Joshua M. Adams

Gaps in preparedness for independent practice are common among recent graduates. Clinical experiences serve as the foundation for learning during residency, yet the breadth and variability of clinical exposure of child neurology residents remain poorly characterized. To inform programmatic curricular development and precision medical education (PME), we must better characterize learners' clinical exposure during training. We aimed to use electronic health record (EHR) data to catalog resident clinical experiences, linking diagnostic codes to educational benchmarks. We performed a retrospective cohort study of 11 child neurology residents at a single institution in their neurology years of training between July 2024 and May 2025. We used an established algorithm to determine which patient encounters were most meaningful for resident education, based on EHR interaction, and extracted International Classification of Disease (ICD)-10 codes from these encounters. We mapped ICD-10 categories to American Board of Psychiatry and Neurology (ABPN) child neurology certification examination content areas. We identified the most frequent ICD-10 categories seen in inpatient and outpatient settings. We also identified the frequency of ABPN content areas seen across encounters and compared with their relative frequency on the certification examination. We identified 3,109 meaningful outpatient and 4,469 meaningful inpatient encounters over an 11-month period. The crosswalk between ICD-10 categories and ABPN content areas contains 385 ICD-10 categories mapped to ABPN content domains. There was 90.0% ICD-10 category capture for outpatient encounters and 73.8% for inpatient encounters. The most frequent ICD-10 categories were “epilepsy and recurrent seizures” and “migraine” (outpatient) and “cerebral infarction” and “convulsions” (inpatient). More than half of ABPN content areas were underrepresented in clinical exposure compared with the certification examination. There was overrepresentation of 3 ABPN content areas: “epilepsy and episodic disorders,” “vascular neurology,” and “headache and pain disorders.” A novel crosswalk between ICD-10 categories and ABPN content areas for child neurology enables transformation of EHR-coded data to educationally meaningful information. Using this crosswalk to characterize resident experiences from EHR data may inform rational curricular design and PME. Programs may use these data to optimize rotations and target experiential learning gaps at individual and program levels, resulting in better preparation for autonomous practice.

During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzymeN-glycanase 1 (NGLY1) is proposed to removeN-glycans from misfoldedN-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulatesDrosophilaBMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish theDrosophilaDpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 then deglycosylates misfolded BMP4 molecules to promote their retrotranslocation and proteasomal degradation, thereby allowing properly-folded BMP4 molecules to proceed through the secretory pathway and activate signaling in other cells. Our study redefines the role of NGLY1 during ERAD and suggests that impaired BMP4 signaling might underlie some of the NGLY1 deficiency patient phenotypes.

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases.

Background and Aims: Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y‐box 9) in late embryonic and neonatal livers of Jag1‐deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. Approach and Results: Conditional removal of one copy of Sox9 in Jag1+/− livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/− livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/− livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5‐month‐old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/− mice without ectopic hepatocyte‐to‐cholangiocyte transdifferentiation or long‐term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. Conclusions: Our results establish Sox9 as a dosage‐sensitive modifier of Jag1+/− liver phenotypes with a permissive role in biliary development. Our data further suggest that liver‐specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.

Mouse is broadly used as a model organism to study biliary diseases. To evaluate the development and function of the biliary system, various techniques are used, including serum chemistry, histological analysis, and immunostaining for specific markers. Although these techniques can provide important information about the biliary system, they often do not present a full picture of bile duct (BD) developmental defects across the whole liver. This is in part due to the robust ability of the mouse liver to drain the bile even in animals with significant impairment in biliary development. Here we present a simple method to calculate the average number of BDs associated with each portal vein (PV) in sections covering all lobes of mutant/transgenic mice. In this method, livers are mounted and sectioned in a stereotypic manner to facilitate comparison among various genotypes and experimental conditions. BDs are identified via light microscopy of cytokeratin-stained cholangiocytes, and then counted and divided by the total number of PVs present in liver section. As an example, we show how this method can clearly distinguish between wild-type mice and a mouse model of Alagille syndrome. The method presented here cannot substitute for techniques that visualize the three-dimensional structure of the biliary tree. However, it offers an easy and direct way to quantitatively assess BD development and the degree of ductular reaction formation in mice.

Alacrima, the lack of tears, is a rare clinical finding that has been reported as a feature of multiple genetic disorders and can serve as a diagnostic clue to some rare conditions. Causes of alacrima range from absence/hyposecretion of tears to agenesis or improper development of lacrimal gland ducts and associated structures. There are 13 known heritable disorders featuring varying degrees and causes of alacrima. Some manifest only the congenital absence of tears, while others affect multiple organ systems and may involve severe developmental delay, intellectual disability, and potentially life‐threatening autonomic dysregulation. To aid in the diagnosis for patients manifesting alacrima, we review the major causes and the various genetic disorders associated with alacrima and provide a differential template for diagnosis.