Publications by Year: 2025

BACKGROUND & AIMS: In response to injury, pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), marked by loss of acinar identity and acquisition of ductal features. Although ADM can resolve to support tissue repair, it may also persist and serve as a precursor to pancreatic cancer. Whether diverse pancreatic stressors drive a shared or context-specific ADM program remains unclear. We sought to comprehensively define metaplastic responses to clinically relevant exocrine pancreas diseases known to increase cancer risk.

METHODS: We profiled ADM and the surrounding microenvironment across mouse models of exocrine disease-including acute, recurrent, and chronic pancreatitis, as well as in the setting of oncogenic Kras-capturing over 300,000 single cells. To enable high-quality transcriptomic profiling in enzyme-rich tissue, we leveraged FixNCut, a method that preserves RNA integrity in the exocrine pancreas. Findings were validated in human pancreas tissue using CosMx spatial transcriptomics.

RESULTS: We identify a conserved acinar response across disease contexts that gives rise to previously unrecognized distinct metaplastic states, including a "gateway" ADM population that precedes more advanced metaplastic states marked by complete loss of acinar identity. In pancreatic intraepithelial neoplasia (PanIN) precancerous lesions, we detect classical-like and basal-like states, suggesting that pancreatic cancer subtypes are specified much earlier than previously appreciated. In Kras-mutant tissue, we identify a second wave of inflammation and the emergence of an immunosuppressive niche, coinciding with PanIN formation.

CONCLUSIONS: Our findings define a conserved program of acinar plasticity across exocrine pancreas diseases. We further link unresolved ADM to immune remodeling during precursor lesion formation and observe the emergence of pancreatic cancer subtypes in early PanIN lesions.

Gene-edited pig hearts may have an application for critically ill infants who are poor candidates for mechanical support. We established a pediatric animal model of gene-edited pig orthotopic cardiac xenotransplantation (OCXT) in baboons to assess its potential as a bridge to allotransplantation. Fifteen OCXTs were performed from genetically-engineered infantile pigs into size-matched baboons. Maintenance immunosuppression was founded on CD40/CD154 costimulation pathway blockade and rapamycin. After being sustained by xenografts for >4 months, 3 xenograft recipients were selected for transition to cardiac allotransplantation. Outcomes were tracked by invasive hemodynamic monitoring, surface echocardiography, and serial blood tests. After OCXT, 8 of 15 (53%) baboons achieved survival of >1 month, with 6 surviving for >3 months. Mortality was more common early in the study, followed by longer and more uniform survival later. The longest survivor lived >24 months postxenotransplantation. There has been no evidence of significant xeno- or allo-sensitization during xenograft support. The aims of these studies were (1) to demonstrate that a gene-edited pig heart can confer months-long survival in pediatric-sized recipient baboons, and (2) to determine whether prolonged xenograft exposure does not preclude subsequent allotransplantation. Our data suggest that these aims may be achievable and warrant further study.

Clinical notes represent a vast but underutilized source of information for disease characterization, whereas structured electronic health record (EHR) data such as ICD codes are often noisy, incomplete, and too coarse to capture clinical complexity. These limitations constrain the accuracy of datasets used to investigate disease pathogenesis and progression and to develop robust artificial intelligence (AI) systems. To address this challenge, we introduce Ci-SSGAN (Clinically Informed Semi-Supervised Generative Adversarial Network), a novel framework that leverages large-scale unlabeled clinical text to reannotate patient conditions with improved accuracy and equity. As a case study, we applied Ci-SSGAN to glaucoma, a leading cause of irreversible blindness characterized by pronounced racial and ethnic disparities. Trained on a demographically balanced subset of 349587 unlabeled ophthalmology notes and 2954 expert-annotated notes (drawn from an institutional corpus of 2.1 million notes), Ci-SSGAN achieved 0.85 accuracy and 0.95 AUROC, representing a 10.19% AUROC improvement compared to ICD-based labels (0.74 accuracy, 0.85 AUROC). Ci-SSGAN also narrowed subgroup performance gaps, with F1 gains for Black patients (+ 0.05), women (+ 0.06), and younger patients (+ 0.033). By integrating semi-supervised learning and demographic conditioning, Ci-SSGAN minimizes reliance on expert annotations, making AI development more accessible to resource-constrained healthcare systems.

OBJECTIVE: Elicit the perspectives of mothers with substance use disorder (SUD) on child well-being and parental substance use.

METHODS: We conducted semistructured focus groups of mothers with SUD on parenting, child well-being, naloxone, and experiences with medical care and Child Protective Services (CPS). Focus group transcripts were iteratively reviewed to generate a codebook, which was applied in NVivo by 2 independent coders. We used inductive thematic analysis to examine codes relevant to child well-being, harm reduction, and clinician reporting to CPS.

