The Surgical Clerkship in the COVID Era: A Natural Language Processing and Thematic Analysis.

INTRODUCTION: Responses to COVID-19 within medical education prompted significant changes to the surgical clerkship. We analyzed the changes in medical student end of course feedback before and after the COVID-19 outbreak. METHODS: Postclerkship surveys from 2017 to 2022 were analyzed including both Likert scale data and free text, excluding the COVID outbreak year 2019-2020. Likert scale questions were compared between pre-COVID (2017-2019) and COVID-era cohorts (2020-2022) with the Mann-Whitney U-test. Free-text comments were analyzed using both thematic analysis and natural language processing including sentiment, word and phrase frequency, and topic modeling. RESULTS: Of the 483 medical students surveyed from 2017 to 2022, 297 responded (61% response rate) to the included end of clerkship surveys. Most medical students rated the clerkship above average or excellent with no significant difference between the pre-COVID and COVID-era cohorts (70.4% Versus 64.8%, P = 0.35). Perception of grading expectations did significantly differ, 51% of pre-COVID students reported clerkship grading standards were almost always clear compared to 27.5% of COVID-era students (P = 0.01). Pre-COVID cohorts more frequently mentioned learning and feedback while COVID-era cohorts more frequently mentioned case, attending, and expectation. Natural language processing topic modeling and formal thematic analysis identified similar themes: team, time, autonomy, and expectations. CONCLUSIONS: COVID-19 presented many challenges to undergraduate medical education. Despite many changes, there was no significant difference in clerkship satisfaction ratings. Unexpectedly, the greater freedom and autonomy of asynchronous lectures and choice of cases became a highlight of the new curriculum. Future research should investigate if there are similar associations nationally with a multi-institutional study.

Formative Evaluation of CLABSI Adoption and Sustainment Interventions in a Pediatric Intensive Care Unit.

Background: Pediatric patients require central venous catheters to maintain adequate hydration, nutritional status, and delivery of life-saving medications in the pediatric intensive care unit. Although central venous catheters provide critical medical therapies, their use increases the risk of severe infection, morbidity, and mortality. Adopting an evidence-based central line-associated bloodstream infection (CLABSI) bundle to guide nursing practice can decrease and sustain low CLABSI rates, but reliable and consistent implementation is challenging. This study aimed to conduct a mixed-methods formative evaluation to explore CLABSI bundle implementation strategies in a PICU. Methods: The team used The Consolidated Framework for Implementation Research to develop the interview guide and data analysis plan. Results: Facilitators and barriers for the CLABSI bundle occurred in four domains: inner setting, process, characteristics of individuals, and innovation characteristics in each cycle that led to recommended implementation strategy opportunities. The champion role was a major implementation strategy that facilitated the adoption and sustainment of the CLABSI bundle. Conclusions: Implementation Science Frameworks, such as Consolidated Framework for Implementation Research (CFIR), can be a beneficial framework to guide quality improvement efforts for evidence-based practices such as the CLABSI bundle. Using a champion role in the critical care setting may be an important implementation strategy for CLABSI bundle adoption and sustainment efforts.

Surgical Residents as Clerkship Scholars May Improve Student Perception of the Surgery Clerkship.

INTRODUCTION: The surgical clerkship is a formative experience in the medical school curriculum and can leave a lasting impression on students' perception of surgery. Given the historical negative stereotypes of surgeons, the clerkship represents an opportunity to impact students in a meaningful way. METHODS: Our institution developed a program in which research residents can serve as junior clerkship coordinators and educators; working closely with medical students on their surgery clerkship. At the end of their clerkship, students were administered a survey with Likert-scale and free text responses regarding satisfaction with the rotation, lectures, feedback, and value of the clerkship. Student survey results were compared before (2015-2016) and after (2017-2019) the implementation of the scholar program with nonparametric statistical analysis and qualitative text analysis. RESULTS: A total of 413 students responded to the survey with no significant difference in response rate by term (P = 0.88). We found no statistical difference with respect to overall course perception (92.3% versus 91.2%, P = 0.84), but a statistically significant difference was noted for the clarity of the provided written clerkship materials (80.3% versus 91.3%, P = 0.02) and usefulness of the feedback (57.5% versus 78.7%, P = 0.01). Qualitative analysis demonstrated an overall positive shift in perception of the clerkship, improvement in the course materials, and organization. CONCLUSIONS: The scholar program was overall well received by the students with improvements in certain aspects of the clerkship: organization, feedback, and course materials. This program represents a potential strategy to improve certain portions of the medical school clerkship experience.

