Faculty Bibliography

BACKGROUND:Approximately half of male factor infertility cases are idiopathic, indicating a need for new methods to supplement male fertility assessment. OBJECTIVES/OBJECTIVE:The objective of this study was to identify differences in the sperm transcriptomes of men with different clinical fertility status. We hypothesized that sperm mRNA profiling could distinguish men presenting for fertility assessment from proven fertile men. MATERIALS AND METHODS/METHODS:We compared two groups of study participants: men who presented for infertility assessment (n = 53, "infertility"), and men without a history of infertility who had fathered a child and were presenting for vasectomy (n = 14, "proven fertile" control). Study participants provided a semen sample for semen analysis and sperm mRNA sequencing. Differentially abundant genes were identified, and a gene expression summary score was constructed to test the ability of RNA-seq data to differentiate between study populations. RESULTS:The semen parameter that best differentiated between study populations was motility (area under the ROC curve = 0.746). In RNA-seq analysis, 1885 total differentially abundant transcripts were identified (q < 0.05, fold difference ≥ 2), 1004 (53.3%) of which were downregulated in infertility study participants. The Gene Ontology term, spermatogenesis, was enriched, with 40 out of 44 differentially abundant genes downregulated in infertility study participants. A gene expression summary score consisting of 100 upregulated and 100 downregulated genes was able to differentiate between the two groups of study participants. DISCUSSION/CONCLUSIONS:Sperm mRNAs differed between proven fertile and infertility study men. Known fertility-associated genes, including PRM1 and PRM2, and potentially novel fertility markers, including HOOK1 and SPATA6, were downregulated in infertility study samples. Future studies should test these results for reproducibility and test whether novel biomarker candidates can provide mechanistic information about etiologies of idiopathic male infertility. CONCLUSION/CONCLUSIONS:Our results support the hypothesis that sperm mRNA abundance differs by clinical fertility status.

OBJECTIVE:To compare cost and reimbursement of robotic and abdominal sacrocolpopexy procedures to evaluate which approach may minimize costs while improving the hospital profit margin. METHODS:We performed an IRB-exempt retrospective cohort study investigating all patients who underwent robotic or abdominal sacrocolpopexy at our hospital between July 1, 2018 and May 31, 2022. Patient demographic, procedural, and postoperative course data were extracted via chart review including duration of procedure, time in operating room, complications, and length of hospital stay. The billing department provided information on estimated cost of stay and reimbursement rates. RESULTS:A total of 203 robotic and 291 abdominal cases were included in analysis. The groups had significant differences in demographics, including race and insurance status. Abdominal procedures were associated with lower costs ($7675.99 vs 8747.48, P <.0001) and higher reimbursement rates ($ 16,210.48 vs $ 10,102.28, P <.0001), with the total collected (reimbursement minus cost), or profit margin, differing significantly ($8534.50 vs $1354.80, P <.0001). Discrepancies in reimbursement and profit remained after controlling for secondary procedures. Abdominal cases also had shorter average duration (129.9 vs 168.4 minutes, P <.0001). Abdominal sacrocolpopexy was associated with higher estimated blood loss (109.2 vs 97.9, P <.0001) and longer hospital stay (26.3 vs 15.9 hours, P <.0001). CONCLUSION:Despite longer hospital stays and slightly higher estimated blood loss, abdominal sacrocolpopexy appears to have lower costs and higher reimbursement rates than robotic sacrocolpopexy, with a higher profit margin for the hospital.

Brown adipose tissue (BAT) is an evolutionary innovation that enables placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure activates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (Slit3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We demonstrate that adipocyte progenitors secrete Slit3, which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which bind distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. We identify Plxna1 as a previously unrecognized receptor for Slit3-C and show that it is essential for sympathetic innervation and cold-induced neurite expansion in BAT. Moreover, we introduce bone morphogenetic protein 1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this work establishes a mechanistic framework for the coordinated regulation of sympathetic innervation and angiogenesis to enhance thermogenic function. The co-regulation of neurovascular expansion by distinct Slit3 fragments offers a bifurcated yet harmonized mechanism to ensure a synchronized BAT response to environmental challenges. Finally, this study provides the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

Since the standardization of the grading system for pathologic diagnosis of antibody-mediated and acute cellular rejection, endomyocardial biopsy has remained the gold-standard. However, biopsies are invasive, costly, and limited by sampling error. As such, adjuvant non-invasive methods including cardiac biomarkers, imaging including cardiac magnetic resonance and echocardiography, and donor-specific antibodies and non-HLA antibodies have been traditionally used. However, all these techniques are limited by either sensitivity or specificity. More recently, there has been a shift to other contemporary non-biopsy surrogate markers for rejection surveillance including donor-derived cell free DNA, gene expression profiling, and messenger RNA and micro-RNA in tissue. Herein we review the methods currently utilized to diagnose rejection and their limitations. We find that while there have been significant advancements in technology and non-invasive techniques, no current method alone adequately diagnoses rejection (Central Image). Thus, future studies are warranted to investigate new strategies involving a multi-modal approach that incorporates non-invasive diagnostic methods and personalized medicine to monitor postoperative progression in heart transplant patients.

