Faculty Bibliography

Neoadjuvant therapy (NAT) is the standard of care for borderline-resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC). It can be used to treat resectable PDAC. This study aimed to investigate how NAT remodels the tumor immune microenvironment (TIME) and whether this remodeling translates into survival benefits. We performed spatial and digital pathology analysis of 27 upfront resection patients (naïve group) and 39 age-, gender-, and stage-matched patients who had surgery after NAT (NAT group). AI-assisted digital pathology was used to annotate cancer cells and CD8 + T lymphocytes. Spatial correlation between CD8 + T lymphocytes and cancer cells for each case was assessed using spatial point pattern analysis, followed by generalized linear modeling (GLM) of quadrat counts of CD8 + T cells, with the quadrat counts of cancer cells as the independent variable. The regression coefficient was used to quantify the strength of their spatial correlation and then further assessed for association with patient survival. The analyses showed that the NAT group, compared with the naïve group, had increased spatial correlation of CD8 + T cells with cancer cells, suggesting enhanced effector T cell-cancer cell engagement in the NAT patients. Additionally, patients with a higher degree of spatial correlation between the two cells showed improved after-surgery survival. Through a new methodological framework that takes advantage of AI-assisted digital pathology and spatial point pattern analysis, our study has successfully captured the subtle effects of NAT-induced TIME remodeling and assessed its impact on prognosis of PDAC patients.

Acute rheumatic fever (ARF) is an immune-mediated nonsuppurative complication of group A streptococcal (GAS) pharyngitis. Approximately 470,000 new cases of ARF occur annually, with a more significant disease burden in developing countries with higher rates of untreated or inadequately treated GAS infections. Globally, over 275,000 deaths yearly are attributed to rheumatic heart disease (RHD). The most significant contributors to the spread of GAS pharyngitis are household overcrowding, poor sanitation, and inadequate access to healthcare. The pathophysiology of ARF is characterized by an aberrant immune response to GAS infection triggered by molecular mimicry between GAS antigens and self-antigens. This immune response typically manifests 2 to 4 weeks after the initial GAS infection and may lead to the development of carditis, valvulitis, Sydenham chorea, subcutaneous nodules, erythema marginatum, and polyarthritis that is usually migratory. The severity and distribution of these manifestations vary significantly between individuals making the diagnosis of ARF challenging. Early recognition of ARF using the modified Jones criteria is essential in treating acute infection and preventing complications. A major long-term consequence is RHD, which carries significant morbidity and mortality.

Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.

IMPORTANCE/OBJECTIVE:Despite its frequent use for visualization of ureteral efflux during pelvic/abdominal surgery, there are limited data on indigo carmine pharmacokinetics and duration of blue color in postdose urine. Understanding how long the blue color persists allows the clinician to make accurate assessments of the urinary system during complex surgical procedures. OBJECTIVES/OBJECTIVE:This study observed the plasma and urinary pharmacokinetics of indigo carmine in healthy volunteers and the voided urine color. STUDY DESIGN/METHODS:This study was an open-label, randomized clinical trial in 16 healthy participants who received either a 2.5-mL or a 5.0-mL intravenous injection of indigo carmine. Blood (pre, 2, 5, 7, 10, 15, 20, 30, 40 minutes and 1, 2, 3, 4, 6, 12 hours post) and urine (predose, 0-2, 2-6, 6-12 hours post) were collected. The first postdose stool was collected. RESULTS:Plasma concentration peaked within 5 minutes, and all plasma concentrations were below the limit of quantification by 2 hours postdose. The estimated plasma half-life of indigo carmine was 12 minutes. Voided urine through 2 hours postdose was visibly discolored compared with the matched predose urine. In some cases, urine discoloration persisted through 6 hours (10/16) and 12 hours (1/16). Unchanged indigo carmine eliminated in stool was observed in 4 of 16 participants (25%). CONCLUSIONS:The short half-life and rapid urinary excretion of indigo carmine favor its clinical use for intraoperative cystoscopy and are consistent with the reported median time of 6 minutes postinjection to ureteral efflux in patients undergoing surgical procedures.