Contralateral Prophylactic Mastectomy Decision-Making: The Partners' Perspective.

BACKGROUND: The rate of contralateral prophylactic mastectomy (CPM) continues to rise despite no improvement in survival, an increased risk of surgical complications, and negative effects on quality of life. This study explored the experiences of the partners of women who undergo CPM. METHODS: This study was part of an investigation into the factors motivating women with early-stage unilateral breast cancer and low genetic risk to opt for contralateral prophylactic mastectomy (CPM). Participating women were asked for permission to invite their partners to take part in interviews. In-depth interviews with partners were conducted using a semi-structured topic guide. A thematic analysis of the data was performed RESULTS: Of 35 partners, all men, 15 agreed to be interviewed. Most perceived their role to be strong and logical. Some hoped their wives would choose a bilateral mastectomy. All felt strongly that the final decision was up to their partners. The partners often framed the decision for CPM as one of life or death. Thus, any aesthetic effects were unimportant by comparison. The male partners had difficulty grasping the physical and emotional changes inherent in mastectomy, which made communicating about sexuality and intimacy very challenging for the couples. In the early recovery period, some noted the stress of managing home life. CONCLUSIONS: The experiences of the male partners provide insight into how couples navigate complex treatment decision-making, both together and separately. There may be a benefit to including partners in pre- and post-surgical counseling to mitigate miscommunication regarding the expected oncologic and emotional outcomes related to CPM.

Revisiting Medical Student Expectations on the Surgery Clerkship.

OBJECTIVE: Medical students frequently report ambiguity of expectations in their feedback of the surgery clerkship. Herein, we aimed to gauge general surgery resident and attending expectations of students on their clerkship. DESIGN: Residents and attending surgeons were surveyed on medical student expectations for rounding and floor duties, the operating room, clinic, and professionalism. RESULTS: There were slight differences in expectations between residents and attendings, which were then utilized to facilitate a discussion to create consensus expectations for students. Early outcomes demonstrate improved understanding of expectations by medical students. CONCLUSION: Identifying differences in resident and attending expectations of medical students on their surgery clerkship can help improve the alignment of such expectations. We hope that longterm, this intervention can facilitate a better learning environment for medical students on their surgery clerkship.

Localized immunomodulation technologies to enable cellular and organoid transplantation.

Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past decade, cell-based immunomodulation therapies saw clinical success in the treatment of cancer and autoimmune diseases. In this review, we describe recent advances in engineering solutions for the development of localized immunomodulation techniques focusing on cellular and organoid transplantation. We begin by describing cell transplantation and highlighting notable clinical successes, particularly in the areas of stem cell therapy, chimeric antigen receptor (CAR)-T cell therapy, and islet transplantation. Next, we detail recent preclinical studies centered on genome editing and biomaterials to enhance localized immunomodulation. We close by discussing future opportunities to improve clinical and commercial success using these approaches to facilitate long-term immunomodulation technologies.

The Landmark Series-Ductal Carcinoma in Situ: The Evolution of Treatment.

The evolution of ductal carcinoma in situ (DCIS) management has been driven by a parallel evolution in our understanding of its natural history. Early trials established the benefit of adjuvant therapies in all patients with DCIS. In contrast, subsequent studies have stratified patients to determine their eligibility for progressively less invasive and less intensive therapies. Large, randomized trials and meta-analyses have supported this shift away from treating DCIS as an homogenous disease treated with similar intensity to invasive breast cancer. This review describes the landmark studies on which current DCIS management is based.

Racial-ethnic variations in phyllodes tumors among a multicenter United States cohort.

