Browsing by Author "Surgery, School of Medicine"

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    07. The Mechanism of NGF Signaling In Innervation-dependent Corneal Epithelial Renewal: New Topical Treatment For Neurotrophic Keratopathy
    (Wolters Kluwer, 2024-04-19) Hussain, Arif; Mirmoeini, Kaveh; Mulenga, Chilando; Crabtree, Jordan; Tajdaran, Kiana; Henrique, Mario; Blum, Noam; Shalom-Feuerstein, Ruby; Borschel, Gregory; Feinberg, Konstantin; Surgery, School of Medicine
    Background: Corneal clarity is essential for vision. Limbal stem cells (LSCs), the source of transparent corneal epithelial cells, are located in the basal epithelium of the limbus at the corneal-conjunctival interface, where they interact with corneal sensory nerves. Besides protection, corneal nerves may stimulate LSC activity. Pathological corneal denervation can lead to ulcers, scarring, and opacification due to impaired healing from repetitive wounds. This condition, termed Neurotrophic Keratopathy (NK), a major cause of corneal blindness, and lacks a definitive cure. Corneal nerves release various trophic factors that regulate epithelial renewal. Nerve growth factor (NGF) has shown positive effects on corneal healing and maintenance in vivo. Topical recombinant human NGF is the only FDA-approved treatment for NK. However, NGF is not efficacious in 30% of cases, requires very frequent dosing, and costs $100k per course. Moreover, NGF’s ability to heal corneal ulcers is limited. Prior studies showed NGF stimulates proliferation and maintenance of cultured human LSCs, which express TrkA and p75NTR receptors, but didn’t establish a link between NGF signaling and corneal sensory innervation-mediated trophic regulation of epithelial renewal. Furthermore, the role and molecular mechanism of NGF signaling in LSC activity remains unidentified. We hypothesize that NGF, locally expressed in its mature and premature (proNGF) forms, regulates LSC activity-dependent homeostatic and wound-induced corneal epithelial renewal via differential activation of its receptors TrkA and p75NTR, a process dependent on corneal sensory innervation. Methods: A) We conducted in vivo experiments in wild-type and mutant mice and rats to elucidate the NGF signaling mechanism in corneal innervation-dependent epithelial renewal. We examined the effect of combinations of TrkA and p75NTR agonists and antagonists on the healing of experimentally wounded corneas, both intact and surgically denervated. B) To understand the role and mechanism of NGF signaling in LSC activity and its relevance to humans, we assessed the clonogenicity of cultured human LSCs (hLSCs) by pharmacologically modulating NGF receptors, as described in (A). Results: A) While inactivation of TrkA completely prevents healing of normally innervated cornea, inactivation of p75NTR combined with a single daily dose of NGF induces complete and rapid healing of denervated de-epithelialized corneas. B) NGF or specific p75NTR inhibitor THX-B supported colonies’ formation by hLSCs that were further augmented by combination of the two compounds. Conclusions: Corneal sensory nerve-associated expression of NGF in its both forms (NGF and proNGF) regulates the proliferation and differentiation of LSCs by differentially stimulating the activity of the NGF receptors. Combined pharmacological activation and inhibition of TrkA and p75NTR, respectively, will be applied in the development of a superior NGF-based treatment of NK.
