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Common cis-regulatory variation modifies the penetrance of pathogenic SHROOM3 variants in craniofacial microsomia
No full textPathogenic coding variants have been identified in thousands of genes, yet the mechanisms underlying the incomplete penetrance in individuals carrying these variants are poorly understood. In this study, in a cohort of 2009 craniofacial microsomia (CFM) patients of Chinese ancestry and 2625 Han Chinese controls, we identified multiple predicted pathogenic coding variants in SHROOM3 in both CFM patients and healthy individuals. We found that the penetrance of CFM correlates with specific haplotype combinations containing likely pathogenic-coding SHROOM3 variants and CFM-associated expression quantitative trait loci (eQTLs) of SHROOM3 expression. Further investigations implicate specific eQTL combinations, such as rs1001322 or rs344131, in combination with other significant CFM-associated eQTLs, which we term combined eQTL phenotype modifiers (CePMods). We additionally show that rs344131, located within a regulatory enhancer region of SHROOM3, demonstrates allele-specific effects on enhancer activity and thus impacts expression levels of the associated SHROOM3 allele harboring any rare coding variant. Our findings also suggest that CePMods may serve as pathogenic determinants, even in the absence of rare deleterious coding variants in SHROOM3 This highlights the critical role of allelic expression in determining the penetrance and severity of craniofacial abnormalities, including microtia and facial asymmetry. Additionally, using quantitative phenotyping, we demonstrate that both microtia and facial asymmetry are present in two separate Shroom3 mouse models, the severity of which is dependent on gene dosage. Our study establishes SHROOM3 as a likely pathogenic gene for CFM and demonstrates eQTLs as determinants of modified penetrance in the manifestation of the disease in individuals carrying likely pathogenic rare coding variants
Artificial intelligence in orthopaedic education: a narrative review
No full textBackground and objective: The integration of artificial intelligence (AI) into medical education is reshaping traditional learning paradigms. In orthopaedic surgery, AI applications such as virtual reality (VR) and augmented reality (AR) simulations and intelligent tutoring systems are being utilized to enhance training. This review aims to explore the current applications, benefits, challenges, and future directions of AI in orthopaedic education, while also addressing relevant ethical and logistical considerations.
Methods: A targeted literature review was conducted using PubMed, prioritizing studies published in 2024 and including relevant articles from 2023. Search terms included "artificial intelligence", "orthopaedic education", "surgical simulation", and related keywords. Studies were selected based on relevance to orthopaedic surgery education, with a particular focus on surgical skill acquisition, diagnostic training, and curriculum development. Both peer-reviewed and selected non-peer-reviewed sources were analyzed to synthesize current trends and emerging practices. Relevant articles were also identified using manual reference searching.
Key content and findings: The review highlights a positive shift in attitudes toward AI among educators and learners, particularly for its ability to simulate surgical environments safely and personalize learning. Current applications include AI-powered VR/AR platforms for realistic procedural training, intelligent tutoring systems that tailor feedback to individual learning gaps, and tools for enhancing diagnostic reasoning. Despite these advances, challenges remain, including concerns about overreliance on technology, institutional readiness, and the need for adjustments to the curriculum.
Conclusions: AI presents a transformative opportunity for orthopaedic education by enabling safer, more personalized, and more efficient learning. While current applications show promising results in improving both knowledge and technical skill, ongoing evaluation, thoughtful integration, and structured implementation are necessary to maximize educational value while addressing limitations and ethical concerns
DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures
No full textPurpose: Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of premature death among individuals with neurofibromatosis type 1 (NF1), and the transcriptional aberrations that precede malignant transformation and contribute to MPNST tumorigenesis remain poorly defined. Alterations involving CDKN2A and components of PRC2 have been implicated as early drivers of peripheral nerve sheath tumor (PNST) evolution, but these events do not occur in all MPNST. Accordingly, emerging data have begun to highlight the importance of molecular-based stratification to improve outcomes in patients with NF1-PNST.
Experimental design: In this study, we perform an integrated analysis of multiple, independent datasets obtained from human patients with NF1 to gain critical insights into PNST evolution and MPNST heterogeneity.