BACKGROUND AND OBJECTIVES: Previous studies have identified racial-ethnic differences in the diagnostic patterns and recurrence outcomes of women with phyllodes tumors (PT). However, these studies are generally limited in size and generalizability. We therefore sought to explore racial-ethnic differences in age, tumor size, subtype, and recurrence in a large US cohort of women with PT. METHODS: We performed an 11-institution retrospective review of women with PT from 2007 to 2017. Differences in age at diagnosis, tumor size and subtype, and recurrence-free survival according to race-ethnicity. RESULTS: Women of non-White race or Hispanic ethnicity were younger at the time of diagnosis with phyllodes tumor. Non-Hispanic Other women had a larger proportion of malignant PT. There were no differences in recurrence-free survival in our cohort. CONCLUSIONS: Differences in age, tumor size, and subtype were small. Therefore, the workup of young women with breast masses and the treatment of women with PT should not differ according to race-ethnicity. These conclusions are supported by our finding that there were no differences in recurrence-free survival.

Development of Serum-Free Media for Cryopreservation of Hydrogel Encapsulated Cell-Based Therapeutics.

Introduction: While hydrogel encapsulation of cells has been developed to treat multiple diseases, methods to cryopreserve and maintain the composite function of therapeutic encapsulated cell products are still needed to facilitate their storage and distribution. While methods to preserve encapsulated cells, and post-synthesis have received recent attention, effective preservation mediums have not been fully defined. Methods: We employed a two-tiered screen of an initial library of 32 different cryopreservation agent (CPA) formulations composed of different cell-permeable and impermeable agents. Formulations were assayed using dark field microscopy to evaluate alginate hydrogel matrix integrity, followed by cell viability analyses and measurements of functional secretion activity. Results: The structural integrity of large > 1 mm alginate capsules were highly sensitive to freezing and thawing in media alone but could be recovered by a number of CPA formulations containing different cell-permeable and impermeable agents. Subsequent viability screens identified two top-performing CPA formulations that maximized capsule integrity and cell viability after storage at - 80 °C. The top formulation (10% Dimethyl sulfoxide (DMSO) and 0.3 M glucose) was demonstrated to preserve hydrogel integrity and retain cell viability beyond a critical USA FDA set 70% viability threshold while maintaining protein secretion and resultant cell potency. Conclusions: This prioritized screen identified a cryopreservation solution that maintains the integrity of large alginate capsules and yields high viabilities and potency. Importantly, this formulation is serum-free, non-toxic, and can support the development of clinically translatable encapsulated cell-based therapeutics. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00739-7.

Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors.

PURPOSE: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. EXPERIMENTAL DESIGN: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. RESULTS: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti-programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. CONCLUSIONS: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010.

Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors.

Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable cytokine delivery platform composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines. Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling predicts clinical translatability to humans. Notably, this platform elicited T cell responses in NHPs, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.

Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice.

BACKGROUND: Current research suggests that the glial scar surrounding penetrating brain injuries is instrumental in preserving the surrounding uninjured tissue by limiting the inflammatory response to the injury site. We recently showed that tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6), a well-established anti-inflammatory molecule, is present within the glial scar. In the present study we investigated the role of TSG-6 within the glial scar using TSG-6 null and littermate control mice subjected to penetrating brain injuries. RESULTS: Our findings show that mice lacking TSG-6 present a more severe inflammatory response after injury, which was correlated with an enlarged area of astrogliosis beyond the injury site. CONCLUSION: Our data provides evidence that TSG-6 has an anti-inflammatory role within the glial scar.

Contralateral Axillary Nodal Metastases: Stage IV Disease or a Manifestation of Progressive Locally Advanced Breast Cancer?

