Simple Interventions for Pediatric Residents' Moral Distress: A Randomized, Controlled Experiment.

BACKGROUND AND OBJECTIVES: Pediatric residents are at high risk for moral distress, knowing the moral or ethically right thing to do but feeling unable to do it, which is associated with poor patient care and burnout. Researchers have proposed numerous interventions to reduce distress, but few (if any) have been supported by experimental evidence. In this study, we used an experimental method to provide proof-of-concept evidence regarding the effect of various simple supports on pediatric residents' reported degree of moral distress. METHODS: We conducted a study of pediatric residents using a split sample experimental design. The questionnaire contained 6 clinical vignettes describing scenarios expected to cause moral distress. For each case, participants were randomly assigned to see 1 of 2 versions that varied only regarding whether they included a supportive statement. After reading each of the 6 cases, participants reported their level of associated moral distress. RESULTS: Two hundred and twenty respondents from 5 residency programs completed the experiment. Cases were perceived to represent common scenarios that cause distress for pediatric residents. The addition of a supportive statement reduced moral distress in 4 of the 6 cases. CONCLUSIONS: In this proof-of-concept study, simple yet effective interventions provided support by offering the resident empathy and shared perspective or responsibility. Interventions that were purely informational were not effective in reducing moral distress.

Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease.

The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes. Finally, we found that IFN-ß stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO.

Metastatic prostate cancer presenting as tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO), or oncogenic osteomalacia, is a paraneoplastic syndrome marked by hypophosphataemia, renal phosphate wasting, bone pain, weakness, and fractures. The syndrome has been reported with both benign and malignant tumours including parotid gland basal cell tumours, thyroid carcinomas, colon adenocarcinomas, and prostate cancer. Often, the syndrome is marked by an insidious course during which patients present with generalised bony pain and weakness, which do not resolve until the underlying tumour is identified and treated. We present a case of a patient with Parkinson's disease whose subacute weakness, lower extremity paresis, and renal phosphate wasting led to the synchronous diagnosis of metastatic prostate adenocarcinoma and TIO.

Ndfip Proteins Target Robo Receptors for Degradation and Allow Commissural Axons to Cross the Midline in the Developing Spinal Cord.

Commissural axons initially respond to attractive signals at the midline, but once they cross, they become sensitive to repulsive cues. This switch prevents axons from re-entering the midline. In insects and mammals, negative regulation of Roundabout (Robo) receptors prevents premature response to the midline repellant Slit. In Drosophila, the endosomal protein Commissureless (Comm) prevents Robo1 surface expression before midline crossing by diverting Robo1 into late endosomes. Notably, Comm is not conserved in vertebrates. We identified two Nedd-4-interacting proteins, Ndfip1 and Ndfip2, that act analogously to Comm to localize Robo1 to endosomes. Ndfip proteins recruit Nedd4 E3 ubiquitin ligases to promote Robo1 ubiquitylation and degradation. Ndfip proteins are expressed in commissural axons in the developing spinal cord and removal of Ndfip proteins results in increased Robo1 expression and reduced midline crossing. Our results define a conserved Robo1 intracellular sorting mechanism between flies and mammals to avoid premature responsiveness to Slit.

Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease.

Foxp3+ T regulatory (Treg) cells suppress immune cell activation and establish normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a coactivator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate altered metabolic signature of Ndfip1-deficient Treg cells and metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Ndfip1 restricts Treg cell metabolism and IL-4 production via distinct mechanisms, as IL-4 deficiency does not prevent hyperproliferation or elevated mTORC1 signalling in Ndfip1-deficient Treg cells. Thus, Ndfip1 preserves Treg lineage stability and immune homeostasis by preventing the expansion of highly proliferative and metabolically active Treg cells and by preventing pathological secretion of IL-4 from Treg cells.

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production.

While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.