BACKGROUND AND AIMS/UNASSIGNED:In patients with achalasia treated via Heller myotomy (HM) or peroral endoscopic myotomy (POEM), incomplete myotomy can lead to a "blown-out myotomy" (BOM) diverticulum, worsening obstruction, and dysphagia. We present peroral direct diverticulotomy (PODD), a salvage technique, similar to the "ultrashort tunnel" Zenker's peroral endoscopic myotomy technique, targeting the residual sphincter at the diverticular septum. METHODS/UNASSIGNED:We performed PODD in a 49-year-old man with type I achalasia who underwent POEM with minimal relief (Eckardt score 4). At 18 months, the esophagram showed delayed emptying, incomplete myotomy, and BOM diverticulum, and endoscopy revealed a "puckered," tight lower esophageal sphincter (LES) and a BOM diverticulum. PODD achieved a 2-cm myotomy at the diverticular septum, completing the initial myotomy. RESULTS/UNASSIGNED:The 25-minute procedure was uneventful, and the patient was discharged after 23 hours. Four-week follow-up endoscopy showed patulous LES, resolution of the septum, and no reflux esophagitis. Endoluminal functional lumen imaging probe and esophagram were consistent with resolution of obstruction. At 6 months, swallowing was improved (Eckardt score 1) with no gastroesophageal reflux disease symptoms. CONCLUSIONS/UNASSIGNED:As POEM spreads to low-volume centers, BOM diverticula-once mainly seen after failed HM-are increasingly seen after POEM. PODD offers a technically simple, effective salvage technique with potential broad applicability in managing POEM and HM failure due to BOM.

Inferior vena cava (IVC) pathology is often underrecognized on non-dedicated imaging examinations, yet it carries significant diagnostic and clinical implications, particularly in acute emergency settings. This review highlights the complementary roles of ultrasound (US) and computed tomography (CT) in the assessment of IVC abnormalities. The US provides real-time, bedside evaluation of IVC patency, caliber, and hemodynamics, whereas CT offers detailed anatomic and structural characterization critical for diagnosis and management. The review aims to systematically discuss congenital variants, thrombotic, traumatic, systemic conditions, and neoplastic involvement of the IVC, emphasizing their imaging features and clinical relevance.

BACKGROUND/UNASSIGNED:Discovery and incorporation of predictive and prognostic biomarkers enhance outcomes for patients with cancer. Clinico-genomic datasets, which retrospectively link real-world clinical data to tumor sequencing data, are important resources for biomarker research, which has historically relied on robust research infrastructures exclusive to large academic centers. The objective was to evaluate the feasibility of a pragmatic, technology-enabled platform at community-based research sites for development of a prospective clinico-genomic database supported by centralized electronic health record (EHR)-based patient ascertainment and data processing. METHODS/UNASSIGNED:Adults with stage IV or recurrent metastatic non-small cell lung cancer or extensive-stage small-cell lung cancer were enrolled at 23 US sites upon initiating a standard line of therapy. Enrollment rates were estimated from eligible populations at individual centers. Clinical data from routinely collected EHR documentation were centrally processed and normalized for quality control. Serial blood samples at pre-specified timepoints (baseline, during treatment and at disease progression/end of therapy) were used for circulating tumor DNA (ctDNA) genomic profiling. RESULTS/UNASSIGNED:Between December 2019 and May 2021, 944 patients enrolled, representing ≈25 % of eligible patients. Eight-hundred seventeen of 944 (87 %), 406 of 606 (67 %) and 398 of 852 (47 %) participants provided qualifying samples for ctDNA testing at baseline, during treatment and at disease progression/end of therapy, respectively. Samples were provided at all three timepoints by 35 % of participants. CONCLUSION/UNASSIGNED:A community-based oncology patient cohort was rapidly enrolled, creating a real-world clinico-genomic dataset. This pragmatic study platform has potential research applications where prospective real-world data may contribute to evidence generation.

BACKGROUND:Next-generation sequencing (NGS) testing in patients with metastatic non-small cell lung cancer (mNSCLC) identifies actionable driver oncogenes (ADO) and targeted treatment (TT). Potential inequities were evaluated in NGS testing and TT in patients with mNSCLC. PATIENTS AND METHODS/METHODS:This retrospective study used a nationwide electronic health record-derived deidentified database for patients ≥18 years diagnosed with mNSCLC between 4/2018 and 4/2024, ≥2 recorded visits, and follow-up ≥90 days post diagnosis. For TT, patients must have received NGS testing before first-line (1L) treatment and harbored ≥1 1L ADO. RESULTS:A total of 15 392 patients with mNSCLC were included: 66% with commercial insurance, 16% with Medicare, 12% with other, 4% with Medicaid, and 3% with other government insurance. Patients with commercial insurance had significantly higher odds of receiving NGS testing vs Medicare, Medicaid, or other insurance. While patient characteristics varied across insurances, the effect of insurance type on NGS testing did not differ by race/ethnicity, age, or socioeconomic status (SES). Site of care was a significant effect modifier, with increased odds of NGS testing for community vs academic settings for commercial, Medicare, and other insurance and decreased odds for Medicaid. When all patients received NGS testing, significantly lower odds of receiving TT occurred for patients with SES 2 vs SES 1 (lowest); higher odds occurred for Asian vs white patients. CONCLUSION/CONCLUSIONS:Insurance is a key contributor to inequity in NGS testing. When all patients received NGS testing, equity was achieved in patients receiving TT, except those with lower SES, who potentially did not qualify for Medicaid.