Medical Specialties Commons^™

Self-Management Intervention Improves Patient Adherence To Swallowing Exercises During Radiation For Head And Neck Cancer, Eileen H Shinn, Adam S Garden, Minxing Chen, Karen Basen-Engquist, Bryan Fellman, Kate Hutcheson, William H Morrison, Susan Peterson, Liang Li

Faculty, Staff and Student Publications

Background: While preventive swallowing exercises reduce the risk of radiation-associated dysphagia in patients with head and neck cancer, strategies are needed to improve patient adherence.

Methods: Before radiation, all participants were taught preventive swallowing exercises and randomized to either an adherence intervention or enhanced usual care. During radiation, all participants met twice with a speech pathologist for swallowing assessment and reinforcement of exercises. Intervention participants met weekly with a counselor in-person or by phone. At 6-week post-radiation follow-up, all participants completed a follow-up assessment of self-reported adherence, which was then corroborated with medical record documentation.

Results: Newly diagnosed pharyngeal and …

Boosting Acetylcholine Signaling By Cannabidiol In A Murine Model Of Alzheimer's Disease, Hesam Khodadadi, Évila Lopes Salles, Sahar Emami Naeini, Bidhan Bhandari, Hannah M Rogers, Jules Gouron, William Meeks, Alvin V Terry, Anilkumar Pillai, Jack C Yu, John C Morgan, Kumar Vaibhav, David C Hess, Krishnan M Dhandapani, Lei P Wang, Babak Baban

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a challenging medical issue that requires efficacious treatment options to improve long-term quality of life. Cannabidiol (CBD) is a cannabis-derived phytocannabinoid with potential health benefits, including reports from our laboratory and others showing a therapeutic role in the pre-clinical treatment of AD; however, the mechanisms whereby CBD affects AD progression remain undefined. Innate lymphoid cells (ILCs) are recently discovered immune cells that initiate and orchestrate inflammatory responses. ILC2, a sub-class of ILCs, is proposed to have a role in cognitive function via unknown mechanisms. In this present study, we explored whether CBD ameliorates AD symptoms via …

Universal Clinical Decision Support Tool For Thromboprophylaxis In Hospitalized Covid-19 Patients: Post Hoc Analysis Of The Improve-Dd Cluster Randomized Trial, Mark Goldin, Nikolaos Tsaftaridis, Ioannis Koulas, Jeffrey Solomon, Michael Qiu, Tungming Leung, Kolton Smith, Kanta Ochani, Thomas Mcginn, Alex C Spyropoulos

Faculty, Staff and Students Publications

Background: Inpatient and extended postdischarge thromboprophylaxis of COVID-19 patients remains suboptimal despite antithrombotic guidelines.

Objectives: To determine whether a novel electronic health record-agnostic clinical decision support (CDS) tool incorporating the International Medical Prevention Registry on Venous Thromboembolism plus D-dimer (IMPROVE-DD) venous thromboembolism (VTE) scores increases appropriate inpatient and extended postdischarge thromboprophylaxis and improves outcomes in COVID-19 inpatients.

Methods: This post hoc analysis of the IMPROVE-DD cluster randomized trial evaluated thromboprophylaxis CDS among COVID-19 inpatients at 4 New York hospitals between December 21, 2020, and January 21, 2022. Hospitals were randomized 1:1 to CDS (intervention, n = 2) vs no CDS …

Trends And Disparities In Coronary Artery Disease And Obesity-Related Mortality In The United States From 1999-2022, Mushood Ahmed, Hira Javaid, Aimen Shafiq, Zain Ali Nadeem, Areeba Ahsan, Abdullah Nofal, Raheel Ahmed, Mahboob Alam, Marat Fudim, Gregg C Fonarow, Mamas A Mamas

Faculty, Staff and Students Publications

BACKGROUND: Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location.

METHODS: The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint …

White Matter And Latency Of Visual Evoked Potentials During Maturation: A Miniature Pig Model Of Adolescent Development, Peter Kochunov, L Elliot Hong, Ann Summerfelt, Si Gao, P Leon Brown, Matthew Terzi, Ashley Acheson, Marty G Woldorff, Els Fieremans, Ali Abdollahzadeh, Korrapati V Sathyasaikumar, Sarah M Clark, Robert Schwarcz, Paul D Shepard, Greg I Elmer

Faculty, Staff and Student Publications

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period.

