Acute lung injury (ALI) results from loss of alveolar-capillary barrier integrity and the evolution of high-permeability pulmonary edema resulting in alveolar flooding and significant morbidity and mortality. HMGB1 is a late mediator of sepsis which uniquely participates in the evolution of sepsis and sepsis-induced ALI. The molecular events by which HMGB1 contributes to ALI remain poorly characterized. We characterized the role of HMGB1 in endothelial cell (EC) cytoskeletal rearrangement and vascular permeability, events essential to paracellular gap formation and barrier dysfunction characteristic of ALI. Initial experiments demonstrated HMGB1-mediated dose-dependent (5–20 μg/ml) decreases in transendothelial cell electrical resistance (TER) in human pulmonary artery EC, a reflection of loss of barrier integrity. Furthermore, HMGB1 produced dose-dependent increases in paracellular gap formation in concert with loss of peripheral organized actin fibers, dissociation of cell-cell junctional cadherins, and development of central stress fibers, a phenotypic change associated with increased contractile activity and increased EC permeability. Using siRNA strategies directed against known HMGB1 receptors (RAGE, TLR2, TLR4), we systematically determined that the receptor for advanced glycation end products (RAGE) is the primary receptor signaling HMGB1-induced TER decreases and paracellular gap formation via p38 MAP kinase activation and phosphorylation of the actin-binding protein, Hsp27. These studies add to understanding of HMGB1-induced inflammatory events and vascular barrier disruption and offer the potential for clinical intervention in sepsis-induced ALI.

The impact of an SC program on change in career plans during medical school was analyzed. Program satisfaction, publication, and female gender were associated with increased intent to participate in career-long research depending on baseline interest in career-long research. Two ways to bolster the physician-scientist workforce are to improve satisfaction with existing SC programs and to formally support student publication. Future work to track outcomes of SC program graduates is warranted.

Ventilator-induced lung injury (VILI) occurs when the lung parenchyma and vasculature are exposed to repetitive and excessive mechanical stress via mechanical ventilation utilized as supportive care for the adult respiratory distress syndrome (ARDS). VILI induces gene expression and systemic release of inflammatory mediators that contribute to the multi-organ dysfunction and morbidity and mortality of ARDS. HMGB1, an intracellular transcription factor with cytokine properties, is a late mediator in sepsis and ARDS pathobiology, however, the role of HMGB1 in VILI remains poorly described. We now report HMGB1 expression in human lung microvessel endothelial cells (EC) exposed to excessive, equibiaxial mechanical stress, an in vitro correlate of VILI. We determined that high amplitude cyclic stretch (18% CS) increased HMGB1 expression (2-4 fold) via a signaling pathway with critical involvement of the transcription factor, STAT3. Concomitant exposure to 18% CS and oxidative stress (H2O2) augmented HMGB1 expression (~13 fold increase) whereas lipopolysaccharide (LPS) challenge increased HMGB1 expression in static EC, but not in 18% CS-challenged EC. In contrast, physiologic, low amplitude cyclic stretch (5% CS) attenuated both oxidative H2O2- and LPS-induced increases in HMGB1 expression, suggesting that physiologic mechanical stress is protective. These results indicate that HMGB1 gene expression is markedly responsive to VILI-mediated mechanical stress, an effect that is augmented by oxidative stress. We speculate that VILI-induced HMGB1 expression acts locally to increase vascular permeability and alveolar flooding, thereby exacerbating systemic inflammatory responses and increasing the likelihood of multi-organ dysfunction.

The boundaries among standard therapy, innovative therapy, and research can be quite fluid. This case illustrates the ethical imperative to consider therapies that may be appropriate for a critically ill child even without evidence predictive of success, to have entry criteria and treatment protocols for such therapies, and to collect data from such experiences to advance the standard of care.

Support of the U.S. health professions investigator workforce is critically important to the continued advancement of health care nationally. Physicianinvestigators comprise one segment of this health professions investigator workforce, which also includes investigators in the nursing, pharmacy, and dentistry professions, and others. Among physician health professionals in particular, the term "physicianinvestigator" has been described as encompassing physicians engaged in research in various ways including "clinical researchers" (physicians with clinical duties who do clinical, patientcentered research), "clinician-scientists" (physicians with clinical roles who perform research in laboratories or using computational tools), and "physicianscientists" (physicians focused on research with little or no clinical activity). Broadly defined, physician-investigators are included in various groups of researchers described in several articles recently published in Academic Medicine; these articles provide details on a range of approaches, with supporting outcomes data, being taken to train, support, and retain physicians in the health professions investigator workforce.The authors of this commentary examine selected literature, including several articles in this issue among others, along with Association of American Medical Colleges data, to offer observations about programs that train physician-investigators. Evidenceinformed single-program approaches for early-career researchers can sustain continued research interest and foster the career development of the emerging physician-investigator workforce. Collaborative multi-institutional approaches offer the benefit of multisite work to power outcomes studies and to increase generalizability beyond a specific institutional program. Systemwide institutional approaches may be particularly critical in supporting physician-investigators across all career stages. Although the articles discussed in this commentary are largely (although not exclusively) focused on various initiatives and programs designed to develop and sustain the physician-investigator workforce, such initiatives and programs may have value in addressing shared challenges of developing, supporting, and retaining the broader investigator workforce across all health professions.

Gender and career plans are associated with importance of SC-related goals in the first year of medical school. This knowledge enables faculty to promote students' appreciation of important learning goals in the setting of student research, which may help students engage in self-directed learning across their medical education.

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The authors highlight the importance of providing individualized mentorship to combat attrition from physician‐scientist training pathways.