Medical Specialties Commons^™

Contrast-Enhanced Magnetic Resonance Imaging Based Calf Muscle Perfusion And Machine Learning In Peripheral Artery Disease, Bijen Khagi, Tatiana Belousova, Christina M Short, Addison A Taylor, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

Peripheral artery disease (PAD) remains underdiagnosed and undertreated and is associated with an increased risk for adverse cardiovascular outcomes. Imaging provides an approach to identifying patients with PAD. However, the role of integrating imaging with machine learning to identify PAD patients and potentially assess disease severity remains understudied. A total of 56 participants, including 36 PAD patients with intermittent claudication and 20 matched controls, underwent contrast-enhanced magnetic resonance imaging (CE-MRI) calf muscle perfusion scanning. CE-MRI-derived dynamic muscle perfusion maps were developed to quantify alterations of the microvascular circulation in the calf muscles based on voxel contrast enhancement. These dynamic muscle …

Neuronal Network Activation Induced By Forniceal Deep Brain Stimulation In Mice, Bin Tang, Zhenyu Wu, Qi Wang, Jianrong Tang

Faculty, Staff and Students Publications

Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry …

Motor Pool Selectivity Of Neuromuscular Degeneration In Type I Spinal Muscular Atrophy Is Conserved Between Human And Mouse, Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson

Faculty, Staff and Students Publications

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support …

Efficacy Of Zenocutuzumab In Nrg1 Fusion-Positive Cancer, Alison M Schram, Koichi Goto, Dong-Wan Kim, Teresa Macarulla, Antoine Hollebecque, Eileen M O'Reilly, Sai-Hong Ignatius Ou, Jordi Rodon, Sun Young Rha, Kazumi Nishino, Michaël Duruisseaux, Joon Oh Park, Cindy Neuzillet, Stephen V Liu, Benjamin A Weinberg, James M Cleary, Emiliano Calvo, Kumiko Umemoto, Misako Nagasaka, Christoph Springfeld, Tanios Bekaii-Saab, Grainne M O'Kane, Frans Opdam, Kim A Reiss, Andrew K Joe, Ernesto Wasserman, Viktoriya Stalbovskaya, Jim Ford, Shola Adeyemi, Lokesh Jain, Shekeab Jauhari, Alexander Drilon, Enrgy Investigators

Faculty, Staff and Student Publications

Background: Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion-positive solid tumors are unclear.

Methods: In this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion-positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall …

Differentiating Between Renal Medullary And Clear Cell Renal Carcinoma With A Machine Learning Radiomics Approach, Rahim Jiwani, Koustav Pal, Iwan Paolucci, Bruno Odisio, Kristy Brock, Nizar M Tannir, Daniel D Shapiro, Pavlos Msaouel, Rahul A Sheth

Faculty, Staff and Student Publications

Background: The objective of this study was to develop and validate a radiomics-based machine learning (ML) model to differentiate between renal medullary carcinoma (RMC) and clear cell renal carcinoma (ccRCC).

Methods: This retrospective Institutional Review Board -approved study analyzed CT images and clinical data from patients with RMC (n = 87) and ccRCC (n = 93). Patients without contrast-enhanced CT scans obtained before nephrectomy were excluded. A standard volumetric software package (MIM 7.1.4, MIM Software Inc.) was used for contouring, after which 949 radiomics features were extracted with PyRadiomics 3.1.0. Radiomics analysis was then performed with RadAR for differential radiomics …

Bi-Allelic Kics2 Mutations Impair Kicstor Complex-Mediated Mtorc1 Regulation, Causing Intellectual Disability And Epilepsy, Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack

Faculty, Staff and Students Publications

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and …

Dna-Binding Affinity And Specificity Determine The Phenotypic Diversity In Bcl11b-Related Disorders, Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar De La Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Undiagnosed Diseases Network, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel

Faculty, Staff and Students Publications

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. …

Acute Mecp2 Loss In Adult Mice Reveals Transcriptional And Chromatin Changes That Precede Neurological Dysfunction And Inform Pathogenesis, Sameer S Bajikar, Jian Zhou, Ryan O'Hara, Harini P Tirumala, Mark A Durham, Alexander J Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari Krishna Yalamanchili, Ying-Wooi Wan, Laura A Banaszynski, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we …

Neutralizing Antibody Immune Correlates For A Recombinant Protein Vaccine In The Covail Trial, Youyi Fong, Lauren Dang, Bo Zhang, Jonathan Fintzi, Shiyu Chen, Jing Wang, Nadine G Rouphael, Angela R Branche, David J Diemert, Ann R Falsey, Cecilia Losada, Lindsey R Baden, Sharon E Frey, Jennifer A Whitaker, Susan J Little, Satoshi Kamidani, Emmanuel B Walter, Richard M Novak, Richard Rupp, Lisa A Jackson, Chenchen Yu, Craig A Magaret, Cindy Molitor, Bhavesh Borate, Tara M Babu, Angelica C Kottkamp, Anne F Luetkemeyer, Lilly C Immergluck, Rachel M Presti, Martín Bäcker, Patricia L Winokur, Siham M Mahgoub, Paul A Goepfert, Dahlene N Fusco, Robert L Atmar, Christine M Posavad, Jinjian Mu, Mat Makowski, Mamodikoe K Makhene, Seema U Nayak, Paul C Roberts, Dean Follmann, Peter B Gilbert

Faculty, Staff and Students Publications

For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Targeting Tiam1 Enhances Hippocampal-Dependent Learning And Memory In The Adult Brain And Promotes Nmda Receptor-Mediated Synaptic Plasticity And Function, Francisco A Blanco, Md Ali Bin Saifullah, Jinxuan X Cheng, Carlota Abella, Federico Scala, Karen Firozi, Sanyong Niu, Jin Park, Jeannie Chin, Kimberley F Tolias

Faculty, Staff and Students Publications

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO) and assessed …

Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis In The Management Of Intermediate-Risk Pulmonary Embolism: Primary Results Of The Peerless Randomized Controlled Trial, Wissam Jaber, Carin Gonsalves, Stefan Stortecky, Samuel Horr, Orestis Pappas, Ripal Gandhi, Keith Pereira, Jay Giri, Sameer Khandhar, Khawaja Afzal Ammar, David Lasorda, Brian Stegman, Lucas Busch, David Dexter, Ezana Azene, Nikhil Daga, Fakhir Elmasri, Chandra Kunavarapu, Mark Rea, Joseph Rossi, Joseph Campbell, Jonathan Lindquist, Adam Raskin, Jason Smith, Thomas Tamlyn, Gabriel Hernandez, Parth Rali, Torrey Schmidt, Jeffrey Bruckel, Juan Camacho, Jun Li, Samy Selim, Catalin Toma, Sukhdeep Singh Basra, Brian Bergmark, Bhavraj Khalsa, David Zlotnick, Jordan Castle, David O'Connor, C. Michael Gibson

Department of Radiology Faculty Papers

BACKGROUND: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

METHODS: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to …

Infection-Related Hospitalization And Incident Heart Failure: The Atherosclerosis Risk In Communities Study, Rebecca L Molinsky, Amil Shah, Melana Yuzefpolskaya, Bing Yu, Jeffrey R Misialek, Bruno Bohn, David Vock, Richard Maclehose, Barry A Borlaug, Paolo C Colombo, Chiadi E Ndumele, Junichi Ishigami, Kunihiro Matsushita, Pamela L Lutsey, Ryan T Demmer

Faculty, Staff and Student Publications

Background: The immune response to infections may become dysregulated and promote myocardial damage contributing to heart failure (HF). We examined the relationship between infection-related hospitalization (IRH) and HF, HF with preserved ejection fraction, and HF with reduced ejection fraction.

Methods and results: We studied 14 468 adults aged 45 to 64 years in the ARIC (Atherosclerosis Risk in Communities) Study who were HF free at visit 1 (1987-1989). IRH was identified using select International Classification of Diseases (ICD) codes in hospital discharge records and was treated as a time-varying exposure. HF incidence was defined as the first occurrence …

Immunogenicity And Reactogenicity Of High- Or Standard-Dose Influenza Vaccine In A Second Consecutive Influenza Season., Hannah Bahakel, Andrew J. Spieker, Haya Hayek, Jennifer E. Schuster, Lubna Hamdan, Daniel E. Dulek, Carrie L. Kitko, Tess Stopczynski, Einas Batarseh, Zaid Haddadin, Laura S. Stewart, Anna Stahl, Molly Potter, Herdi Rahman, Justin Amarin, Spyros A. Kalams, Claire E. Bocchini, Elizabeth A. Moulton, Susan E. Coffin, Monica I. Ardura, Rachel L. Wattier, Gabriela Maron, Michael Grimley, Grant Paulsen, Christopher J. Harrison, Jason Freedman, Paul A. Carpenter, Janet A. Englund, Flor M. Munoz, Lara Danziger-Isakov, Natasha Halasa, Pediatric Hct Flu Study

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Pediatric hematopoietic cell transplant (HCT) recipients are at high risk for morbidity from influenza virus infection. We demonstrated in a primary phase 2 randomized controlled trial that 2 post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given 4 weeks apart were more immunogenic than 2 doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present the immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen.

METHODS: A subcohort of study participants reenrolled and had hemagglutinin inhibition titers measured at baseline and 4 weeks after each vaccine dose in year 2. We estimated …

Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis In The Management Of Intermediate-Risk Pulmonary Embolism: Primary Results Of The Peerless Randomized Controlled Trial, Wissam A Jaber, Carin F Gonsalves, Stefan Stortecky, Samuel Horr, Orestis Pappas, Ripal T Gandhi, Keith Pereira, Jay Giri, Sameer J Khandhar, Khawaja Afzal Ammar, David M Lasorda, Brian Stegman, Lucas Busch, David J Dexter, Ezana M Azene, Nikhil Daga, Fakhir Elmasri, Chandra R Kunavarapu, Mark E Rea, Joseph S Rossi, Joseph Campbell, Jonathan Lindquist, Adam Raskin, Jason C Smith, Thomas M Tamlyn, Gabriel A Hernandez, Parth Rali, Torrey R Schmidt, Jeffrey T Bruckel, Juan C Camacho, Jun Li, Samy Selim, Catalin Toma, Sukhdeep Singh Basra, Brian A Bergmark, Bhavraj Khalsa, David M Zlotnick, Jordan Castle, David J O'Connor, C Michael Gibson, Peerless Committees And Investigators

Faculty, Staff and Student Publications

Background: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

Methods: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to …

Estrogen Receptor-Α Ablation Reverses Muscle Fibrosis And Inguinal Hernias, Tanvi Potluri, Tianming You, Ping Yin, John Coon, Jonah J Stulberg, Yang Dai, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun

Faculty, Staff and Student Publications

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with …

A Randomized, Double-Blind, Placebo-Controlled Trial Of Il-7 In Critically Ill Patients With Covid-19, Manu Shankar-Hari, Bruno Francois, Kenneth E Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S Martin, Nitin J Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel Van Den Brink, Richard Hotchkiss

Faculty, Staff and Student Publications

Background: Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.

Methods: We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including …

Theranostic Nanoemulsions Suppress Macrophage-Mediated Acute Inflammation In Rats, Riddhi Vichare, Yalcin Kulahci, Rebecca Mccallin, Fatih Zor, Fatma Nurefsan Selek, Lu Liu, Caitlin Crelli, Anneliese Troidle, Michele Herneisey, James M Nichols, Andrew J Shepherd, Vijay S Gorantla, Jelena M Janjic

Faculty, Staff and Student Publications

In inflammatory diseases or following an injury, dysregulated inflammation is a common driver of pain and tissue damage. Macrophages are immune cells that contribute to the initiation, maintenance, and resolution of inflammation due to their phenotypic plasticity in response to signals from inflammatory microenvironments. Macrophages infiltrate and polarize toward a pro-inflammatory phenotype (M

Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis In The Management Of Intermediate-Risk Pulmonary Embolism: Primary Results Of The Peerless Randomized Controlled Trial., Wissam A Jaber, Carin F Gonsalves, Stefan Stortecky, Samuel Horr, Orestis Pappas, Ripal T Gandhi, Keith Pereira, Jay Giri, Sameer J Khandhar, Khawaja Afzal Ammar, David M Lasorda, Brian Stegman, Lucas Busch, David J Dexter, Ezana M Azene, Nikhil Daga, Fakhir Elmasri, Chandra R Kunavarapu, Mark E Rea, Joseph S Rossi, Joseph Campbell, Jonathan Lindquist, Adam Raskin, Jason C Smith, Thomas M Tamlyn, Gabriel A Hernandez, Parth Rali, Torrey R Schmidt, Jeffrey T Bruckel, Juan C Camacho, Jun Li, Samy Selim, Catalin Toma, Sukhdeep Singh Basra, Brian A Bergmark, Bhavraj Khalsa, David M Zlotnick, Jordan Castle, David J O'Connor, C Michael Gibson

Heart and Vascular Articles

BACKGROUND: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

METHODS: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to …

Development And Validation Of Risk Stratification For Heart Failure After Acute Coronary Syndrome Based On Dynamic S100a8/A9 Levels, Jie Ma, Ke Ma, Jing Chen, Xinying Yang, Fei Gao, Hai Gao, Hui Zhang, Xin-Liang Ma, Jie Du, Ping Li, Yulin Li

Department of Emergency Medicine Faculty Papers

BACKGROUND: The early assessment of heart failure (HF) risk in patients with acute coronary syndrome (ACS) can help reduce mortality. S100A8/A9 is not only rapidly released after myocardial ischemia, but is also involved in reperfusion injury, which is an important predictor of HF after ACS. We attempted to construct a reliable HF risk stratification tool for evaluating patients with ACS after reperfusion therapy based on S100A8/A9 dynamic changes.

METHODS AND RESULTS: This prospective study included 3 independent cohorts of patients with ACS who received reperfusion therapy. The discovery cohort was divided into 2 subgroups: the longitudinal subgroup (n=264) with serum …

Safety And Tolerability Of Letetresgene Autoleucel (Gsk3377794): Pilot Studies In Patients With Advanced Non-Small Cell Lung Cancer, Mehmet Altan, Gilberto Lopes, T Jeroen N Hiltermann, Ramaswamy Govindan, Liza C Villaruz, Emiliano Calvo, Martin J Edelman, Muhammad Furqan, Joel Neal, Enriqueta Felip, Jennifer W Carlisle, John V Heymach, Róisín Eilish O'Cearbhaill, Marjorie Zauderer, Michael Chisamore, Ellie Corigliano, Ioanna Eleftheriadou, Stefan Zajic, Ben Jenkins, Sophia Goodison, Sunil Suchindran, Natalia Ramos-Hernandez, Nidale Tarek, Adam J Schoenfeld

Faculty, Staff and Student Publications

Purpose: The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.

Patients and methods: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.

Results: More than 2,500 patients were …

Phase I/Ii Study Of The Aurora Kinase A Inhibitor Alisertib And Pembrolizumab In Refractory, Rb-Deficient Head And Neck Squamous Cell Carcinomas, Faye M Johnson, Madison P O'Hara, Lacin Yapindi, Peixin Jiang, Hai T Tran, Alexandre Reuben, Weihong Xiao, Maura L Gillison, Xiaowen Sun, Alexander Khalaf, J Jack Lee, Jagannadha K Sastry, Soma Ghosh

Faculty, Staff and Student Publications

Purpose: Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.

Patients and methods: Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).

Results: The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that …

Plant-Nanoparticles Enhance Anti-Pd-L1 Efficacy By Shaping Human Commensal Microbiota Metabolites, Yun Teng, Chao Luo, Xiaolan Qiu, Jingyao Mu, Mukesh K Sriwastva, Qingbo Xu, Minmin Liu, Xin Hu, Fangyi Xu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Zhanxu Liu, Xiang Zhang, Raobo Xu, Jun Yan, Michael L Merchant, Craig J Mcclain, Huang-Ge Zhang

Faculty, Staff and Student Publications

Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid …

The Landscape Of Ctdna In Appendiceal Adenocarcinoma, Michael G White, Mohammad A Zeineddine, Eleanor A Fallon, Fadl A Zeineddine, Julia Dansby, Saikat Chowdhury, Nicholas Hornstein, Abdelrahman Yousef, Mahmoud Yousef, Neal Bhutiani, Yue Gu, Bryan Kee, Arvind Dasari, Michael J Overman, Kanwal Raghav, Scott Kopetz, Abhineet Uppal, Melissa Taggart, Timothy Newhook, Keith Fournier, Beth Helmink, Leylah M Drusbosky, John Paul Shen

Faculty, Staff and Student Publications

Purpose: Appendiceal adenocarcinoma is a rare malignancy with distinct histopathologic subtypes and a natural history with metastasis primarily limited to the peritoneum. Little is known about the molecular pathogenesis of appendiceal adenocarcinoma relative to common tumors.

Experimental design: We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with appendiceal adenocarcinoma at our institution (from October 2004-September 2022) for whom ctDNA mutation profiling (liquid biopsy) was performed (n = 168) and extracted clinicopathologic and outcomes data. Of these 168 patients, 57 also had tissue-based tumor mutational profiling, allowing for …

Characterizing The Genetic Basis For Inherited Retinal Disease: Lessons Learned From The Foundation Fighting Blindness Clinical Consortium's Gene Poll, Kari Branham, Lassana Samarakoon, Isabelle Audo, Allison R Ayala, Janet K Cheetham, Stephen P Daiger, Patty Dhooge, Jacque L Duncan, Todd A Durham, Abigail T Fahim, Rachel M Huckfeldt, Robert B Hufnagel, Susanne Kohl, Ramiro S Maldonado, Michele Melia, Michel Michaelides, Mark E Pennesi, José-Alain Sahel, Juliana M Ferraz Sallum, Mandeep S Singh, Dror Sharon, Kimberly Stepien, Kaylie Jones, Christina Y Weng

Faculty, Staff and Students Publications

PURPOSE: The Foundation Fighting Blindness (FFB) Consortium is a collaboration of 41 international clinical centers that manage patients affected with inherited retinal diseases (IRDs). The annual Consortium gene poll was initiated in 2020 to capture the genetic cause of disease in patients with IRD and associated clinical practices of Consortium sites. Data from the 2022 gene poll are reported here.

METHODS: In 2022, academic, private practice, and government ophthalmology clinics that are members of the Consortium centers were polled to identify per-case IRD genetic causality from a list of 387 syndromic and nonsyndromic IRD genes. The survey also assessed how …

Dairy Consumption And The Colonic Mucosa-Associated Gut Microbiota In Humans-A Preliminary Investigation, Ellie Chen, Nadim J Ajami, Donna L White, Yanhong Liu, Shawn Gurwara, Kristi Hoffman, David Y Graham, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

Background: Dairy consumption has been associated with various health outcomes that may be mediated by changes in gut microbiota.

Methods: This cross-sectional study investigated the association between the colonic mucosa-associated gut microbiota and the self-reported intake of total dairy, milk, cheese, and yogurt. A total of 97 colonic mucosal biopsies collected from 34 polyp-free individuals were analyzed. Dairy consumption in the past year was assessed using a food frequency questionnaire. The 16S rRNA gene V4 region was amplified and sequenced. Operational taxonomic unit (OTU) classification was performed using the UPARSE and SILVA databases. OTU diversity and relative abundance were compared …

Prediction Of Lacosamide Concentrations To Support Dose Optimization During Pregnancy, Jessica M. Barry, Sílvia M. Illamola, Page B. Pennell, Catherine M.T. Sherwin, Kimford J. Meador, Angela K. Birnbaum

Pediatrics Faculty Publications

Objective: We aimed to quantify and predict lacosamide exposure during pregnancy by developing a pregnancy physiologically-based pharmacokinetic model, allowing the prediction of potential dose increases to support maintaining a patient's preconception lacosamide concentrations. Methods: Models for nonpregnant adults and pregnant female patients were constructed using physiochemical and pharmacological parameters identified from literature review. Evaluation of plasma concentration data from human males was digitized froM.T.he literature. Concentration data in nonpregnant and pregnant human females were available froM.T.he Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a longitudinal observational study which followed 11 nonpregnant and 16 pregnant women receiving lacosamide. …

Prediction Models Of Basal Energy Expenditure In Children And Adolescents Across The Bmi Spectrum Based On Room Calorimetry: A Cross-Sectional Cohort Study, Maurice Puyau, Roman Shypailo, Nancy F Butte, Salma Musaad, Fida Bacha

Children’s Nutrition Research Center Staff Publications

Background: Existing equations for prediction of basal energy expenditure (BEE) may not be accurate in children with overweight or obesity (OW/OB).

Objectives: We aimed to develop BEE prediction equations applicable to children and adolescents across a wide BMI spectrum using gold standard room calorimetry.

Methods: We measured weight, height, waist and hip circumferences, body composition (DXA), and BEE (whole room calorimetry) in a cross-sectional cohort of 1155 healthy children, 5-19 years of age. 67% of the males and 51% of the females were classified as OW/OB. We applied multiple linear regression analyses to develop BEE prediction models for each sex. …

Leptin Receptor Neurons In The Dorsomedial Hypothalamus Require Distinct Neuronal Subsets For Thermogenesis And Weight Loss, Marie Francois, Laura Kaiser, Yanlin He, Yong Xu, J Michael Salbaum, Sangho Yu, Christopher D Morrison, Hans-Rudolf Berthoud, Heike Münzberg

Children’s Nutrition Research Center Staff Publications

The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable …

Association Between Maternal Stress And Child Sleep Quality: A Nationwide Echo Prospective Cohort Study, Sarah Dee Geiger, Aruna Chandran, Marie L Churchill, Maxwell Mansolf, Cai Zhang, Salma Musaad, Courtney K Blackwell, Stephanie M Eick, Dana E Goin, Susan Korrick, Akram Alshawabkeh, Patricia A Brennan, Carrie V Breton, Jose F Cordero, Sean Deoni, Viren D'Sa, Anne L Dunlop, Amy J Elliott, Assiamira Ferrara, Arlene Keddie, Monique Lebourgeois, Kaja Z Lewinn, Daphne Koinis-Mitchell, Maristella Lucchini, Sara S Nozadi, Thomas O'Connor, Yeyi Zhu, Emily Zimmerman, Susan L Schantz

Children’s Nutrition Research Center Staff Publications

Background: Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures.

Objectives: To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association.

Method: Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression …

Rescue Stenting For Failed Mechanical Thrombectomy In Acute Basilar Artery Occlusions: Analysis Of The Pc-Search Registry., Santiago Ortega-Gutierrez, Aaron Rodriguez-Calienes, Adam T Mierzwa, Milagros Galecio-Castillo, Mahmoud Dibas, Sami Al Kasab, Ashley Nelson, Ashutosh P Jadhav, Shashvat Desai, Gabor Toth, Anas Alrohimi, Mohamad Abdalkader, Piers Klein, Thanh N Nguyen, Hisham Salahuddin, Aditya Pandey, Sravanthi Koduri, Niraj Vora, Nameer Aladamat, Khaled Gharaibeh, Ehad Afreen, Syed Zaidi, Mouhammad Jumaa

Neuroscience Articles

BACKGROUND: We aimed to investigate whether rescue stenting (RS) following failed mechanical thrombectomy (MT) for acute basilar artery occlusion results in superior functional outcomes and enhanced safety compared with the natural history of failed MT.

METHODS: This retrospective cohort study utilized data from the Posterior Circulation Ischemic Stroke Evaluation: Analyzing Radiographic and Intra-Procedural Predictors for Mechanical Thrombectomy registry, encompassing 8 high-volume centers in the United States and covering the period from 2015 to 2021. Patients with basilar artery occlusion who experienced failed MT (modified Thrombolysis in Cerebral Infarction score of 0-2a after at least 1 attempt of clot retrieval) were …