Methods: Eight Sinclair™ minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1 Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms …

Increased White Blood Cell In Young Adults With Family Histories Of Alcohol And Other Substance Use Disorders, Mustafa N Mithaiwala, Nikki S Phillips, Dylan H Nguyen, Melanie S Beehler, Harrison S Ballard, Andrea S Vincent, William R Lovallo, Peter Kochunov, L Elliot Hong, Jason C O'Connor, Steve Cole, Ashley Acheson

Faculty, Staff and Student Publications

Individuals with a family history of alcohol or other substance use disorders (FH+) are at increased risk for developing alcohol and other substance use disorders (AUD/SUD) compared to individuals with no such family histories (FH-). FH+ young adults have blunted stress reactivity, lower cognitive performance and altered frontal white matter microstructure compared to FH- controls. We hypothesized that family history of AUD/SUD disrupts neuroendocrine regulation of the immune system in FH+ individuals, resulting in altered blood immune cell composition, inflammation and neurocognitive alterations that, ultimately, increases risk for AUD/SUD and associated psychopathology. We examined white blood cell (WBC) parameters derived …

Secondary Acquisition Of The Philadelphia Chromosome In Acute Lymphoblastic Leukemia, Qiudan Shen, Elias J Jabbour, Guilin Tang, Hong Fang, Wei Wang, Nicholas J Short, M James You, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Student Publications

No abstract provided.

Molecular, Socioeconomic, And Clinical Factors Affecting Racial And Ethnic Disparities In Colorectal Cancer Survival, Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad M Fanaeian, Mark Knafl, Jennifer Peterson, Mohammad Zeineddine, Kristin Alfaro, Fadl Zeineddine, Drew Goldstein, Nicholas Hornstein, Arvind Dasari, Ryan Huey, Benny Johnson, Victoria Higbie, Alisha Bent, Bryan Kee, Michael Lee, Maria Pia Morelli, Van Karlyle Morris, Daniel Halperin, Michael J Overman, Christine Parseghian, Eduardo Vilar, Robert Wolff, Kanwal P Raghav, Michael G White, Abhineet Uppal, Ryan Sun, Wenyi Wang, Scott Kopetz, Jason Willis, John Paul Shen

Faculty, Staff and Student Publications

Importance: Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown.

Objective: To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer.

Design, setting, and participants: This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables …

Genome-Wide Study Of Gene-By-Sex Interactions Identifies Risks For Cleft Palate, Kelsey Robinson, Randy Parrish, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Jeffrey C Murray, Gary M Shaw, Seth M Weinberg, Harrison Brand, Mary L Marazita, David J Cutler, Michael P Epstein, Jingjing Yang, Elizabeth J Leslie

Faculty, Staff and Student Publications

Structural birth defects affect 3–4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified …

Ctla4 Blockade Abrogates Keap1/Stk11-Related Resistance To Pd-(L)1 Inhibitors, Ferdinandos Skoulidis, Haniel A Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C Arbour, Natalie Vokes, Stephanie T Schmidt, David Molkentine, Dwight H Owen, Regan Memmott, Pradnya D Patil, Melina E Marmarelis, Mark M Awad, Joseph C Murray, Jessica A Hellyer, Justin F Gainor, Anastasios Dimou, Christine M Bestvina, Catherine A Shu, Jonathan W Riess, Collin M Blakely, Chad V Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J Mooradian, Adrian G Sacher, Sally C M Lau, Andreas N Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D Davies, Mark G Woodcock, Valsamo Anagnostou, Kristen A Marrone, Patrick M Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M Van Allen, Amy L Cummings, Jonathan W Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T Azok, Jeremy Segal, Lauren Ritterhouse, Joel W Neal, Ludovic Lacroix, Yasir Y Elamin, Marcelo V Negrao, Xiuning Le, Vincent K Lam, Whitney E Lewis, Haley N Kemp, Brett Carter, Jack A Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R Parra Cuentas, Carmen Behrens, Ignacio I Wistuba, Jianjun Zhang, George R Blumenschein, Carl Gay, Lauren A Byers, Don L Gibbons, Anne Tsao, J Jack Lee, Trever G Bivona, D Ross Camidge, Jhannelle E Gray, Natasha B Leighl, Benjamin Levy, Julie R Brahmer, Marina C Garassino, David R Gandara, Edward B Garon, Naiyer A Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S Herbst, Heather A Wakelee, Nathan A Pennell, Alice T Shaw, Pasi A Jänne, David P Carbone, Matthew D Hellmann, Charles M Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L Johnson, Kwok K Wong, Alan Huang, Monte M Winslow, Michael J Rosen, Ian P Winters, Vassiliki A Papadimitrakopoulou, Tina Cascone, Philip Jewsbury, John V Heymach

Faculty, Staff and Student Publications

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added …

Efficacy Of Trastuzumab Deruxtecan In Her2-Expressing Solid Tumors By Enrollment Her2 Ihc Status: Post Hoc Analysis Of Destiny-Pantumor02, Ana Oaknin, Jung-Yun Lee, Vicky Makker, Do-Youn Oh, Susana Banerjee, Antonio González-Martín, Kyung Hae Jung, Iwona Ługowska, Luis Manso, Aránzazu Manzano, Bohuslav Melichar, Salvatore Siena, Daniil Stroyakovskiy, Anitra Fielding, Soham Puvvada, Ann Smith, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Introduction: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results …

