Characterizing Moral Injury and Distress in US Military Surgeons Deployed to Far-Forward Combat Environments in Afghanistan and Iraq.

Importance: Moral injury and distress (MID), which occurs when individuals have significant dissonance with their belief system and overwhelming feelings of being powerless to do what is believed to be right, has not been explored in the unique population of military surgeons deployed far forward in active combat settings. Deployed military surgeons provide care to both injured soldiers and civilians under command-driven medical rules of engagement (MROE) in variably resourced settings. This practice setting has no civilian corollary for comparison or current specific tool for measurement. Objective: To characterize MID among military surgeons deployed during periods of high casualty volumes through a mixed-methods approach. Design, Setting, and Participants: This qualitative study using convergent mixed methods was performed from May 2020 to October 2020. Participants included US military surgeons who had combat deployments to a far-forward role 2 treatment facility during predefined peak casualty periods in Iraq (2003-2008) and Afghanistan (2009-2012), as identified by purposeful snowball sampling. Data analysis was performed from October 2020 to May 2021. Main Outcomes and Measures: Measure of Moral Distress for Healthcare Professionals (MMD-HP) survey and individual, semistructured interviews were conducted to thematic saturation. Results: The total cohort included 20 surgeons (mean [SD] age, 38.1 [5.2] years); 16 (80%) were male, and 16 (80%) had 0 or 1 prior deployment. Deployment locations were Afghanistan (11 surgeons [55%]), Iraq (9 surgeons [45%]), or both locations (3 surgeons [15%]). The mean (SD) MMD-HP score for the surgeons was 104.1 (39.3). The primary thematic domains for MID were distressing outcomes (DO) and MROE. The major subdomains of DO were guilt related to witnessing horrific injuries; treating pregnant women, children, and US soldiers; and second-guessing decisions. The major subdomains for MROE were forced transfer of civilian patients, limited capabilities and resources, inexperience in specialty surgical procedures, and communication with command. Postdeployment manifestations of MID were common and affected sleep, medical practice, and interpersonal relationships. Conclusions and Relevance: In this qualitative study, MID was ubiquitous in deployed military surgeons. Thematic observations about MID, specifically concerning the domains of DO and MROE, may represent targets for further study to develop an evaluation tool of MID in this population and inform possible programs for identification and mitigation of MID.

Implementation of a Pilot Clinic for Pediatric to Adult Cancer Survivorship Transitions.

Childhood cancer survivors are recommended to have lifelong survivorship care, yet many become disengaged during pediatric to adult care transitions. We implemented a pilot clinic for adult survivors of pediatric or adolescent and young adult (AYA) leukemia transitioning to adult-focused survivorship care. The clinic featured AYA-specific care, bidirectional communication with primary care, and a quality improvement (QI) cycle. During the 1-year QI period, 27 patients were seen and 21 completed postvisit interviews. The clinic was positively received by patients and primary care providers, showed promise for improving self-management and care coordination, and highlighted the need for novel approaches to connect survivors with primary care.

Organizing a Successful Practice and Considering Tax and Estate Planning.

To care for your family and to do "good" for your alma mater, religious organization, and the other charities you love, you need to do "well," which is to build a successful practice. To achieve a successful practice, following the principles of the dozen A's is helpful: Ability, Availability, Amicability, Approachable, Attuned, Aware, Attentive to patients, Attentive to others, Attentive to details, Apology (ability to apologize and accept apology gracefully), Assimilate, Affordable. Another way to put it is "skills to treat, heart to care at a sensible price."

Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a common childhood cancer that shares features with developing skeletal muscle. Yet, the conservation of cellular hierarchy with human muscle development and the identification of molecularly defined tumor-propagating cells has not been reported. Using single-cell RNA-sequencing, DNA-barcode cell fate mapping and functional stem cell assays, we uncovered shared tumor cell hierarchies in RMS and human muscle development. We also identified common developmental stages at which tumor cells become arrested. Fusion-negative RMS cells resemble early myogenic cells found in embryonic and fetal development, while fusion-positive RMS cells express a highly specific gene program found in muscle cells transiting from embryonic to fetal development at 7-7.75 weeks of age. Fusion-positive RMS cells also have neural pathway-enriched states, suggesting less-rigid adherence to muscle-lineage hierarchies. Finally, we identified a molecularly defined tumor-propagating subpopulation in fusion-negative RMS that shares remarkable similarity to bi-potent, muscle mesenchyme progenitors that can make both muscle and osteogenic cells.

Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression.

Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.

tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish.

The TP53 tumor-suppressor gene is mutated in >50% of human tumors and Li-Fraumeni patients with germ line inactivation are predisposed to developing cancer. Here, we generated tp53 deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that tp53del/del enhanced invasion and metastasis in kRASG12D-induced embryonal rhabdomyosarcoma (ERMS), but did not alter the overall frequency of cancer stem cells, suggesting novel pro-metastatic roles for TP53 loss-of-function in human muscle tumors. In summary, we have developed a Li-Fraumeni zebrafish model that is amenable to large-scale transplantation and direct visualization of tumor growth in live animals.

Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma.

Tumor growth and relapse are driven by tumor propagating cells (TPCs). However, mechanisms regulating TPC fate choices, maintenance, and self-renewal are not fully understood. Here, we show that Van Gogh-like 2 (Vangl2), a core regulator of the non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway, affects TPC self-renewal in rhabdomyosarcoma (RMS)-a pediatric cancer of muscle. VANGL2 is expressed in a majority of human RMS and within early mononuclear progenitor cells. VANGL2 depletion inhibited cell proliferation, reduced TPC numbers, and induced differentiation of human RMS in vitro and in mouse xenografts. Using a zebrafish model of embryonal rhabdomyosarcoma (ERMS), we determined that Vangl2 expression enriches for TPCs and promotes their self-renewal. Expression of constitutively active and dominant-negative isoforms of RHOA revealed that it acts downstream of VANGL2 to regulate proliferation and maintenance of TPCs in human RMS. Our studies offer insights into pathways that control TPCs and identify new potential therapeutic targets.

The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma.

Tumor-propagating cells (TPCs) share self-renewal properties with normal stem cells and drive continued tumor growth. However, mechanisms regulating TPC self-renewal are largely unknown, especially in embryonal rhabdomyosarcoma (ERMS)-a common pediatric cancer of muscle. Here, we used a zebrafish transgenic model of ERMS to identify a role for intracellular NOTCH1 (ICN1) in increasing TPCs by 23-fold. ICN1 expanded TPCs by enabling the de-differentiation of zebrafish ERMS cells into self-renewing myf5+ TPCs, breaking the rigid differentiation hierarchies reported in normal muscle. ICN1 also had conserved roles in regulating human ERMS self-renewal and growth. Mechanistically, ICN1 upregulated expression of SNAIL1, a transcriptional repressor, to increase TPC number in human ERMS and to block muscle differentiation through suppressing MEF2C, a myogenic differentiation transcription factor. Our data implicate the NOTCH1/SNAI1/MEF2C signaling axis as a major determinant of TPC self-renewal and differentiation in ERMS, raising hope of therapeutically targeting this pathway in the future.