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    105. Long Term Surgical and Patient Reported Outcomes After Cross Face Nerve Graft Reconstruction in Pediatric Facial Paralysis
    (Wolters Kluwer, 2022) Zuo, Kevin J.; Heinelt, Martina; Ho, Emily; Borschel, Gregory; Zuker, Ronald; Surgery, School of Medicine
    Purpose: Free functioning muscle transfer is the gold standard for pediatric facial paralysis reconstruction and using the contralateral facial nerve for neurotization via a cross face nerve graft enables spontaneous smile restoration. Outcomes of pediatric facial reanimation beyond 10 years are not known, including how smiles change with aging and how adult patients report their facial function and quality of life. This study evaluated long term surgical and patient-reported outcomes for adults who underwent facial reanimation as children. Methods: This cross-sectional study enrolled patients who underwent facial reanimation with a staged cross face nerve graft and free gracilis muscle transfer as children at least 10 years ago. FACE-Gram software was used to quantify commissure excursion on frontal photographs in repose and maximal smile at three time points: preoperative, early postoperative within 2 years, and current (long term follow up). Patient-reported outcomes were evaluated quantitatively using the FaCE Scale and FACE-Q instruments for patient satisfaction, and qualitatively with semi-structured interviews. Results are reported as mean ± SD and parametric statistical analysis was performed with alpha of 0.05. Results: Eighteen patients who underwent facial reanimation as children more than 10 years ago were included (14 females, 5 males; 10 congenital, 8 acquired; age at stage 1 surgery 7.4 ± 3.6 years). Commissure excursion was measured as -1.3 ± 3.5 mm preoperatively, 5.9 ± 2.3 mm postoperatively within 2 years, and 7.6 ± 3.5 mm at long term follow up (mean 20.5 ± 6.9 years). Commissure excursion increased 7.2 ± 4.9 mm from preoperative to early postoperative time points (p<0.0001) and did not significantly increase or decrease at long term follow up (p>0.05). For patient reported outcomes, mean FaCE scale score for facial movement was 44/100 when including eyebrow function and 79/100 when excluding eyebrow function. Mean FaCE scale scores were 63/100 for eye comfort and 81/100 for social function. On the FACE-Q Satisfaction with Outcome scale, 17/18 respondents somewhat agreed or definitely agreed with the statement, “I am pleased with the result.” On the FACE-Q Social Function scale, 16/18 respondents somewhat agreed or definitely agreed with the statement, “I feel confident when I meet a new person.” Conclusions: Pediatric facial reanimation with cross face nerve grafting improves commissure excursion and this is maintained with aging. Adult patients report overall high satisfaction and social functioning. Ongoing ocular issues remains a problem for many patients, underscoring the importance of refining techniques for reanimation of the eye.
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    142. Optimization of the Murine Hindlimb Lymphedema Model
    (Wolters Kluwer, 2025-04-24) Ahmed, Shahnur; Mohan, Ganesh; Sullivan, Steven J.; Jorge, Miguel; Sinha, Mithun; Hassanein, Aladdin H.; Surgery, School of Medicine
    PURPOSE: Secondary lymphedema is limb swelling from lymphatic injury. It frequently occurs following lymph node dissection and radiation during the treatment of malignancies such as breast cancer or melanoma. The murine tail is the most commonly used model to study secondary lymphedema and involves full thickness tail skin excision and lymphatic vessel disruption. The murine hindlimb model, which has been less frequently used in the literature, offers a more clinically translatable method. However, there is inconsistency and variability, including the benefit of radiation, which have contributed to the model being less widely adapted than the tail model. The purpose of this study is to 1) optimize the murine hindlimb lymphedema to achieve consistent results and 2) assess the effect of radiation on outcome in the murine hindlimb model. METHODS: C57BL/6 mice either underwent 20 Gy irradiation of one hindlimb seven days prior to surgery (n=11) or no preoperative radiation (n=9). For all mice, a circumferential skin incision was created at the proximal hindlimb exposing the subcutaneous soft tissues. Lymphatics were identified with isosulfan blue dye injection into the paw and disrupted. Popliteal lymph nodes were excised. The skin was sutured leaving a 3 mm gap. The contralateral hindlimb served as the control. Paw thickness and calf thickness measurements were obtained at weekly intervals and indocyanine green (ICG) near-infrared laser lymphangiography was used to assess lymphatic function. RESULTS: For the irradiated mice, the average paw thickness of the operated hindlimb on postoperative day (POD) 14 was 3.5±0.3 cm compared to 2.1±0.05 cm on the contralateral limb (p=0.0001). At POD-90, the average paw thickness of the irradiated, operated hindlimb was 2.4±0.1 cm compared to 2.1±0.1 cm for the contralateral limb (p=0.01). ICG lymphangiography at 24-hours postinjection on POD-42 demonstrated an average signal intensity of 97.7±28.5 arbitrary fluorescent units (AFU) in the operated hindlimb compared to 33.6±6.2 AFU in the non-operated hindlimb (p=0.003). In the mice that did not undergo radiation, the average paw thickness was 2.5±0.2 cm on POD-42 was greater than the contralateral limb (2.1±0.1 cm) (p=0.0002) but smaller than hindlimbs that underwent radiation (3.2±0.1 cm) (p=0.0002). The nonradiated mice had greater paw thickness than the contralateral control until POD-56 whereas the radiated mice sustained significant paw thickness until Day 90. CONCLUSION: Radiation of the murine hindlimb model results in sustained lymphedema compared to non-irradiated mice. The murine hindlimb lymphedema model is clinically more translatable than the murine tail model and includes limb lymphatic vessel disruption, and popliteal lymphadenectomy and ideally radiation for consistent results with lymphedema sustained for 90 days.