RESULTS: Twenty-three women participated in 5 focus groups. Four themes emerged: 1) mothers felt their substance use negatively impacted their ability to provide attentive supervision and emotional support; 2) mothers discussed strategies to minimize harm to children but had limited familiarity with naloxone use for unintentional ingestions; 3) mothers viewed child well-being as a spectrum but felt that clinicians often approached well-being as a binary of "safe" or "unsafe"; and 4) mothers recognized that clinicians are obligated to report child abuse or neglect and recommended transparent CPS reporting.

CONCLUSIONS: Participants viewed child well-being in the setting of parental substance use as a multidimensional construct. Mothers acknowledged the potential emotional harms of substance use, an important target for family-based intervention. Mothers used harm reduction strategies to keep their children safe, but not all were aware that naloxone could be used to reverse pediatric overdoses. Improved provider guidance on comprehensively assessing child well-being, supporting harm reduction, and trauma-informed CPS reporting may help clinicians partner with families to support child health and safety.

White matter alterations are increasingly implicated in neurological diseases and their progression. Diffusion-weighted magnetic resonance imaging (DW-MRI) has been included in many international-scale studies to identify alterations in white matter microstructure and connectivity. Yet, quantitative investigation of DW-MRI data is hindered by a lack of consistency due to variations in acquisition protocols, sites, and scanners. Specifically, there is a need to harmonize the preprocessing of DW-MRI datasets to ensure that compatible and reproducible quantitative metrics are derived from each site, including (1) bundle-wise microstructure measures, (2) features of white matter fiber bundles, and (3) connectomics measures. In the MICCAI CDMRI 2023 QuantConn challenge, participants are provided raw data from the same individuals taken with two different acquisition protocols on a single 4 tesla scanner in the same scanning session and asked to preprocess the data in order to minimize acquisition differences while retaining biological variation. Here, we outline the testing framework, provide baseline pre-harmonized results, and discuss the learning implications of this challenge.

BACKGROUND: The CXCR4 and CXCR2 chemokine receptor axes play critical but opposing roles in regulating neutrophil retention and release from the bone marrow (BM). Gain-of-function (GOF) variants in CXCR4 are associated with WHIM syndrome, characterized by neutropenia, lymphopenia, frequent infections, warts, and myelokathexis. Similarly, loss-of-function (LOF) variants in CXCR2 also result in neutropenia, increased infection susceptibility and myelokathexis. Mavorixafor, an orally bioavailable CXCR4 antagonist, has shown meaningful increases in absolute neutrophil count and reduced infections in WHIM syndrome patients. However, it remains unclear whether CXCR4 antagonism can mitigate the pathogenic characteristics observed in individuals with CXCR2 LOF mutations.

METHODS: This study investigated the effects of chronic oral administration of a CXCR4 antagonist on neutrophil abnormalities and infection susceptibility in a CXCR2 LOF mouse model. Mice received the CXCR2 antagonist navarixin orally and then the CXCR4 antagonist compound 1 or vehicle control daily for 7 days. Blood and BM samples were collected for analysis. Treated mice were inoculated with Streptococcus pneumoniae to induce pneumonia. Lung tissues were harvested to assess bacterial load and neutrophil counts, and overall survival was monitored.

RESULTS: Pharmacologically induced CXCR2 LOF in mice recapitulated multiple phenotypic features analogous to those observed in patients with CXCR2 LOF, including peripheral blood neutropenia, an elevated myeloid/erythroid ratio (M/E ratio), and neutrophil accumulation with myelokathexis-like (MK-like) morphology in BM, and increased pneumonia susceptibility. Treatment with the CXCR4 antagonist resulted in the correction of these pathologic features, as evidenced by normalization of absolute neutrophil count in peripheral blood, reversal of neutrophil accumulation in BM, normalization of the M/E ratio in BM and reduced the frequency of MK-like neutrophils in BM, and the incidence of myelokathexis. Furthermore, CXCR4 antagonism ameliorated the severity of pneumonia and facilitated the emigration of neutrophils into infected tissues in the CXCR2 LOF mice.

CONCLUSIONS: Our findings provide evidence that oral administration of a CXCR4 antagonist can effectively correct blood and BM neutrophil abnormalities and reduce infection susceptibility in a CXCR2 LOF mouse model. These findings suggest potential therapeutic benefits of CXCR4 antagonist therapy in addressing peripheral blood neutropenia and other pathogenic phenotypes in patients with CXCR2 LOF variants.

PURPOSE: Retinoblastoma is the most common intraocular cancer in infants and children, with a significant potential for metastasis. The mini-peptide ribosomal protein L41 (RPL41) has demonstrated extensive antitumor effects in vitro by promoting the degradation of activating transcription factor 4 (ATF4). This study aims to evaluate the therapeutic effect of RPL41 on retinoblastoma and elucidate its potential mechanisms.

