Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach ...to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.
This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).
Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.
For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
Depression and burnout are highly prevalent among residents, but little is known about modifiable personality variables, such as resilience and stress from uncertainty, that may predispose to these ...conditions. Residents are routinely faced with uncertainty when making medical decisions.
To determine how stress from uncertainty is related to resilience among pediatric residents and whether these attributes are associated with depression and burnout.
We surveyed 86 residents in pediatric residency programs from 4 urban freestanding children's hospitals in North America in 2015. Stress from uncertainty was measured with the use of the Physicians' Reaction to Uncertainty Scale, resilience with the use of the 14-item Resilience Scale, depression with the use of the Harvard National Depression Screening Scale; and burnout with the use of single-item measures of emotional exhaustion and depersonalization from the Maslach Burnout Inventory.
Fifty out of 86 residents responded to the survey (58.1%). Higher levels of stress from uncertainty correlated with lower resilience (r = −0.60; P < .001). Five residents (10%) met depression criteria and 15 residents (31%) met burnout criteria. Depressed residents had higher mean levels of stress due to uncertainty (51.6 ± 9.1 vs 38.7 ± 6.7; P < .001) and lower mean levels of resilience (56.6 ± 10.7 vs 85.4 ± 8.0; P < .001) compared with residents who were not depressed. Burned out residents also had higher mean levels of stress due to uncertainty (44.0 ± 8.5 vs 38.3 ± 7.1; P = .02) and lower mean levels of resilience (76.7 ± 14.8 vs 85.0 ± 9.77; P = .02) compared with residents who were not burned out.
We found high levels of stress from uncertainty, and low levels of resilience were strongly correlated with depression and burnout. Efforts to enhance tolerance of uncertainty and resilience among residents may provide opportunities to mitigate resident depression and burnout.
Workplace-based assessment (WBA) serves a critical role in supporting competency-based medical education (CBME) by providing assessment data to inform competency decisions and support learning. Many ...WBA systems have been developed, but little is known about how to effectively implement WBA. Filling this gap is important for creating suitable and beneficial assessment processes that support large-scale use of CBME. As a step toward filling this gap, the authors describe what is known about WBA implementation and use to identify knowledge gaps and future directions.
The authors used Arksey and O'Malley's 6-stage scoping review framework to conduct the review, including: (1) identifying the research question; (2) identifying relevant studies; (3) study selection; (4) charting the data; (5) collating, summarizing, and reporting the results; and (6) consulting with relevant stakeholders.
In 2019-2020, the authors searched and screened 726 papers for eligibility using defined inclusion and exclusion criteria. One hundred sixty-three met inclusion criteria. The authors identified 5 themes in their analysis: (1) Many WBA tools and programs have been implemented, and barriers are common across fields and specialties; (2) Theoretical perspectives emphasize the need for data-driven implementation strategies; (3) User perceptions of WBA vary and are often dependent on implementation factors; (4) Technology solutions could provide useful tools to support WBA; and (5) Many areas of future research and innovation remain.
Knowledge of WBA as an implemented practice to support CBME remains constrained. To remove these constraints, future research should aim to generate generalizable knowledge on WBA implementation and use, address implementation factors, and investigate remaining knowledge gaps.
Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, ...preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac LCPT) with a delayed absorption profile.
Randomized prospective crossover study.
50 African American maintenance kidney recipients on stable IR-Tac dosing.
Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose.
Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype.
CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles.
∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4).
This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes.
Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT.
Registered at ClinicalTrials.gov, with study number NCT01962922.
To describe trajectories in level of supervision ratings for linked entrustable professional activities (EPAs) among pediatric learners in medical school, residency, fellowship.
The authors performed ...secondary analyses of 3 linked datasets of level of supervision ratings for the Core EPAs for Entering Residency, the General Pediatrics EPAs, and the Subspecialty Pediatrics EPAs. After identifying 9 activities in common across training stages and aligning the level of entrustment-supervision scales across the datasets, piecewise ordinal and linear mixed effects models were fitted to characterize trajectories of supervision ratings.
Within each training period, learners were rated as needing less supervision over time in each activity. When transitioning from medical school to residency or during the first year of residency, learners were rated as needing greater supervision in activities related to patient management, teamwork, emergent care, and public health/QI than in earlier periods. When transitioning from residency to fellowship, learners were always rated as needing greater supervision than they had been accorded at the end of residency and sometimes even more than they had been accorded at the start of residency.
Although development over training is often imagined as continuous and monotonically increasing competence, this study provides empirical evidence supporting the idea that entrustment is a set of discrete decisions. The relaxation of supervision in training is not a linear process. Even with a seamless curriculum, supervision is tightly bound to the training setting. Several explanations for these findings are discussed.
Program evaluation approaches that center the achievement of specific, measurable, achievable, realistic, and time-bound goals are common in health professions education (HPE) but can be challenging ...to articulate when evaluating emergent programs. Principles-focused evaluation is an alternative approach to program evaluation that centers on adherence to guiding principles, not achievement of goals. The authors describe their innovative application of principles-focused evaluation to an emergent HPE program.
The authors applied principles-focused evaluation to the Children's Hospital of Philadelphia Medical Education Collaboratory, a works-in-progress program for HPE scholarship. In September 2019, the authors drafted 3 guiding principles. In May 2021, they used feedback from Collaboratory attendees to revise the guiding principles: Advance Excellence , Build Bridges , and Cultivate Learning .
In July 2021, the authors queried participants about the extent to which their experience with the Collaboratory adhered to the revised guiding principles. Twenty of the 38 Collaboratory participants (53%) responded to the survey. Regarding the guiding principle Advance Excellence , 9 respondents (45%) reported that the Collaboratory facilitated engagement in scholarly conversation only by a small extent, and 8 (40%) reported it facilitated professional growth only by a small extent. Although some respondents expressed positive regard for the high degree of rigor promoted by the Collaboratory, others felt discouraged because this degree of rigor seemed unachievable. Regarding the guiding principle Build Bridges , 19 (95%) reported the Collaboratory welcomed perspectives within the group. Regarding the guiding principle Cultivate Learning , 19 (95%) indicated the Collaboratory welcomed perspectives within the group and across disciplines, and garnered collaboration.
Next steps include improving adherence to the principle of Advancing Excellence , fostering a shared mental model of the Collaboratory's guiding principles, and applying a principles-focused approach to the evaluation of multi-site HPE programs.
To establish a research and development agenda for Entrustable Professional Activities (EPAs) for the coming decade, the authors, all active in this area of investigation, reviewed recent research ...papers, seeking recommendations for future research. They pooled their knowledge and experience to identify 3 levels of potential research and development: the micro level of learning and teaching; the meso level of institutions, programs, and specialty domains; and the macro level of regional, national, and international dynamics. Within these levels, the authors categorized their recommendations for research and development. The authors identified 14 discrete themes, each including multiple questions or issues for potential exploration, that range from foundational and conceptual to practical. Much research to date has focused on a variety of issues regarding development and early implementation of EPAs. Future research should focus on large-scale implementation of EPAs to support competency-based medical education (CBME) and on its consequences at the 3 levels. In addition, emerging from the implementation phase, the authors call for rigorous studies focusing on conceptual issues. These issues include the nature of entrustment decisions and their relationship with education and learner progress and the use of EPAs across boundaries of training phases, disciplines and professions, including continuing professional development. International studies evaluating the value of EPAs across countries are another important consideration. Future studies should also remain alert for unintended consequences of the use of EPAs. EPAs were conceptualized to support CBME in its endeavor to improve outcomes of education and patient care, prompting creation of this agenda.
Most medical faculty receive little or no training about how to be effective teachers, even when they assume major educational leadership roles. To identify the competencies required of an effective ...teacher in medical education, the authors developed a comprehensive conceptual model. After conducting a literature search, the authors met at a two-day conference (2006) with 16 medical and nonmedical educators from 10 different U.S. and Canadian organizations and developed an initial draft of the "Teaching as a Competency" conceptual model. Conference participants used the physician competencies (from the Accreditation Council for Graduate Medical Education ACGME) and the roles (from the Royal College's Canadian Medical Education Directives for Specialists CanMEDS) to define critical skills for medical educators. The authors then refined this initial framework through national/regional conference presentations (2007, 2008), an additional literature review, and expert input. Four core values grounded this framework: learner engagement, learner-centeredness, adaptability, and self-reflection. The authors identified six core competencies, based on the ACGME competencies framework: medical (or content) knowledge; learner- centeredness; interpersonal and communication skills; professionalism and role modeling; practice-based reflection; and systems-based practice. They also included four specialized competencies for educators with additional programmatic roles: program design/implementation, evaluation/scholarship, leadership, and mentorship. The authors then cross-referenced the competencies with educator roles, drawing from CanMEDS, to recognize role-specific skills. The authors have explored their framework's strengths, limitations, and applications, which include targeted faculty development, evaluation, and resource allocation. The Teaching as a Competency framework promotes a culture of effective teaching and learning.
PURPOSETo determine whether higher rates of medical errors were associated with positive screenings for depression or burnout among resident physicians.
METHODThe authors conducted a prospective ...cohort study from 2011 to 2013 in seven pediatric academic medical centers in the United States and Canada. Resident physicians were screened for burnout and depression using the Maslach Burnout Inventory–Human Services Survey (MBI-HSS) and Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS). A two-step surveillance methodology, involving a research nurse and two physician reviewers, was used to measure and categorize errors. Bivariate and mixed-effects regression models were used to evaluate the relationship between burnout, depression, and rates of harmful, nonharmful, and total errors.
RESULTSA total of 388/537 (72%) resident physicians completed the MBI-HSS and HANDS surveys. Seventy-six (20%) and 178 (46%) resident physicians screened positive for depression and burnout, respectively. Screening positive for depression was associated with a 3.0-fold higher rate of harmful errors (incidence rate ratio = 2.99 95% CI 1.40–6.36, P = .005). However, there was no statistically significant association between depression and total or nonharmful errors or between burnout and harmful, nonharmful, or total errors.
CONCLUSIONSResident physicians with a positive depression screen were three times more likely than those who screened negative to make harmful errors. This association suggests resident physician mental health could be an important component of patient safety. If further research confirms resident physician depression increases the risk of harmful errors, it will become imperative to determine what interventions might mitigate this risk.
The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer ...treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.
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