictable timing of bad news delivery serve as barriers to the exchange of meaningful feedback. Purpose of study: The goal of this educational innovation was to improve internal medicine residents' communication skills during challenging BBN encounters. A formal BBN training programme and innovative on-demand task force were part of this two-phase project. Study design: Internal medicine residents at a large academic medical centre participated in an interactive workshop focused on BBN. Workshop survey results served as a needs assessment for the development of a novel resident-led BBN task force. The task force was created to provide observations at the bedside and feedback after BBN encounters. Training of task force members incorporated video triggers and a feedback checklist. Inter-rater reliability was analysed prior to field testing, which provided data on real-world implementation challenges. Results: 148 residents were trained during the 2-hour communications skills workshop. Based on survey results, 73% (108 of 148) of the residents indicated enhanced confidence in BBN after participation. Field testing of the task force on a hospital ward revealed potential workflow barriers for residents requesting observations and prompted troubleshooting. Solutions were implemented based on field testing results. Conclusions: A trainee-led BBN task force and communication skills workshop is offered as an innovative model for improving residents' interpersonal and communication skills in BBN. We believe the model is both sustainable and reproducible. Lessons learnt are offered to aid in implementation in other settings.

Students as catalysts for curricular innovation: A change management framework.

Introduction: The role of medical students in catalyzing and leading curricular change in US medical schools is not well described. Here, American Medical Association student and physician leaders in the Accelerating Change in Medical Education initiative use qualitative methods to better define student leadership in curricular change.Methods: The authors developed case studies describing student leadership in curricular change efforts. Case studies were presented at a national medical education workshop; participants provided worksheet reflections and were surveyed, and responses were transcribed. Kotter's change management framework was used to categorize reported student roles in curricular change. Thematic analysis was used to identify barriers to student engagement and activators to overcome these barriers.Results: Student roles spanned all eight steps of Kotter's change management framework. Barriers to student engagement were related to faculty (e.g. view student roles narrowly), students (e.g. fear change or expect faculty-led curricula), or both (e.g. lack leadership training). Activators were: (1) recruiting collaborative faculty, staff, and students; (2) broadening student leadership roles; (3) empowering student leaders; and (4) recognizing student successes.Conclusions: By applying these activators, medical schools can build robust student-faculty partnerships that maximize collaboration, moving students beyond passive educational consumption to change agency and curricular co-creation.

Low UBE4B expression increases sensitivity of chemoresistant neuroblastoma cells to EGFR and STAT5 inhibition.

Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors underlies resistance to chemotherapeutics. UBE4B, an E3/E4 ubiquitin ligase involved in EGFR degradation, is located on chromosome 1p36, a region in which loss of heterozygosity is observed in approximately one-third of neuroblastoma tumors and is correlated with poor prognosis. In chemoresistant neuroblastoma cells, depletion of UBE4B yielded significantly reduced cell proliferation and migration, and enhanced apoptosis in response to EGFR inhibitor, Cetuximab. We have previously shown that UBE4B levels are inversely correlated with EGFR levels in neuroblastoma tumors. We searched for additional targets of UBE4B that mediate cellular alterations associated with tumorogenesis in chemoresistant neuroblastoma cells depleted of UBE4B using reverse phase protein arrays. The expression of STAT5a, an effector protein downstream of EGFR, doubled in the absence of UBE4B, and verified by quantitative immunoblotting. Chemoresistant neuroblastoma cells were treated with SH-4-54, a STAT5 inhibitor, and observed insignificant effects on cell proliferation, migration, and apoptosis. However, SH-4-54 significantly enhanced the anti-proliferative and anti-migratory effects of Cetuximab in naïve SK-N-AS neuroblastoma cells. Interestingly, in UBE4B depleted SK-N-AS cells, SH-4-54 significantly potentiated the effect of Cetuximab rendering cells increasingly sensitive an otherwise minimally effective Cetuximab concentration. Thus, neuroblastoma cells with low UBE4B levels were significantly more sensitive to combined EGFR and STAT5 inhibition than parental cells. These findings may have potential therapeutic implications for patients with 1p36 chromosome LOH and low tumor UBE4B expression.

Author Correction: A recellularized human colon model identifies cancer driver genes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A recellularized human colon model identifies cancer driver genes.

Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

A New Imaging Platform for Visualizing Biological Effects of Non-Invasive Radiofrequency Electric-Field Cancer Hyperthermia.

Herein, we present a novel imaging platform to study the biological effects of non-invasive radiofrequency (RF) electric field cancer hyperthermia. This system allows for real-time in vivo intravital microscopy (IVM) imaging of radiofrequency-induced biological alterations such as changes in vessel structure and drug perfusion. Our results indicate that the IVM system is able to handle exposure to high-power electric-fields without inducing significant hardware damage or imaging artifacts. Furthermore, short durations of low-power (< 200 W) radiofrequency exposure increased transport and perfusion of fluorescent tracers into the tumors at temperatures below 41°C. Vessel deformations and blood coagulation were seen for tumor temperatures around 44°C. These results highlight the use of our integrated IVM-RF imaging platform as a powerful new tool to visualize the dynamics and interplay between radiofrequency energy and biological tissues, organs, and tumors.

Adjuvant cationic liposomes presenting MPL and IL-12 induce cell death, suppress tumor growth, and alter the cellular phenotype of tumors in a murine model of breast cancer.

Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1ß and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1ß, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80(+) macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response.

Multivalent presentation of MPL by porous silicon microparticles favors T helper 1 polarization enhancing the anti-tumor efficacy of doxorubicin nanoliposomes.

Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1ß levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages.

Porous silicon advances in drug delivery and immunotherapy.

Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators.