Background:The PCP pathway controls many cell processes during development. Results: The PCP pathway induces nephrin endocytosis when cultured podocytes are treated with Wnt5a. Loss of PCP protein Vangl2 decreases nephrin endocytosis. Conclusion: During glomerular development, endocytosis of nephrin is regulated by the PCP pathway. Significance: Implicating the PCP pathway in nephrin endocytosis is important for understanding the complexity of PCP signaling during mammalian development.

The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane. Podocyte cell protrusions (foot processes) are critical for glomerular permselectivity; loss of foot process architecture results in proteinuria and FSGS. Previously, we showed a profound effect of PCP signaling on podocyte shape, actin rearrangement, cell motility, and nephrin endocytosis. To test our hypothesis that the PCP pathway is involved in glomerular development and function and circumvent lethality of the ubiquitous Vangl2 mutation in the Looptail mouse, we generated a mouse model with a podocyte-specific ablation of the Vangl2 gene. We report here that podocyte-specific deletion of Vangl2 leads to glomerular maturation defects in fetal kidneys. In adult mice, we detected significantly smaller glomeruli, but it did not affect glomerular permselectivity in aging animals. However, in the context of glomerular injury induced by injection of antiglomerular basement membrane antibody, deletion of Vangl2 resulted in exacerbation of injury and accelerated progression to chronic segmental and global glomerular sclerosis. Our results indicate that Vangl2 function in podocytes is important for glomerular development and protects against glomerular injury in adult animals. 26: 576-586, 201526: 576-586, . doi: 10.1681 Renal glomerular visceral epithelial cells (podocytes) are highly polarized cells with complex threedimensional architecture characterized by the presence of unique actin-based projections (foot processes [FPs]). 1 The FPs from neighboring podocytes form intercellular bridges, slit diaphragms, that are the only points of contact between adjacent cells and the base for the permselective filtration barrier, allowing small solutes to pass into the urinary space while retaining large proteins in the blood. 1 Slit diaphragm protein complexes are connected with the podocyte cytoskeleton by various adaptor proteins and serve as a signaling nexus to relay information from the FP surface to control podocyte structure. 2 The characteristic shape of podocytes is directly related to glomerular filtration. Mutations in proteins that link slit diaphragms and the cytoskeleton (e.g., a-actinin-4 and CD2-associated protein) 3,4 or regulators of actin polymerization and organization (e.g., Inverted Formin-2, Myosin 1e, Rho GDP-Dissociation Inhibitor 1, and Cdc42) 5-9 give rise to glomerular dysfunction, such as proteinuria, J Am Soc Nephrol

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Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gammaglutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Introduction The United States Medical Licensing Examination (USMLE) was designed as a universal assessment tool for states to determine physician’s medical licensure's candidacy. Recent changes in the USMLE exam have changed the way future surgical residency candidate applications will be reviewed. The survey aimed to assess the effect of changes in USMLE exams—USMLE Step 1 pass/fail, complete dissolution of USMLE clinical skills exam, and the role of holistic review in future surgical residency candidacy selection. Methods An anonymous online survey was created and distributed to general surgery program directors and coordinators across the USA. The survey aimed to assess attitudes toward changes to USMLE exams and the potential changes with a holistic review of candidate applications. Results The response rate was 63.7%. Most program directors and coordinators disagree with changing USMLE Step 1 to a pass/fail scoring system. The majority felt that contacts, the medical school's name, and performance in clinical electives and sub-internships would hold more significance. They also believe that a holistic review of application will decrease socioeconomic discrepancies and promote a more diverse and inclusive resident cohort. Conclusion Step 2 clinical knowledge (CK) will gain more importance in future residency matches because of the change in the scoring system of Step 1. The medical school's name, personal contacts, and clinical performance in rotations will hold more significance.