Medicine and Health Sciences Commons^™

Emerging Cell And Molecular Targets For Treating Mucus Hypersecretion In Asthma, Ana M Jaramillo, Eszter K Vladar, Fernando Holguin, Burton F Dickey, Christopher M Evans

Faculty, Staff and Student Publications

Mucus provides a protective barrier that is crucial for host defense in the lungs. However, excessive or abnormal mucus can have pathophysiological consequences in many pulmonary diseases, including asthma. Patients with asthma are treated with agents that relax airway smooth muscle and reduce airway inflammation, but responses are often inadequate. In part, this is due to the inability of existing therapeutic agents to directly target mucus. Accordingly, there is a critical need to better understand how mucus hypersecretion and airway plugging are affected by the epithelial cells that synthesize, secrete, and transport mucus components. This review highlights recent advances in …

Cholesterol-Dependent Lxr Transcription Factor Activity Represses Pronociceptive Effects Of Estrogen In Sensory Neurons And Pain Induced By Myelin Basic Protein Fragments, Swathi K Hullugundi, Jennifer Dolkas, Andrei V Chernov, Tony L Yaksh, Kelly A Eddinger, Mila Angert, Glaucilene Ferreira Catroli, Alex Y Strongin, Patrick M Dougherty, Yan Li, Oswal Quehenberger, Aaron Armando, Veronica I Shubayev

Faculty, Staff and Student Publications

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP

METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP

RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP

CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of …

Effects Of Vitamin D Supplementation On A Deep Learning-Based Mammographic Evaluation In Swog S0812, Julia E Mcguinness, Garnet L Anderson, Simukayi Mutasa, Dawn L Hershman, Mary Beth Terry, Parisa Tehranifar, Danika L Lew, Monica Yee, Eric A Brown, Sebastien S Kairouz, Nafisa Kuwajerwala, Therese B Bevers, John E Doster, Corrine Zarwan, Laura Kruper, Lori M Minasian, Leslie Ford, Banu Arun, Marian L Neuhouser, Gary E Goodman, Powel H Brown, Richard Ha, Katherine D Crew

Faculty, Staff and Student Publications

Deep learning-based mammographic evaluations could noninvasively assess response to breast cancer chemoprevention. We evaluated change in a convolutional neural network-based breast cancer risk model applied to mammograms among women enrolled in SWOG S0812, which randomly assigned 208 premenopausal high-risk women to receive oral vitamin D3 20 000 IU weekly or placebo for 12 months. We applied the convolutional neural network model to mammograms collected at baseline (n = 109), 12 months (n = 97), and 24 months (n = 67) and compared changes in convolutional neural network-based risk score between treatment groups. Change in convolutional neural network-based risk score was …

Valine Aminoacyl-Trna Synthetase Promotes Therapy Resistance In Melanoma, Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, Pierre-René Körner, Coralie Capron, Lorena Martin-Morales, Patrick Roncarati, Arnaud Lavergne, Arnaud Blomme, Silvia Turchetto, Eric Goffin, Palaniraja Thandapani, Ivan Tarassov, Laurent Nguyen, Bernard Pirotte, Alain Chariot, Jean-Christophe Marine, Michael Herfs, Francesca Rapino, Reuven Agami, Pierre Close

Faculty, Staff and Student Publications

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Neighborhood-Level Social Determinants Of Health Burden Among Adolescent And Young Adult Cancer Patients And Impact On Overall Survival, Elizabeth R Rodriguez, Tori Tonn, Midhat Jafry, Sairah Ahmed, Branko Cuglievan, J Andrew Livingston, Christopher R Flowers, Gregory J Aune, Karen H Albritton, Michael E Roth, Qian Xiao, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

BACKGROUND: Neighborhood socioeconomic deprivation has been linked to adverse health outcomes, yet it is unclear whether neighborhood-level social determinants of health (SDOH) measures affect overall survival in adolescent and young adult patients with cancer.

METHODS: This study used a diverse cohort of adolescent and young adult patients with cancer (N = 10 261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI values representing worse SDOH.

RESULTS: ADI was statistically significantly worse (P < .050) for Black (61.7) and Hispanic (65.3) patients than for White patients (51.2). Analysis of ADI by cancer type showed statistically significant differences, mainly driven by worse ADI in patients with cervical cancer (62.3) than with other cancers. In multivariable models including sex, age at diagnosis, cancer diagnosis, and race and ethnicity, risk of shorter survival for people residing in neighborhoods with the least favorable ADI quartile was greater than for individuals in the most favorable ADI quartile (hazard ratio = 1.09, 95% confidence interval = 1.00 to 1.19, P = .043).

CONCLUSION: Adolescent and young adult patients with cancer and the worst ADI …

Polatuzumab Vedotin, Venetoclax, And An Anti-Cd20 Monoclonal Antibody In Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma, Sam Yuen, Tycel J Phillips, Rajat Bannerji, Paula Marlton, Giuseppe Gritti, John F Seymour, Anna Johnston, Christopher Arthur, Anna Dodero, Sunil Sharma, Jamie Hirata, Lisa Musick, Christopher R Flowers

Faculty, Staff and Student Publications

The Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed-dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21-day cycles) received post-induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety-evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months …

Cone-Beam Ct With A Noncircular (Sine-On-Sphere) Orbit: Imaging Performance Of A Clinical System For Image-Guided Interventions, A Kyle Jones, Moiz Ahmad, Shaan M Raza, Stephen R Chen, Jeffrey H Siewerdsen

Faculty, Staff and Student Publications

Purpose: We aim to compare the imaging performance of a cone-beam CT (CBCT) imaging system with noncircular scan protocols (sine-on-sphere) to a conventional circular orbit.

Approach: A biplane C-arm system (ARTIS Icono; Siemens Healthineers) capable of circular and noncircular CBCT acquisition was used, with the latter orbit (sine-on-sphere, "Sine Spin") executing a sinusoidal motion with ±10deg tilt amplitude over the half-scan orbit. A test phantom was used for the characterization of image uniformity, noise, noise-power spectrum (NPS), spatial resolution [modulation transfer function (MTF) in axial and oblique directions], and cone-beam artifacts. Findings were interpreted using an anthropomorphic head phantom with …

Lacrimal Gland Adenocarcinoma Clinicopathologic Features And Outcomes Compared With Those Of Lacrimal Gland Adenoid Cystic Carcinoma, Hila Goldberg, Xinyang Jiang, Janet Fan, Jiawei Zhao, Jing Ning, Michelle Williams, Steven Frank, Amy Moreno, Brandon Gunn, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

Purpose: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC).

Methods: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed.

Results: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All …

50-Nm Gas-Filled Protein Nanostructures To Enable The Access Of Lymphatic Cells By Ultrasound Technologies, Qionghua Shen, Zongru Li, Yixian Wang, Matthew D Meyer, Marc T De Guzman, Janie C Lim, Han Xiao, Richard R Bouchard, George J Lu

Faculty, Staff and Student Publications

Ultrasound imaging and ultrasound-mediated gene and drug delivery are rapidly advancing diagnostic and therapeutic methods; however, their use is often limited by the need for microbubbles, which cannot transverse many biological barriers due to their large size. Here, the authors introduce 50-nm gas-filled protein nanostructures derived from genetically engineered gas vesicles(GVs) that are referred to as

Evolving Horizons In Radiation Therapy Auto-Contouring: Distilling Insights, Embracing Data-Centric Frameworks, And Moving Beyond Geometric Quantification, Kareem A Wahid, Carlos E Cardenas, Barbara Marquez, Tucker J Netherton, Benjamin H Kann, Laurence E Court, Renjie He, Mohamed A Naser, Amy C Moreno, Clifton D Fuller, David Fuentes

Faculty, Staff and Student Publications

Historically, clinician-derived contouring of tumors and healthy tissues has been crucial for radiation therapy (RT) planning. In recent years, advances in artificial intelligence (AI), predominantly in deep learning (DL), have rapidly improved automated contouring for RT applications, particularly for routine organs-at-risk.1, 2, 3 Despite research efforts actively promoting its broader acceptance, clinical adoption of auto-contouring is not yet standard practice.