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    153. Quantification of Lymphangiogenesis in Murine Lymphedema Tail Model Using Intravital Microscopy
    (Wolters Kluwer, 2023-05-19) Mohan, Ganesh; Khan, Imran; Diaz, Stephanie M.; Neumann, Colby R.; Jorge, Miguel D.; Sinha, Mithun; Gordillo, Gayle M.; Sen, Chandan K.; Hassanein, Aladdin H.; Surgery, School of Medicine
    PURPOSE: Lymphedema is limb swelling caused by lymphatic dysfunction. It occurs in 30% of patients that undergo axillary lymph node dissection in the treatment of breast cancer. There is no cure for this disease. Understanding the mechanisms of lymphatic growth will play a pivotal role in developing therapeutic strategies against these conditions. Visualization of lymphangiogenesis and functional assessment remains a challenge. Intravital two-photon microscopy (IVM) is a powerful imaging tool for investigating various biological processes in live animals. Tissue nanotransfection technology (TNT) facilitates a direct, transcutaneous non-viral vector gene delivery using a chip with nanochannel poration in a rapid (<100ms) focused electric field. TNT was used in this study to deliver the genetic cargo in the murine tail lymphedema to assess the lymphangiogenesis. The purpose of this study is to experimentally evaluate the applicability of IVM to visualize and quantify lymphatics. METHODS: The murine tail model of lymphedema was utilized. A 3 mm full thickness skin excision and lymphatic vessel disruption was performed 20 mm from the base of the tail in twelve C57BL/6 mice. TNT was applied to the murine tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: Group I (control) was given pCMV6 (expression vector backbone alone) (n=6); Group II had pCMV6-Prox1 (n=6). Post-TNT (day 10), a 3 cm segment of murine tail was deskinned distal to the site of occlusion to optimize visualization. FITC-Dextran (2000 kD) injected intradermally at the distal tail region for lymphatic uptake. Lymphatic vessels are visualized at the second skin excision site with the Leica SP8 Confocal/Multiphoton Microscope and assessed for number of branching points to determine the newly formed lymphatics. Lymphatic vessel density was also observed by immunostaining with anti-Podoplanin antibody. RESULTS: The experimental group II exhibited increased branching points (3-fold) using filamentation analysis compared to control group I at the site of TNT treatment (n=6, p<0.05). Increased lymphatic vessel density was also observed with Podoplanin immunostaining post-TNT application. Intensity quantification of immunohistochemistry revealed greater expression of Podoplanin in Group II when compared to Group I (n=6, p<0.05). CONCLUSION: This study demonstrates a novel, powerful imaging tool for investigating lymphatic vessels in live murine tail model of lymphedema. Intravital microscopy can be utilized for functional assessment of lymphatics and visualization of lymphangiogenesis following gene-based therapy.
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    177. Prophylactic Absorbable Antibiotic Beads For High Risk Implant-based Reconstruction: A Single Institution Pilot Study
    (Wolters Kluwer, 2023-05-19) Ahmed, Shahnur; Lee, Jason T. C.; Roth, Dylan D.; Liu, Steven; Fisher, Carla S.; Fan, Betty; Imeokparia, Folasade; Ludwig, Kandice; Lester, Mary E.; Hassanein, Aladdin H.; Surgery, School of Medicine
    PURPOSE: Infections are problematic in implant-based reconstruction after mastectomies. Infection rates have been reported to be as high as 31%. Strategies to reduce the risk of infection include various antibiotic irrigation solutions, “no-touch” techniques, optimizing sterility, and empiric antibiotic use for skin flora coverage. Absorbable antibiotic beads have been well described for other indications, including orthopedic and pressure sore reconstruction. The purpose of this study is to evaluate the use of prophylactic biodegradable antibiotic beads during pre-pectoral and sub-pectoral implant-based breast reconstruction following mastectomy. METHODS: A single-center retrospective review of patients who underwent implant-based breast reconstruction post-mastectomy between 2019 to 2022. Patients were divided into two groups: Group I were deemed “high risk” by the senior author and received biodegradable antibiotic beads (1 gram vancomycin, 240 mg gentamicin) during tissue expander or implant reconstruction (pre-pectoral or subpectoral) while Group II (control) had no antibiotic beads. Demographic data, diabetes, body mass index (BMI), implant plane (pre-pectoral or sub-pectoral), smoking and use of mesh were recorded. Outcome variables included postoperative cellulitis or infection requiring oral or intravenous antibiotics and tissue expander loss at 90 days. RESULTS: In our study period, 19 patients (36 total implants/expanders) received biodegradable antibiotic beads during implant-based breast reconstruction (Group I). There were 174 patients (290 total expanders) who did not receive antibiotic beads (Group II). Patients in Group I had a history of previous expander/implant infection in 73.6%. Pre-pectoral placement of implants occurred in 84.2% of patients in Group I and 74.1% in Group II. Diabetes was prevalent in 15.8% of Group I compared to 5.7% seen in Group II patients. The mean BMI in Group I was 30.5 kg/m2 compared to 27.8 kg/m2 in Group II (p-value 0.88). Implant infection rate of Group I at 90 days was 8.3% (3/36 total expanders) compared to 8.6% (25/290 total expanders) in Group II. Implant loss in Group I was 5.5% (2/26 total expanders) compared to 7.6% (22/290) in Group II. CONCLUSION: The incidence of infection in high risk patients who have absorbable antibiotic beads placed during the time of reconstruction appears to be normalized to the control group in this pilot study, suggesting that absorbable antibiotic beads may decrease postoperative infection complications. Future studies may further clarify its benefit in selected groups.