OBJECTIVES/OBJECTIVE:Inequities in race, ethnicity and socioeconomic status have been well documented in postpartum hemorrhage (PPH) and hemorrhage-associated morbidity. However, little is known about the impact of language barriers on maternal outcomes in PPH. Our study aim was to investigate language-based inequities in maternal outcomes among gravidas with PPH. METHODS:This is a retrospective cohort of patients with PPH who delivered at an urban academic institution between January 2020 and December 2022. Maternal language is categorized as English primary language (EPL) or non-English primary language (NEPL). PPH is defined as a quantitative blood loss (QBL) greater than 1000 mL within 24 h of delivery. QBL is a calculated measurement of peripartum and postpartum blood loss. Primary outcome is transfusion of packed red blood cells (pRBC). Secondary outcomes include transfusion of 4 + units of pRBC, disseminated intravascular coagulation (DIC) and admission to intensive care unit (ICU). Multivariable logistic regression was used to estimate the association of primary language with maternal outcomes. RESULTS:1723 patients with PPH were included: 1314 (76.3%) with EPL and 409 (23.7%) with NEPL. English-speaking and non-English speaking patients had similar QBL rates (1530.2 ± 634.2 vs 1496.0 ± 668.1, p = 0.3). However, transfusion rates were lower in those with NEPL, when compared to EPL (28.2% vs 22.9%, p = 0.039). After adjusting for age, race/ethnicity, nulliparity, body mass index, pre-eclampsia and pre-delivery anemia, gravidas with NEPL were less likely to be transfused compared with EPL (aOR 0.7, 95% CI 1.012-1.806, p = 0.04). Rates of DIC, ICU admission and transfusion of 4 + units of pRBC were similar between groups. CONCLUSIONS FOR PRACTICE: Despite a similar postpartum blood loss, patients with NEPL had lower rates of blood transfusion in PPH compared to patients with EPL. Further research is needed in health literacy and language proficiency that may impede access to transfusion in patients with PPH.

PURPOSE/OBJECTIVE:Overactive bladder (OAB) is a prevalent condition that can have a significant impact on quality of life. Sacral neuromodulation (SNM) is proven as an effective treatment option for OAB patients. Rechargeable devices have gained popularity in recent years. However, there is a paucity of data investigating revision rates for rechargeable SNM devices and associated impacting factors. MATERIALS AND METHODS/METHODS:We conducted a retrospective cohort study to investigate the revision rates of SNM devices in patients diagnosed with OAB. Patients who underwent implantation of rechargeable or non-rechargeable SNM devices at our institution between January 2019 and June 2023 were included. Revision events, reasons for revisions, and patient demographics were analyzed and compared between the device groups. RESULTS:The study included 246 patients. One hundred fifty received rechargeable SNM devices and 96 received non-rechargeable devices. Revision rates were significantly different between the two groups, with 34% of patients in the rechargeable device group requiring revisions compared to 13.5% in the non-rechargeable group (p < 0.001). The most common reasons for revision in the rechargeable group included difficulty charging (35.3%) and reduction of symptom improvement (23.5%). Having a rechargeable device resulted in a significantly higher probability of requiring a revision over time compared to non-rechargeable (p < 0.001). CONCLUSION/CONCLUSIONS:Our study demonstrated that patients who received rechargeable SNM devices were more likely to require revision. Factors such as device malfunction or difficulties connecting to the device may contribute to the higher revision rates. Further studies are needed to elucidate factors affecting revision rates in SNM devices.

BACKGROUND:Female sexual dysfunction (FSD) is a prevalent and multifaceted condition affecting women's sexual well-being. This randomized controlled trial aimed to evaluate the efficacy of percutaneous tibial nerve stimulation (PTNS) compared to a validated sham control in the treatment of FSD. METHODS:We conducted a single-center randomized controlled trial. Participants with FSD were recruited and randomly assigned at a 1:1 allocation ratio to either PTNS or a validated sham control using transcutaneous nerve stimulation (TENS). Treatment was performed through weekly 30-min session for 12 weeks total. Sexual function was assessed at baseline, 6 weeks, and 12 weeks primarily using the Female Sexual Function Index (FSFI) questionnaire. Urogenital distress inventory-6 was collected to evaluate for any baseline urinary incontinence/voiding dysfunction. Linear mixed-effect models for longitudinal data were used to compare FSFI scores across different time points. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc. Cary, NC). RESULTS:In total, 34 PTNS and 31 TENS subjects were included in our final analysis. Overall, 48% (16/34) of PTNS subjects versus 29% (11/33) of TENS subjects were no longer at risk for FSD (FSFI > 26.55) after 12 weekly treatments. Both PTNS and TENS subjects demonstrated similar improvements in FSFI total scores after 12 weeks of treatments. Interestingly, patients who did not present with baseline urogenital distress symptoms reported a statistically significant larger improvement in sexual satisfaction after PTNS treatments as compared to placebo (p = 0.017). CONCLUSION/CONCLUSIONS:This study demonstrated a sustained efficacy of PTNS in improving sexual function. Specifically, patients who did not have coexisting urinary dysfunction reported significant improvement in sexual satisfaction after PTNS. Our study suggested that PTNS may have a direct neuromodulation effect on sexual dysfunction and may hold promise as a treatment modality for FSD.