Results: We show that delta-like noncanonical Notch ligand 1 (DLK1) is significantly increased in MPNST and provide evidence that DLK1 overexpression may precede histologic changes consistent with malignancy. In complementary analyses, we find that serum levels of DLK1 are significantly higher in both mice and humans harboring MPNST compared with those without malignancy. Importantly, although DLK1 expression is increased in MPNST overall, through the integration of multiple, independent datasets, we demonstrate that divergent levels of DLK1 expression distinguish MPNST subsets characterized by unique molecular programs and potential therapeutic vulnerabilities. Specifically, we show that overexpression of DLK1 is associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment, and a worse overall survival in patients with NF1-MPNST.
Conclusions: Collectively, our findings provide critical insights into MPNST tumorigenesis and support prospective studies evaluating the utility of DLK1 tissue and serum levels in augmenting diagnosis, risk assessment, and therapeutic stratification in the setting of NF1-PNST
Civic Integration of Displaced Youth: Immigrant Organizations and Police Athletic Leagues as Examples of Methods for Nonprofit Analyses
No full textThis chapter focuses on displaced youth civic integration and the role of nonprofit initiatives. The first section summarizes immigrant and youth civic integration. These theories are then explored within applications to studying philanthropic organizations that provide immigrant legal aid and mentoring to displaced youth. Then, two empirical examples are presented. The first example explores the role of immigrant nonprofits in supporting the legal rights and social inclusion of children and youth refugees, asylum seekers, and unaccompanied minors. The second example examines refugees and asylum seekers within a broader context of youth mentoring activities in police athletic leagues (PALs). Both examples illustrate how researchers can access existing national public big data sources based on nonprofit 990 tax forms, navigate the limitations of pre-existing categorizations in identifying specific types of nonprofits, and identify a relevant sample of philanthropic and nonprofit organizations. In describing the processes in these two examples, this chapter aims to help emerging scholars and researchers understand more generally how studies can draw upon existing data while integrating a particular lens based on the study’s aims, in this case by focusing on organizations serving displaced youth
Racial and ethnic disparities in liver transplant access vary within and across transplant referral regions
No full textPrior studies have demonstrated racial disparities in access to liver transplantation, but the determinants of these disparities remain poorly understood. We used geographic catchment areas for transplant centers (transplant referral regions, TRRs) to characterize transplant environment contributors to racial and ethnic disparities in liver transplant access. Data were obtained from the Scientific Registry for Transplant Recipients and the National Center for Health Statistics from 2015 to 2021. The primary outcome was the difference in the listing-to-end-stage liver disease death ratio between Black, Hispanic, and non-Hispanic White patients for each TRR. We accounted for demographics, socioeconomic status, health care access, organ availability, and transplant center competition using multivariable linear regression. We examined intra-TRR differences in waitlist composition using Levene's test of variance. Across the 66 included TRRs, Black patients had lower listing-to-end-stage liver disease death ratios than White patients in 80% of TRRs, while Hispanic patients had equal or higher listing-to-end-stage liver disease death ratios compared to White patients in 56% of TRRs. The majority of variation in racial disparities across TRRs remained unexplained by multivariable models. Disparities were attenuated after excluding patients with HCC-associated mortality. Among the 27 TRRs that contained more than one transplant center, variance across TRRs was statistically significant for Black and Hispanic waitlist composition. We observed substantial geographic variation in the magnitude of racial disparities in liver transplant access across the United States. Findings highlight the need for targeted health equity interventions in regions with high disparities and the development of disparity-sensitive access metrics for transplant centers
Tunneling nanotube–like structures regulate distant cellular interactions during heart formation
No full textIn the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and initiated myocardial growth toward the heart lumen to form ventricular trabeculae-like structures. Loss of TNTLs disturbed signaling interactions and, subsequently, ventricular patterning
Benefits of enhanced recovery after surgery in robotic nephrectomy
No full textPurpose: Enhanced recovery after surgery (ERAS) is an evidence-based perioperative care approach aimed at attenuating surgical stress response and facilitating patient recovery. This study compared postoperative outcomes between an ERAS perioperative model to a traditional, unstandardized perioperative care practice in patients undergoing robotic nephrectomy.