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    1H NMR-Based Metabolic Signatures in the Liver and Brain in a Rat Model of Hepatic Encephalopathy
    (ACS, 2020) Pathania, Anjana; Rawat, Atul; Dahiya, Sitender Singh; Dhanda, Saurabh; Barnwal, Ravi Pratap; Baishya, Bikash; Sandhir, Rajat; Surgery, School of Medicine
    Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication associated with acute and chronic liver failure. It is characterized by diverse symptoms with variable severity that includes cognitive and motor deficits. The aim of the study is to assess metabolic alterations in the brain and liver using nuclear magnetic resonance (NMR) spectroscopy and subsequent multivariate analyses to characterize metabolic signatures associated with HE. HE was developed by bile duct ligation (BDL) that resulted in hepatic dysfunctions and cirrhosis as shown by liver function tests. Metabolic profiles from control and BDL rats indicated increased levels of lactate, branched-chain amino acids (BCAAs), glutamate, and choline in the liver, whereas levels of glucose, phenylalanine, and pyridoxine were decreased. In brain, the levels of lactate, acetate, succinate, citrate, and malate were increased, while glucose, creatine, isoleucine, leucine, and proline levels were decreased. Furthermore, neurotransmitters such as glutamate and GABA were increased, whereas choline and myo-inositol were decreased. The alterations in neurotransmitter levels resulted in cognitive and motor defects in BDL rats. A significant correlation was found among alterations in NAA/choline, choline/creatine, and NAA/creatine with behavioral deficits. Thus, the data suggests impairment in metabolic pathways such as the tricarboxylic acid (TCA) cycle, glycolysis, and ketogenesis in the liver and brain of animals with HE. The study highlights that metabolic signatures could be potential markers to monitor HE progression and to assess therapeutic interventions.
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    A 20-year multicenter analysis of dialysis-dependent patients who had aortic or mitral valve replacement: Implications for valve selection
    (Elsevier, 2019) Manghelli, Joshua L.; Carter, Daniel I.; Khiabani, Ali J.; Gauthier, Jason M.; Moon, Marc R.; Munfakh, Nabil A.; Damiano, Ralph J.; Corvera, Joel S.; Melby, Spencer J.; Surgery, School of Medicine
    Objective Valve selection in dialysis-dependent patients can be difficult because long-term survival is diminished and bleeding risks during anticoagulation treatment are greater in patients with renal failure. In this study we analyzed long-term outcomes of dialysis-dependent patients who underwent valve replacement to help guide optimal prosthetic valve type selection. Methods Dialysis-dependent patients who underwent aortic and/or mitral valve replacement at 3 institutions over 20 years were examined. The primary outcome was long-term survival. A Cox regression model was used to estimate survival according to 5 ages, presence of diabetes, and/or heart failure symptoms. Results Four hundred twenty-three available patients were analyzed; 341 patients had biological and 82 had mechanical valves. Overall complication and 30-day mortality rates were similar between the groups. Thirty-day readmission rates for biological and mechanical groups were 15% (50/341) and 28% (23/82; P = .005). Five-year survival was 23% and 33% for the biological and mechanical groups, respectively. After adjusting for age, New York Heart Association (NYHA) class, and diabetes using a multivariable Cox regression model, survival was similar between groups (hazard ratio, 0.93; 95% confidence interval, 0.66-1.29; P = .8). A Cox regression model on the basis of age, diabetes, and heart failure, estimated that patients only 30 or 40 years old, with NYHA class I-II failure without diabetes had a >50% estimated 5-year survival (P < .001). Conclusions Dialysis-dependent patients who underwent valve replacement surgery had poor long-term survival. Young patients without diabetes or NYHA III or IV symptoms might survive long enough to justify placement of a mechanical valve; however, a biological valve is suitable for most patients.