BACKGROUND: Contralateral axillary nodal metastases (CAM) is classified as stage IV disease, although many centers treat CAM with curative intent. We hypothesized that patients with CAM, treated with multimodality therapy, would have improved overall survival (OS) versus patients with distant metastatic disease (M1) and similar OS to those with locally advanced breast cancer (LABC). METHODS: Using the NCDB (2004-2016), we categorized adult patients with node-positive breast cancer into three study groups: LABC, CAM, and M1. Kaplan-Meier curves were used to visualize the unadjusted OS. Cox proportional hazards models were used to estimate the association of study group with OS. RESULTS: A total of 94,487 patients were identified: 122 with CAM, 12,325 with LABC, and 82,040 with M1 (median follow-up 63.6 months). LABC and CAM patients had similar histology and rates of chemotherapy and endocrine therapy receipt. However, the CAM group had significantly larger tumors, more estrogen-receptor expression, higher T-stage, and more mastectomies than the LABC group. Compared with M1 patients, CAM patients were more likely to have grade 3 and cT4 tumors. Patients with CAM and LABC had similar 5-year unadjusted OS and significantly improved OS vs M1 patients. After adjustment, LABC and CAM patients continued to have similar OS and better OS vs M1 patients. CONCLUSIONS: CAM patients who receive multi-modal therapy with curative intent may have OS more comparable to LABC patients than M1 patients. Out data support a reevaluation of whether CAM should remain classified as M1, as N3 may better reflect disease prognosis and treatment goals.

Clinical translation of immunomodulatory therapeutics.

Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest-growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide greater therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics.

The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans.

Silicone is widely used in chronic implants and is generally perceived to be safe. However, textured breast implants have been associated with immune-related complications, including malignancies. Here, by examining for up to one year the foreign body response and capsular fibrosis triggered by miniaturized or full-scale clinically approved breast implants with different surface topography (average roughness, 0-90 µm) placed in the mammary fat pads of mice or rabbits, respectively, we show that surface topography mediates immune responses to the implants. We also show that the surface surrounding human breast implants collected during revision surgeries also differentially alters the individual's immune responses to the implant. Moreover, miniaturized implants with an average roughness of 4 µm can largely suppress the foreign body response and fibrosis (but not in T-cell-deficient mice), and that tissue surrounding these implants displayed higher levels of immunosuppressive FOXP3+ regulatory T cells. Our findings suggest that, amongst the topographies investigated, implants with an average roughness of 4 µm provoke the least amount of inflammation and foreign body response.

Targeting the extracellular matrix for immunomodulation: applications in drug delivery and cell therapies.

Host immune cells interact bi-directionally with their extracellular matrix (ECM) to receive and deposit molecular signals, which orchestrate cellular activation, proliferation, differentiation, and function to maintain healthy tissue homeostasis. In response to pathogens or damage, immune cells infiltrate diseased sites and synthesize critical ECM molecules such as glycoproteins, proteoglycans, and glycosaminoglycans to promote healing. When the immune system misidentifies pathogens or fails to survey damaged cells effectively, maladies such as chronic inflammation, autoimmune diseases, and cancer can develop. In these conditions, it is essential to restore balance to the body through modulation of the immune system and the ECM. This review details the components of dysregulated ECM implicated in pathogenic environments and therapeutic approaches to restore tissue homeostasis. We evaluate emerging strategies to overcome inflamed, immune inhibitory, and otherwise diseased microenvironments, including mechanical stimulation, targeted proteases, adoptive cell therapy, mechanomedicine, and biomaterial-based cell therapeutics. We highlight various strategies that have produced efficacious responses in both pre-clinical and human trials and identify additional opportunities to develop next-generation interventions. Significantly, we identify a need for therapies to address dense or fibrotic tissue for the treatment of organ tissue damage and various cancer subtypes. Finally, we conclude that therapeutic techniques that disrupt, evade, or specifically target the pathogenic microenvironment have a high potential for improving therapeutic outcomes and should be considered a priority for immediate exploration. A schematic showing the various methods of extracellular matrix disruption/targeting in both fibrotic and cancerous environments. a Biomaterial-based cell therapy can be used to deliver anti-inflammatory cytokines, chemotherapeutics, or other factors for localized, slow release of therapeutics. b Mechanotherapeutics can be used to inhibit the deposition of molecules such as collagen that affect stiffness. c Ablation of the ECM and target tissue can be accomplished via mechanical degradation such as focused ultrasound. d Proteases can be used to improve the distribution of therapies such as oncolytic virus. e Localization of therapeutics such as checkpoint inhibitors can be improved with the targeting of specific ECM components, reducing off-target effects and toxicity.