Notably, within several AI communities, there has been growing enthusiasm to shift from conventional “model-centric” AI approaches (ie, improving a model while keeping the data fixed), to “data-centric” AI approaches (ie, improving the data while keeping a …

Impact Of Lifetime Stressor Exposure On Neuroenergetics In Schizophrenia Spectrum Disorders, Joshua Chiappelli, Anya Savransky, Yizhou Ma, Si Gao, Mark D Kvarta, Peter Kochunov, George M Slavich, L Elliot Hong

Faculty, Staff and Student Publications

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of …

Paying A Heavy Price: Costs Of Care For People With Severe Obesity In Nursing Homes, Luisa Fernandez, Bianca Shieu, Alison Trinkoff, Nicholas Castle, David G Wolf, Steven Handler, John A Harris

Faculty, Staff and Student Publications

Background and objectives: The prevalence of resident obesity in nursing homes has increased dramatically from 22% to 28% between 2005 and 2015. To provide care for people with obesity, nursing homes have changed their admissions, staffing, and equipment, but underlying these changes are increased resources and financial costs of care. The purpose of this study is to describe nursing home organizational aspects of caring for older adults with obesity, with a focus on economic factors, from the perspective of nursing home staff and leadership.

Research design and methods: This qualitative study used descriptive approaches; data were collected through semistructured telephone …

The Multifaceted Life Of Macrophages In White Adipose Tissue: Immune Shift Couples With Metabolic Switch, Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We …

Plozasiran (Aro-Apoc3) For Severe Hypertriglyceridemia: The Shasta-2 Randomized Clinical Trial, Daniel Gaudet, Denes Pall, Gerald F Watts, Stephen J Nicholls, Robert S Rosenson, Karen Modesto, Javier San Martin, Jennifer Hellawell, Christie M Ballantyne

Faculty, Staff and Students Publications

Importance: Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains.

Objective: To determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering-RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG.

Design, setting, and participants: The Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 …

Should The Incretin Hype Be The Same For Older Adults: Promise + Cautions, John A Batsis, Kathryn N Porter Starr, Dennis T Villareal

Faculty, Staff and Students Publications

No abstract provided.

Liver Disease And Transplantation In Telomere Biology Disorders: An International Multicenter Cohort, Yunzu Michele Wang, Batul Kaj-Carbaidwala, Adam Lane, Suneet Agarwal, Fabian Beier, Alison Bertuch, Kristin A Borovsky, Steven K Brennan, Rodrigo T Calado, Luiz Fernando B Catto, Carlo Dufour, Christen L Ebens, Francesca Fioredda, Neelam Giri, Nicholas Gloude, Frederick Goldman, Paula M Hertel, Ryan Himes, Sioban B Keel, Divya T Koura, Christian P Kratz, Sakil Kulkarni, Iris Liou, Taizo A Nakano, Silvia Nastasio, Marena R Niewisch, Daniel D Penrice, Ghadir S Sasa, Sharon A Savage, Douglas A Simonetto, David S Ziegler, Alexander G Miethke, Kasiani C Myers

Faculty, Staff and Students Publications

Background: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes.

Methods: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study.

Results: Group A ("Advanced") included 40 patients with advanced liver disease. Of …

Evaluation Of Tibial Slope On Radiographs In Pediatric Patients With Tibial Spine Fractures: An Age- And Sex-Matched Study, Chang Ho Shin, Akbar N Syed, Morgan E Swanson, Indranil V Kushare, Kevin G Shea, Asteroid, Theodore J Ganley, Soroush Baghdadi, Aristides I Cruz, Henry B Ellis, Peter D Fabricant, Theodore J Ganley, Daniel W Green, Alicia Kerrigan, Julia Kirby, Mininder Kocher, Indranil V Kushare, R Jay Lee, James P Macdonald, Scott D Mckay, Shital N Parikh, Neeraj M Patel, Yi-Meng Yen, Gregory A Schmale, Kevin G Shea, R Justin Mistovich

Faculty, Staff and Students Publications

BACKGROUND: A recent study has reported that the radiographic measurement of posterior tibial slope (PTS) is larger in male pediatric patients with tibial spine fractures (TSF) than in controls. However, they found no difference in PTS between female patients and controls.

PURPOSE: (1) To identify whether PTS is larger in female pediatric patients with TSF than in female controls and (2) to validate the relationship between PTS and pediatric TSF in male patients.

STUDY DESIGN: Cross-sectional study; Level of evidence, 3.

METHODS: After an a priori power analysis, 84 pediatric patients with TSF (50 female patients and 34 male patients) …

Anticoagulant Medications: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation Collaborative Consensus Conference, Katherine Cashen, Arun Saini, Leonardo R Brandão, Jennifer Le, Paul Monagle, Katie M Moynihan, Lindsay M Ryerson, Alison Gehred, Elizabeth Lyman, Jennifer A Muszynski, Peta M A Alexander, Heidi J Dalton

Faculty, Staff and Students Publications

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE).

DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

STUDY SELECTION: Included studies assessed anticoagulation used in pediatric ECMO.

DATA EXTRACTION: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form.

DATA SYNTHESIS: …

Priorities For Clinical Research In Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation Collaborative Consensus Conference, Jennifer A Muszynski, Melania M Bembea, Alison Gehred, Elizabeth Lyman, Katherine Cashen, Ira M Cheifetz, Heidi J Dalton, Adam S Himebauch, Oliver Karam, Katie M Moynihan, Marianne E Nellis, Caroline Ozment, Lakshmi Raman, Natalie E Rintoul, Ahmed Said, Arun Saini, Marie E Steiner, Ravi R Thiagarajan, Kevin Watt, Ariane Willems, Nicole D Zantek, Ryan P Barbaro, Katherine Steffen, Adam M Vogel, Peta M A Alexander

Faculty, Staff and Students Publications

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus.

DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children.

STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children.

DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third …

Gene Expression Networks Regulated By Human Personality, Coral Del Val, Elisa Díaz De La Guardia-Bolívar, Igor Zwir, Pashupati P Mishra, Alberto Mesa, Ramiro Salas, Guillermo F Poblete, Gabriel De Erausquin, Emma Raitoharju, Mika Kähönen, Olli Raitakari, Liisa Keltikangas-Järvinen, Terho Lehtimäki, Claude Robert Cloninger

Faculty, Staff and Students Publications

Genome-wide association studies of human personality have been carried out, but transcription of the whole genome has not been studied in relation to personality in humans. We collected genome-wide expression profiles of adults to characterize the regulation of expression and function in genes related to human personality. We devised an innovative multi-omic approach to network analysis to identify the key control elements and interactions in multi-modular networks. We identified sets of transcribed genes that were co-expressed in specific brain regions with genes known to be associated with personality. Then we identified the minimum networks for the co-localized genes using bioinformatic …

Multicenter Analysis Of Valganciclovir Prophylaxis In Pediatric Solid Organ Transplant Recipients, Marc Foca, Salih Demirhan, Flor M Munoz, Kristen G Valencia Deray, Claire E Bocchini, Tanvi S Sharma, Gilad Sherman, William J Muller, Taylor Heald-Sargent, Lara Danziger-Isakov, Samantha Blum, Juri Boguniewicz, Samantha Bacon, Tuhina Joseph, Jodi Smith, Monica I Ardura, Yin Su, Gabriela M Maron, Jose Ferrolino, Betsy C Herold

Faculty, Staff and Students Publications

BACKGROUND: Valganciclovir is the only approved antiviral for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation (SOT). Additional approaches may be needed to improve outcomes.

METHODS: A multicenter retrospective study from 2016 to 2019 was conducted of pediatric SOT recipients in whom at least 3 months of valganciclovir prophylaxis was planned. Episodes of CMV DNA in blood (DNAemia), CMV disease, drug-related toxicities, as well as other infections in the first year posttransplant and demographic and clinical data were collected. CMV DNAemia in the first year after prophylaxis or during prophylaxis (breakthrough) was analyzed by multivariate hazard models.

RESULTS: Among the …

Mechanisms Of Gelofusine Protection In An In Vitro Model Of Polymyxin B-Associated Renal Injury, Cole S Hudson, Anirban Roy, Qingtian Li, Aniket S Joshi, Taijun Yin, Ashok Kumar, David Sheikh-Hamad, Vincent H Tam

Faculty, Staff and Students Publications

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was …

Gender And Emergency Physicians’ Experiences Of Leading Decision Making About Restraint Use: A Qualitative Study, Anita Chary, Beatrice Torres, Elise Brickhouse, Datonye Charles, Ynhi Thomas, Michelle Suh

Faculty, Staff and Students Publications

No abstract provided.

Optimizing Sexual Reproductive Health Of Men And Women With Cystic Fibrosis: A Systematic Review, Anand G Iyer, Benjamin Yu, Amit Reddy, Mohit Khera

Faculty, Staff and Students Publications

This systematic review summarizes the impact of cystic fibrosis (CF) on sexual and reproductive health (SRH) in males and females, covering pubertal development, hormonal function, family planning, and fertility. Included articles featured historical CF diagnostic criteria, preclinical or clinical data (retrospective cohorts or open label trials), while excluded articles lacked full text availability, explicit methodology, or comparisons between CF and non-CF patients. Genotype differences in CFTR mutations influenced symptom severity. Males with CF experienced delayed puberty, hypogonadism, infertility from obstructive azoospermia, and semen parameter issues. Female CF patients showed decreased fertility, possibly linked to disrupted ionic balance and ovarian cystic …

An Electronic Health Record Model For Predicting Risk Of Hepatic Fibrosis In Primary Care Patients, Aaron P Thrift, Theresa H Nguyen Wenker, Kyler Godwin, Maya Balakrishnan, Hao T Duong, Rohit Loomba, Fasiha Kanwal, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND: One challenge for primary care providers caring for patients with nonalcoholic fatty liver disease is to identify those at the highest risk for clinically significant liver disease.

AIM: To derive a risk stratification tool using variables from structured electronic health record (EHR) data for use in populations which are disproportionately affected with obesity and diabetes.

METHODS: We used data from 344 participants who underwent Fibroscan examination to measure liver fat and liver stiffness measurement [LSM]. Using two approaches, multivariable logistic regression and random forest classification, we assessed risk factors for any hepatic fibrosis (LSM > 7 kPa) and significant hepatic …

Epigenetic Activation Of Sox11 Is Associated With Recurrence And Progression Of Ductal Carcinoma In Situ To Invasive Breast Cancer, Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin Wong, Farah A Ladha, Tristian Nguyen, Brian Menegaz, Wei Lu, Fei Yang, Barbara Mino, Ximing Tang, Mihai Gagea, Harsh Batra, Maria Gabriela Raso, Ignacio I Wistuba, Savitri Krishnamurthy, Sarah E Pinder, Elinor J Sawyer, Alastair M Thompson, Subrata Sen

Faculty, Staff and Student Publications

Background: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.

Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.

Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. …

Post-Trial Responsibilities In Pragmatic Clinical Trials: Fulfilling The Promise Of Research To Drive Real-World Change, Stephanie R Morain, P Pearl O'Rourke, Joseph Ali, Vasiliki Rahimzadeh, Devon K Check, Hayden B Bosworth, Jeremy Sugarman

Center for Medical Ethics and Health Policy Staff Publications

While considerable scholarship has explored responsibilities owed to research participants at the conclusion of explanatory clinical trials, no guidance exists regarding responsibilities owed at the conclusion of a pragmatic clinical trial (PCT). Yet post-trial responsibilities in PCTs present distinct considerations from those emphasized in existing guidance and prior scholarship. Among these considerations include the responsibilities of the healthcare delivery systems in which PCTs are embedded, and decisions about implementation for interventions that demonstrate meaningful benefit following their integration into usual care settings-or deimplementation for those that fail to do so. In this article, we present an overview of prior scholarship …

Clinical Exome Sequencing Uncovers Genetic Disorders In Neonates With Suspected Hypoxic-Ischemic Encephalopathy: A Retrospective Analysis, Christian M Parobek, Roni Zemet, Matthew A Shanahan, Brian A Burnett, Elizabeth Mizerik, Jill A Rosenfeld, Liesbeth Vossaert, Steven L Clark, Jill V Hunter, Seema R Lalani

Faculty, Staff and Students Publications

Hypoxic-ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014-2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic-ischemic injury. Of 24 patients …

Whole-Transcriptome Sequencing-Based Profiling Of The Cutaneous Virome In Patients With Secondary Immunodeficiency, Leila Youssefian, Amir Hossein Saeidian, Zahra Saffarian, Mona Ariamanesh, Fahimeh Abdollahimajd, Sara Molkara, Mohammad Shahidi-Dadras, Reem Diab, Fatemeh Vahidnezhad, Sirous Zeinali, Vivien Béziat, Emmanuelle Jouanguy, Jean-Laurent Casanova, Jouni Uitto, Hassan Vahidnezhad

Faculty, Staff and Students Publications

Most viral infections can be self-limited, with no requirement for medical intervention. However, the same viruses can cause severe diseases in patients with compromised immunity due to single-gene diseases, acquired immune deficiency syndrome, or hematologic malignancies or those receiving immunosuppressive drugs. Occasionally, these immunocompromised patients harbor >1 infectious agent, requiring several concomitant diagnostic tests. We have developed, to our knowledge, a previously unreported whole-transcriptome sequencing-based pipeline that allows virome profiling, quantitation, and expression pattern analysis of 926 distinct viruses by sequencing of RNA isolated from a single lesional skin biopsy. This pipeline can also explore host genetics if there is …