METHODS: A xenografted retinoblastoma model was constructed in nude mice. The effects of xenografted RPL41 on tumor proliferation, invasion and metastasis were evaluated by local injection. Mass spectrometry identified differentially expressed genes in Y79 and Weri-RB1 retinoblastoma cells pre- and post-treatment. We utilized quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry to assess the expression levels of ARL5B(ADP ribosylation factor like GTPase 5B) in retinoblastoma cell lines and tissues. We also explored ATF4's regulatory role on ARL5B expression through chromatin immunoprecipitation (ChIP) experiments and luciferase reporter gene assays.

RESULTS: RPL41 inhibits the growth of subcutaneous retinoblastoma xenografts. ARL5B expression was significantly downregulated in treated Y79 and Weri-RB1 cells. ARL5B was upregulated in retinoblastoma cells and clinicopathological tissues. RPL41 treatment led to ATF4 degradation, reducing the expression levels of ARL5B and lysotransfer-related molecules. Knocking down ATF4 decreased ARL5B protein levels. ChIP experiments and dual-luciferase assays confirmed ATF4 positively regulates ARL5B. Rescue experiments indicated that ARL5B overexpression partially reversed the effects of RPL41 therapy or ATF4 knockdown on lysosomal pathways and cell migration.

CONCLUSIONS: RPL41 down-regulates the expression of ARL5B by degrading ATF4 and the impaired ARL5B-related lysosomal trafficking is a mechanism to inhibit the metastasis of retinoblastoma.

BACKGROUND: Resident workload can significantly influence resident education, resident well-being, and patient care. Components of workload include duty hours and patient census, though their roles within the complexities of workload and subsequent effects remain underexplored. This scoping review aims to investigate how patient census impacts patient outcomes.

METHODS: Our scoping review searched multiple databases in April 2022 using a query framework that captured articles reporting the effect of inpatient service census on patient outcomes. English-language studies conducted in the United States were included. Three authors independently screened results, followed by full-text review. The data extracted contained study characteristics, characterization of census, patient outcomes, and intervention utilization.

RESULTS: Thirteen articles met the inclusion criteria. The majority of articles (92.3%) were published after 2003, the time of the initial Accreditation Council for Graduate Medical Education duty hour restrictions mandate. All studies were conducted in internal medicine programs. Most commonly studied outcomes were readmission, length of stay, mortality, quality and safety measures, and patient satisfaction. Five studies performed an intervention to optimize census, which included adding residents to the team and implementing census caps. The overall paucity and heterogeneity of the present literature led to variable findings on how census affects patient outcomes.

CONCLUSIONS: There remains an incomplete understanding of the impact of patient census on patient outcomes and its role in workload, particularly among surgical specialties. Further efforts are needed to characterize the complexities of workload, compare differences in workload between surgical and nonsurgical specialties, and evaluate its impact on resident education, resident well-being, and patient care.

Congenital heart disease (CHD) is a complex group of cardiac abnormalities arising during fetal development. Despite advancements in diagnostics and surgery, CHD mechanisms remain elusive due to inadequate disease models. Recent innovations in artificial intelligence (AI)-assisted organoid construction, which replicate tissue architecture and function, provide a promising in vitro platform for modeling cardiac development and CHD progression with high precision. This review summarizes AI-driven approaches in CHD organoid construction, focusing on machine learning (ML) applications in self-assembly, three-dimensional (3D) bioprinting, tissue engineering, and microfluidic organ-on-a-chip (OOC) technologies. We also discuss refinements in AI algorithms - such as support vector machines (SVMs), decision trees, and neural networks - to enhance cell-cell interaction analysis, optimize drug screening, and improve toxicity/efficacy assessments. Looking ahead, AI is poised to accelerate CHD organoid translation to clinical practice, advancing precision medicine.

OBJECTIVE: Develop a new hospital surgery report card for use in performance improvement.

BACKGROUND: When evaluating quality, a surgical program is aided by benchmark comparisons with outcomes achieved at other hospitals. To be credible, benchmarking should be based on the same surgical procedures and patient risk, despite there being many types of patients and procedures.

METHODS: Using Medicare patients undergoing general, orthopedic, or vascular surgery, each patient in a hospital is closely matched to 10 control patients from typical hospitals and to 10 control patients from well-resourced hospitals throughout the United States. Patients were matched on 200 characteristics, including procedure, comorbidities, socio-demographics, and the presence of multimorbidity. Hospitals were graded based on the differences in outcomes between matched sets of patients. As an illustration, we examine the 20 highest volume hospitals in Pennsylvania and provide detailed report cards on 2 example hospitals.

RESULTS: The hospitals studied differed in quality and grades, with better outcomes than matched controls for Hospital A and significantly worse outcomes than controls for Hospital B, depending on the type of surgery and patient. For the 20 largest hospitals in Pennsylvania, 5 had significantly elevated mortality, and 2 had significantly lower mortality than matched controls.

CONCLUSIONS: Surgical programs benefit from knowing how their outcomes compare with those of other hospitals, both their overall outcomes and their outcomes for subsets of patients, such as patients with or without multimorbidity. Detailed reports based on matching can help identify meaningful deficiencies and strengths in programs concerning specific surgeries and patient types.