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    2020 Women in Thoracic Surgery update on the status of women in cardiothoracic surgery
    (Elsevier, 2020) Ceppa, DuyKhanh P.; Antonoff, Mara B.; Tong, Betty C.; Timsina, Lava; Ikonomidis, John S.; Worrell, Stephanie G.; Stephens, Elizabeth H.; Gillaspie, Erin A.; Schumacher, Lana; Molena, Daniela; Kane, Lauren C.; Blackmon, Shanda; Donington, Jessica S.; Surgery, School of Medicine
    Background Women in Thoracic Surgery (WTS) has previously reported on the status of women in cardiothoracic (CT) surgery. We sought to provide a 10-year update on women in CT. Methods An anonymous REDCap survey link was emailed to female diplomats of the ABTS. Survey questions queried respondents regarding demographics, training, accolades, practice details, and career satisfaction. The survey link was open for 30 days. Results were compared to the 2019 Society of Thoracic Surgeons work force survey. Descriptive analyses were performed using frequency and proportions. Comparisons were performed using Student’s t-tests, Fisher exact and chi-squared tests. Results Of 354 female diplomats, 309 were contacted and 176 (57%) responded. The majority of respondents were age 36-50 (59%), Caucasian (67.4%), and graduated from traditional-track programs (91.4%). Most respondents reported practicing in an urban (64%) and academic setting (73.1%). 36.4% and 23.9% reported a general thoracic and adult cardiac practice (22.7% mixed practice, 9.6% congenital). Fifty percent of respondents reported salaries between $400,000-700,000 annually; 37.7% reported salaries <90% of their male colleagues. 21.6% of respondents in academia are full professor; 53.4% report having a leadership role. While 74.1% would pursue a career in CT again, only 27.3% agreed that CT surgery is a healthy and positive environment for women. Conclusions The number of women in CT surgery has steadily increased. While women are rising in academic rank and into leadership positions, salary disparities and the CT surgery work environment remain important issues in achieving a diverse work force.
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    217 The impact of preoperative glucagon-like peptide-1 receptor agonists (GLP1) utilization on bariatric surgery outcomes
    (Cambridge University Press, 2025-04-11) Yuce, Tarik; AbuHasan, Qais; Kpormegbey, Daniel E.; Funk, Luke M.; Allison, David B.; Holl, Jane L.; Stefanidis, Dimitrios; Surgery, School of Medicine
    Objectives/Goals: Glucagon-like peptide-1 (GLP1) use prior to bariatric surgery may represent a novel approach to treating obesity. The objectives of this study were to describe trends in pre-bariatric GLP1 use, investigate social and clinical factors associated with their use, and evaluate differences in clinical outcomes based on preoperative GLP1RA use. Methods/Study Population: Patients who underwent bariatric surgery at three Indiana hospitals from 2018 to 2023 were identified. Patients who utilized GLP1 in the year preceding surgery were compared to those who did not. Social determinants of health included insurance, income, and unemployment. Outcomes included rates of GLP1 use, 30-day postoperative readmissions, ED visits, and percent total weight lost (%TWL) at one year. Associations between preoperative GLP1 use and outcomes of interest were evaluated using multivariable logistic and linear regressions. Results/Anticipated Results: Of 2,169 patients who underwent surgery, 293 (13.5%) utilized GLP1 preoperatively. The rate of GLP1 utilization increased threefold from 2018 to 2023. Males were more likely to receive preoperative GLP1 (20.1% vs, 12.2%, p<0.001). There were no significant differences in social determinants of health or 30-day postoperative outcomes between patients who did and did not use GLP1RA preoperatively. Similarly, there were no significant differences in %TWL at one year postoperatively between groups (median 25.5% vs. 27.3%, coefficient: -0.78, 95%CI: -2.26–0.70). Discussion/Significance of Impact: Utilization of GLP1 in the year prior to bariatric surgery has significantly increased. Preoperative GLP1 use is not associated with worse 30-day outcomes or differences in %TWL at one year postoperatively. Further work is needed to evaluate whether GLP1 dosing and duration of treatment impact postoperative outcomes.
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    23rd Annual Meeting of the American Society of Breast Surgeons: Back to In-Person Scientific Exploration
    (Springer, 2022) Fisher, Carla S.; Teshome, Mediget; Blair, Sarah L.; Surgery, School of Medicine