Engaging Women With Lived Experience: A Novel Cross-Canada Approach.

Women with heart disease, stroke, and vascular cognitive impairment (VCI) experience gender inequities across the health care continuum. The Heart and Stroke Foundation of Canada conducted needs assessment to inform its approach in addressing health inequities experienced by women with heart disease, stroke, and VCI across the continuum of care. Although specific input is confidential, this article outlines the engagement methods used and the evaluation results. The 3-stage engagement process consisted of an internal content review, 18 in-person discussion groups via a cross-Canada tour, 14 expert interviews, and a collaboration session. In total, 204 and 57 participants were recruited for the cross-Canada tour and collaboration session, respectively. Using the Public and Patient Engagement Evaluation Tool, participants scored the engagement processes positively and found participation to be a valuable use of their time. This undertaking highlighted aspects to consider when engaging people with lived experience and how engagement can support the recovery journey. Insights presented throughout this article can help inform future research that seeks to engage stakeholders at a national level.

Effects of Immunosuppressive Medications on Mitochondrial Function.

BACKGROUND: Immunosuppressive medications are widely used for the prevention of allograft rejection in transplantation and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Despite their clinical utility, these medications are accompanied by multiple off-target effects, some of which may be mediated by their effects on mitochondria. METHODS: We examined the effect of commonly used immunosuppressive reagents, mycophenolate mofetil (MMF), cyclosporine A (CsA), rapamycin, and tacrolimus on mitochondrial function in human T-cells. T-cells were cultured in the presence of immunosuppressive medications in a range of therapeutic doses. After incubation, mitochondrial membrane potential, reactive oxygen species (ROS) production, and apoptotic cell death were measured by flow cytometry after staining with DiOC6, MitoSOX Red, and Annexin V and 7-AAD, respectively. Increases in cytosolic cytochrome c were demonstrated by Western blot. T-cell basal oxygen consumption rates were measured using a Seahorse bioanalyzer. RESULTS: T-cells demonstrated significant levels of mitochondrial depolarization after treatment with therapeutic levels of MMF but not after treatment with CsA, tacrolimus, or rapamycin. Only MMF induced T-cell ROS production and induced significant levels of apoptotic cell death that were associated with increased levels of cytosolic cytochrome c. MMF decreased T-cell basal oxygen consumption within its therapeutic range, and CsA demonstrated a trend toward this result. CONCLUSIONS: The impairment of mitochondrial function by commonly used immunosuppressive reagents may impair T-cell differentiation and function by decreasing energy production, producing toxic ROS, and inducing apoptotic cell death.

Machine perfusion of donor kidneys may reduce graft rejection.

Recent evidence suggests that hypothermic machine perfusion of donor kidneys reduces delayed graft function (DGF). This study addresses the effect of machine perfusion (MP) on allograft rejection in the United States. We assembled a retrospective cohort of patients undergoing kidney-alone transplants in the UNOS database from June 30, 2004 to May 31, 2017. DGF was defined as dialysis requirement in the first week post-transplant; graft rejection was defined at 6 months and 1 year. Multivariable logistic regression adjusted for recipient and donor factors evaluated the effect of MP on DGF and graft rejection. Records for 79 300 kidney transplants meeting inclusion criteria were abstracted, 42% of which underwent MP. MP kidneys came from older donors, were more likely to have been obtained following donation after cardiac death, and had longer cold ischemic times. Rates of DGF and rejection were similar between MP and static storage kidneys. Following adjustment, recipients of MP kidneys were less likely to experience rejection at 1 year (OR 0.91 [95% CI 0.86-0.97] P = .002), but not at 6 months post-transplantation (OR 0.94 [0.88-1.02] P = .07). This effect persisted following adjustment for cold ischemic time. This study adds to the accumulating evidence demonstrating improved outcomes following MP of kidneys. We encourage protocolized consideration of MP for kidney grafts.