Faculty Bibliography

BACKGROUND:Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in genome-wide association studies but are often limited by a single-cell context. OBJECTIVE:We hypothesized that modeling GReX across multiple conditions could enhance power to identify causal genes for complex inflammatory diseases. METHODS:We conducted TWAS on 400 transcriptomes under 8 proinflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against genome-wide association studies from 7 inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, systemic lupus erythematosus, and vitiligo. RESULTS:), and our method successfully captured >85% of all genes with colocalizing expression quantitative trait loci. Single-cell-resolution spatial profiling further demonstrated the modulation of TWAS signals in keratinocytes by close proximity to TNF/IL-17-expressing cells in psoriatic skin. CONCLUSION/CONCLUSIONS:Modeling gene expression across relevant cellular states substantially improves the power and resolution of TWAS.

Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient's quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.

Nasoalveolar molding (NAM) is an established form of presurgical infant orthopedics (PSIO), whereas presurgical lip, alveolus, and nose approximation (PLANA) is a novel approach. This study compared presurgical outcomes between infants with a unilateral cleft lip treated with PLANA and NAM using an objective method for assessment of cleft severity and PSIO outcomes. A single-institution retrospective review was conducted of all patients treated with NAM (2017-2019) and PLANA (2023-2025). Anthropometric measurements including columellar angle, nostril width ratio, and lateral subnasale displacement were collected at the initiation and completion of therapy, and predefined thresholds were used to classify patients by cleft severity (mild, moderate, severe, and very severe) and outcome (poor, good, and excellent). A total of 64 patients were identified, including 36 patients treated with NAM and 28 treated with PLANA. At baseline, the 2 cohorts exhibited similar distributions in cleft severity categories. At the completion of therapy, statistically significant differences were observed between NAM (27.8% mild, 52.8% moderate, 16.7% severe, and 2.8% very severe) and PLANA (67.9% mild, 28.6% moderate, 3.6% severe, 0.0% very severe). This translated to significant differences in PSIO outcomes between NAM (11.1% excellent, 55.6% good, and 33.3% poor) and PLANA (60.7% excellent, 35.7% good, and 3.6% poor). Numerically, the 2 cohorts were statistically similar at baseline, but after PSIO the PLANA cohort displayed more favorable anthropometrics and larger improvements in all 3 parameters. Using an objective method for evaluating cleft severity, patients treated with PLANA exhibited superior morphologic outcomes in comparison to NAM.

UNLABELLED:Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCLs derive from follicular B cells engaged in adaptive immune responses. By studying cooccurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extrafollicular trajectory. Using animal models and human specimens, we find that this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory, and a distinct, autoimmune B cell-like state. This trajectory is associated with sex-biased outcomes: Female patients and mice exhibit reduced survival compared with males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of Toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy. SIGNIFICANCE/UNASSIGNED:The findings in this article support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.

PURPOSE/OBJECTIVE:The term white dot syndromes (WDS) has historically grouped multiple non-infectious posterior uveitis (NIPU) entities based on a similar funduscopic appearance of "white dots." Despite decades of use, the clinical relevance of this umbrella terminology has been questioned. This perspective critically examines whether WDS remains a valid conceptual and diagnostic construct in the era of advanced retinal and choroidal imaging. DESIGN/METHODS:Perspective review. METHODS:Critical interpretation of the available literature on imaging and current pathophysiological evidence, combined with observations collected using cutting edge imaging technology (structural high-resolution optical coherence tomography (OCT), OCT angiography, and indocyanine green [ICG] angiography [ICGA]) for 6 of the NIPU classically considered as WDS: multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis with panuveitis (MFCPU), punctate inner choroiditis (PIC), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis (SC), and birdshot chorioretinitis (BSCR). RESULTS:Although these diseases share some overlapping clinical features, multimodal imaging reveals profound differences, with each entity having distinct anatomic features on multimodal imaging. OCT angiography (OCTA) demonstrate distinct patterns of tissue involvement-from photoreceptor/retinal pigment epithelium (RPE) injury in MEWDS, to Bruch's membrane disruption in MFCPU and PIC, to profound choriocapillaris ischemia in APMPPE and SC, and deep stromal choroidal infiltration in BSCR. ICGA further differentiates these entities by choroidal perfusion characteristics, distinguishing true vascular non-perfusion from other inflammatory reactions leading to tissue damage. Imaging-based hypotheses of immunopathogenesis suggest that these entities may arise from different immunopathogenic pathways-transient outer retinal inflammation (MEWDS), possible antigenic exposure from structural disruptions (MFCPU/PIC), primary inflammatory inner choroidal vascular occlusive process (APMPPE), a possible autoimmune or autoinflammatory choroidal ischemic mechanism (SC), and a likely Human Leukocyte Antigen (HLA)-A29-associated autoimmune response affecting the inner retina and choroid (BSCR) CONCLUSIONS: The label WDS, originally based on appearance alone, does not take into consideration major biological and prognostic differences among these NIPU. Current imaging-guided hypotheses of immunopathogenesis suggest that these conditions should no longer be grouped under a single classification. A paradigm shift toward disease-specific terminology is warranted to improve diagnostic precision, guide management, and reflect presumed pathophysiological diversity.