Materials and methods: A total of 206 patients who underwent robotic renal surgery were stratified into traditional and ERAS cohorts. In total, 111 patients received the ERAS pathway, and 95 received traditional care. Data was collected through a retrospective review of electronic medical records. The primary outcome was length of hospital stay (LOS). The secondary outcomes included patient recovery milestones, pain scores, opioid use, patient complications, 30-day readmission rates, incidence of surgical site infection, and total hospital costs.
Results: Implementation of the ERAS pathway was associated with shorter hospital stay (median LOS 2.2 days vs. 2.3 days p = 0.011), lower post-operative pain scores and lower total opioid requirements at all analyzed time points (0-1, 1-24, and 24-48 h). No statistically significant differences were observed in adverse events, rates of ileus, time to first flatus, surgical site infection, or oral intake. Hospital costs were similar between groups. 30-day readmission was higher in the traditional care cohort (9% vs. 2% p = 0.035).
Conclusions: ERAS was associated with reduced length of hospital stay, improved pain scores, reduced opioid use, and lower incidence of hospital readmission in patients undergoing robotic nephrectomy
"Star of the snowbelt": On the Genealogy of Indianapolis Charter Schools
No full textIUIThis thesis traces the ideological genealogy of the charter schools Indianapolis from the 1980s to the mid-2010s, examining how power over public education shifted from democratic school boards to a complex network of political, philanthropic, and market actors. Using archival research from the Indianapolis Mayoral Archives and a historical genealogical approach, this study reveals how national reform discourse materialized into distinctive local governance structures that fundamentally reconfigured educational power relationships.
The analysis unfolds in three parts. First, it examines how the 1983 “A Nation at Risk” government report created a crisis narrative that enabled educational alternatives. Second, it analyzes how charter school legislation proliferated across states. Each state adapted the concept to local political contexts while federal administrations from Clinton through Obama provided bipartisan support through different governance mechanisms. Third, Indianapolis is used as a case study of how this mechanism evolved in Indiana’s capital city.
The Indianapolis landscape reveals unique factors that shaped charter development: Unigov’s exclusion of school districts created institutional space for mayoral intervention; demographic transformation of Indianapolis Public Schools following white flight provided the crisis narrative for reform; and intermediary organizations like The Mind Trust channeled philanthropic capital into local charter expansion. The city developed distinctive features including mayoral authorization of charter school and Innovation network Schools that hybridized charter autonomy with district oversight.
Qualitative analysis empirical data on school outcomes reveals the contradictions in charter reform. While Herron High School achieved success, Flanner House Elementary perpetrated systemic fraud, and approximately one-third of Indianapolis charter school shutter due to financial and administrative failures. Such divergent outcomes demonstrate that reconfigured educational governance created possibilities for both innovation and exploitation.
This thesis concludes that charter school reform in Indianapolis represents neither simple privatization nor democratic renewal. Rather, it is a fundamental reconfiguration of who, or what, has power over educational governance, one that blurs boundaries between public and private control. This transformation illustrates how neoliberal reforms operate through local adaptation rather than wholesale replacement of public institutions, raising questions about democratic accountability in public education
Voices from the Hallway: School Staff Perspectives on Building Healthier School Communities
No full textGpr101 Expression during Early Stages of Murine Development
No full textThe orphan G protein coupled receptor GPR101, which is implicated in X-linked acrogigantism (X-LAG), a rare pituitary disorder characterized by rapid growth a few years after birth, has received significant attention for its expression pattern in adult vertebrate tissues. However, the characterization of GPR101 expression during early embryonic development is poorly characterized. In this study, we investigated the spatiotemporal expression patterns of Gpr101 during early embryonic mouse development (E7.5-E15.5) using a global Gpr101 knock-in mouse model with an inserted LacZ reporter, Gpr101tm1b(KOMP)Mbp. Similar to previously published studies using adult tissues, we found that LacZ reporter expression was largely restricted to regions of the central nervous system. Expression was not detected until E10.5 in a region near the telencephalic vesicle. In contrast to what has been reported in adult tissues, Gpr101 expression was absent in the hypothalamus and pituitary gland during the developmental timepoints assessed. These novel observations provide a more comprehensive characterization of GPR101's expression and may offer insights into its role in growth and development across species