Astrocyte loss occurs in various neurological conditions and can disrupt local tissue homeostasis. While astrocytes surrounding border-forming lesions adopt reactive states without restoring astrocyte networks, how astrocytes respond to spatially confined astrocyte loss remains poorly understood. Here we used longitudinal in vivo two-photon microscopy, combined with spatiotemporal transcriptional profiling, to examine astrocyte responses following focal aquaporin-4 antibody-mediated ablation in the somatosensory cortex of adult mouse brain, a model of astrocytopathy relevant to neuromyelitis optica spectrum disorder. Here we show that perilesional astrocytes undergo pronounced structural remodeling during lesion repopulation, characterized by cell proliferation, prolonged multinucleated astrocyte states, polarized process extension into the depleted area and gradual displacement of nuclei into previously unoccupied astrocyte territories. Spatial transcriptomics reveal an injury-associated molecular response that resolves as the astrocyte network is restored. Together, our findings delineate the spatiotemporal dynamics of astrocyte regeneration after astrocyte loss, extending current understanding of astroglial plasticity in the adult brain.

In response to declining public trust in healthcare institutions, the Institute for Healthcare Improvement (IHI) and the American Board of Internal Medicine Foundation (ABIMF) began a collaborative to identify changes that healthcare organizations could make to regain the trust of their care teams and communities. Using IHI and ABIMF's theory of change as a guide, six healthcare organizations tested this framework on-site and shared lessons learned, identifying the critical role of not just acknowledging past breaches but also demonstrating accountability as crucial steps to strengthening trust. The experiences of three healthcare organizations are summarized here.

Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been widely used in Ayurvedic medicine for its adaptogenic properties and therapeutic potential and has been investigated for its benefits related to sleep and stress management by Western medicine. However, concerns regarding its teratogenic and abortifacient effects have emerged following reports from the World Health Organization (WHO) and regulatory bodies. This systematic and ethnobotanical review critically evaluates these claims by assessing ashwagandha's toxicokinetics, toxicodynamics, and available safety data. A comprehensive literature review following PRISMA guidelines was conducted to identify studies on its reproductive toxicity, molecular interactions, and traditional usage. Historical ethnobotanical reports suggest potential abortifacient effects, but citation distortion and lack of primary source validation raise concerns regarding the validity of such claims. Toxicological studies in animal models demonstrate high tolerability, with no significant reproductive toxicity observed at doses relevant to human consumption. Human clinical studies also show no adverse effects on thyroid function, hormonal balance, or reproductive health. Altogether, evidence supporting significant teratogenic or abortifacient activity remains inconclusive. This review highlights the need for standardized, high-quality research addressing fertility and developmental outcomes in controlled conditions. Given the widespread use of ashwagandha as a dietary supplement ingredient and traditional medicine, a balanced and evidence-based approach is required to assess its safety, ensuring that regulatory actions are informed by robust scientific data rather than historical speculation.

BACKGROUND:Ureteroenteric strictures (UES) are a challenging complication after urinary diversion and may lead to infection, renal dysfunction, and the need for reintervention. Robotic repair has emerged as an effective minimally invasive option, but data remain limited, particularly in complex and heterogeneous cohorts. METHODS:We conducted a retrospective review of 40 patients who underwent robotic UES repair at a single tertiary center between July 2014 and May 2024. Seventeen patients were treated with the Xi system and 23 with the single-port (SP) platform, all by a single experienced surgeon. Patient demographics, stricture characteristics, operative details, perioperative outcomes, and follow-up data were analyzed. Surgical success was defined by symptom resolution, stent- or nephrostomy-free status, radiological patency, and stable renal function. RESULTS:A total of 40 patients representing 50 ureteral units were included. The cohort included a range of stricture characteristics and reconstructive approaches. Primary anastomosis was most commonly performed for shorter strictures, whereas flap, graft, and interposition techniques were used for longer or more complex disease. Overall, robotic repair was associated with high success rates (95%) and acceptable morbidity (12.5% major complications). Perioperative outcomes improved over time, with reductions in operative time, blood loss, and length of stay, likely reflecting increasing surgical experience and technical refinement. CONCLUSIONS:Robotic repair of UES is safe and effective across both multiport and SP platforms. This series reflects a decade of evolving technique and highlights practical refinements that facilitate reconstruction in complex postdiversion cases.

BACKGROUND:The Essentials in Minimally Invasive Gynecologic Surgery (EMIGS) is a new assessment employed by the American Board of Obstetrics and Gynecology to evaluate physicians' surgical skills for certification. The program assesses the minimal laparoscopic skills needed to qualify for the certifying exam. We aimed to use checklist assessments to predict performance on the Running Stitch task of EMIGS OBJECTIVES: We strove to develop and evaluate a novel metric to predict competency in the EMIGS Running Stitch task. Secondarily to assess resident PGY year, prior laparoscopic suturing experience, and prior laparoscopic simulation experience correlation with passage. STUDY DESIGN/METHODS:A novel task specific checklist was developed by expert teaching surgeons to assess the Running Stitch task of EMIG. The checklist was tested for inter-rater reliability. Settings Residency programs at four participating academic centers PARTICIPANTS: 71 participants completed 97 videotaped trials Interventions participants completed a pre-study survey prior to each video-taped laparoscopic skills session (one to four sessions over four months of study). The video and the completed EMIGS task Penrose were evaluated both by the study team with checklists and later by EMIGs MEASUREMENT: The two scores were correlated using linear regression and Bland-Altman plots for agreement. RESULTS:53% of trials received a passing score by AAGL. AAGL and study team checklist scores were moderately correlated (0.73) however study team metrics consistently overrated performance. Laparoscopic case numbers and PGY level correlated with passing score. CONCLUSIONS:Scoring using our novel metric correlated with passing scores but overrated performance. This tool may aid educators in assessment during resident preparation for the EMIGS skills exam, but metrics for grading of this examination remain poorly understood.