Molecular Profiling Of Braf-V600e-Mutant Metastatic Colorectal Cancer In The Phase 3 Beacon Crc Trial, Scott Kopetz, Danielle A Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Hedieh Saffari, Xiaosong Zhang, Phineas Hamilton, Tao Xie, Rona Yaeger, Josep Tabernero

Faculty, Staff and Student Publications

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic …

Bacillus Licheniformis Suppresses Clostridium Perfringens Infection Via Modulating Inflammatory Response, Antioxidant Status, Inflammasome Activation And Microbial Homeostasis In Broilers, Xiao Xiao, Songke Qin, Tiantian Cui, Jinsong Liu, Yanping Wu, Yifan Zhong, Caimei Yang

Faculty, Staff and Student Publications

Pathogenic bacteria infection, especially Clostridium perfringens (C. perfringens), markedly threatened the health of animals, and further caused huge economic loss. In this study, Bacillus licheniformis HJ0135 (BL) was used. Oxford cup bacteriostatic test and inhibitory rate test were conducted to evaluate the antibacterial ability of BL. Results showed the strongest inhibitory role of BL on C. perfringens (P < 0.05). Afterwards, 540 one-day-old yellow-feather broilers (32.7 ± 0.2 g) were randomly allocated into 3 groups, including CON group (basal diet), CP group (basal diet + 1 × 109 CFU C. perfringens in gavage), and BL + CP group (basal diet containing 7.5 × 106 CFU/g BL + 1 × 109 CFU C. perfringens in gavage). At d 70, broilers in the CP and BL + CP groups were treated with C. perfringens by continuously oral administration for 5 d. The experiment lasted for 75 d. The serum, immune organs, jejunal mucosa, and cecal contents were collected for analysis. In vivo experiment showed that BL supplementation markedly improved (P < 0.05) BW, ADG, thymus index, serum immunoglobins and antioxidases, reduced feed conversion ratio (FCR) and serum pro-inflammatory cytokines of C. perfringens-infected broilers. Furthermore, the increased jejunal injury and levels of pro-inflammatory cytokines, decreased gene expressions of tight junction proteins in the jejunal mucosa were significantly alleviated (P < 0.05) by BL. More importantly, the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was inhibited (P < 0.05) by BL to further attenuate jejunal damage. Besides, BL supplementation markedly increased (P < 0.05) the cecal isobutyric acid and isovaleric acid. Microbial analysis showed that BL changed the composition and relative abundances of microbiota in the cecal contents (P < 0.05), especially the short chain fatty acids (SCFAs)-producing bacteria including Eubacterium_coprostanoligenes_group, Megamonas, Faecalibacterium, and Lactobacillus, which further protected against C. perfringens-induced jejunal inflammation in broilers. Our study laid a theoretical basis for the application of probiotics in lessening C. perfringens-related diseases in poultry farming.

Consensus Molecular Subtyping Of Metastatic Colorectal Cancer Expands Biomarker-Directed Therapeutic Benefit For Patients With Cms1 And Cms2 Tumors, Saikat Chowdhury, Joanne Xiu, Jennifer R Ribeiro, Theodore Nicolaides, Jian Zhang, W Michael Korn, Kelsey A Poorman, Heinz-Josef Lenz, John L Marshall, Matthew J Oberley, George W Sledge, David Spetzler, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).

Methods: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant).

Results: CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer …

Association Analysis Of Mitochondrial Dna Heteroplasmic Variants: Methods And Application, Xianbang Sun, Katia Bulekova, Jian Yang, Meng Lai, Achilleas N Pitsillides, Xue Liu, Yuankai Zhang, Xiuqing Guo, Qian Yong, Laura M Raffield, Jerome I Rotter, Stephen S Rich, Goncalo Abecasis, April P Carson, Ramachandran S Vasan, Joshua C Bis, Bruce M Psaty, Eric Boerwinkle, Annette L Fitzpatrick, Claudia L Satizabal, Dan E Arking, Jun Ding, Daniel Levy, Chunyu Liu

Faculty, Staff and Student Publications

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden …

Decitabine, Venetoclax, And Ponatinib For Advanced Phase Chronic Myeloid Leukaemia And Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial, Nicholas J Short, Daniel Nguyen, Elias Jabbour, Jayastu Senapati, Zhihong Zeng, Ghayas C Issa, Hussein Abbas, Cedric Nasnas, Wei Qiao, Xuelin Huang, Gautam Borthakur, Kelly Chien, Fadi G Haddad, Naveen Pemmaraju, Omer S Karrar, Danielle Nguyen, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, …

Surgical Predictors Of Clinical Outcome 6 Years After Revision Acl Reconstruction, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, Annunziato Ned Amendola, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown.

Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 2.

Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) …

Three-Year Outcomes Following Tavr In Younger (<75 Years) Low-Surgical-Risk Severe Aortic Stenosis Patients., Thomas Modine, Didier Tchétché, Nicolas M Van Mieghem, G Michael Deeb, Stanley J Chetcuti, Steven J Yakubov, Paul Sorajja, Hemal Gada, Mubashir Mumtaz, Basel Ramlawi, Tanvir Bajwa, John Crouch, Paul S Teirstein, Neal S Kleiman, Ayman Iskander, Rodrigo Bagur, Michael W A Chu, Pierre Berthoumieu, Arnaud Sudre, Rik Adrichem, Saki Ito, Jian Huang, Jeffrey J Popma, John K Forrest, Michael J Reardon

Heart and Vascular Articles

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an alternative to surgery in patients with severe aortic stenosis, but data are limited on younger, low-risk patients. This analysis compares outcomes in low-surgical-risk patients agedsurgery.

METHODS: The Evolut Low Risk Trial randomized 1414 low-risk patients to treatment with a supra-annular, self-expanding TAVR or surgery. We compared rates of all-cause mortality or disabling stroke, associated clinical outcomes, and bioprosthetic valve performance at 3 years between TAVR and surgery patients aged < 75 >years.

RESULTS: In patients < 75 >years, 352 were randomized to TAVR and 351 to surgery. Mean age was 69.1±4.0 years (minimum 51 and maximum …

Increased Expression Of Cd70 In Relapsed Acute Myeloid Leukemia After Hypomethylating Agents, Mario L Marques-Piubelli, Bijender Kumar, Rafet Basar, Siler Panowski, Surabhi Srinivasan, Kevin Norwood, Sacha Prashad, Victoria Szenes, Arun Balakumaran, Akanksha Arandhya, Wei Lu, Khaja Khan, Daniela Duenas, Salome Mcallen, Javier A Gomez, Jared K Burks, Sunil Acharyal, Gautam Borthakur, Wei-Lien Wang, Wei Wang, Sa Wang, Luisa M Solis, David Marin, Katayoun Rezvani, May Daher, Francisco Vega

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, …

Glymphatic Dysfunction In Multiple Sclerosis And Its Association With Disease Pathology And Disability, Ahmed Bayoumi, Khader M Hasan, Joseph A Thomas, Akram Yazdani, John A Lincoln

Faculty, Staff and Student Publications

Background: The role of the glymphatic system in multiple sclerosis (MS)-related disability remains underexplored. Diffusion-tensor image analysis along the perivascular space (DTI-ALPS) offers a non-invasive method to assess glymphatic function.

Objective: To evaluate glymphatic function in MS patients with lower and higher disability.

Methods: This study included 118 MS patients who underwent structural, diffusion-weighted imaging, and clinical assessment. The participants were divided into lower (MS-L, n = 57) and higher disability (MS-H, n = 61) subgroups. Brain parenchymal fraction (BPF), lesion load (LL), and DTI-ALPS index were measured. Subgroup differences and correlations between DTI-ALPS index and other measures were explored. …

A Comparison Of The Diagnostic Capability Of Kato-Katz And Real-Time Pcr For The Assessment Of Treatment Efficacy Of Ivermectin And Albendazole Combination Against T Trichiura Infections, Gabriela Matamoros, Ana Sanchez, Ruben Cimino, Alejandro Krolewiecki, Rojelio Mejia

Faculty, Staff and Students Publications

BACKGROUND: Trichuris trichiura is humans' second most prevalent soil-transmitted helminth (STH) infection after Ascaris lumbricoides, affecting approximately 460 million people worldwide. Despite its sub-optimal sensitivity, especially in low prevalence and infection intensity settings, the modified Kato-Katz (K-K) is still recommended as a diagnostic method by the World Health organization (WHO) guidelines.

METHODOLOGY/PRINCIPAL FINDINGS: Within a randomized clinical trial (RCT) comprising four treatment arms with two different anthelmintics, the present study reports an important secondary research objective to determine the diagnostic agreement between K-K and real-time PCR evaluating treatment efficacy against T. trichiura. The parasitological results were analyzed, including cure rates …

Secondary Acmg And Non-Acmg Genetic Findings In A Multiethnic Cohort Of 16,713 Pediatric Participants, Amir Hossein Saeidian, Michael E March, Leila Youssefian, Deborah J Watson, Esha Bhandari, Xiang Wang, Xiaonan Zhao, Nichole Marie Owen, Alanna Strong, Margaret H Harr, Elizabeth Bhoj, Elaine Zackai, Hassan Vahidnezhad, Johann E Gudjonsson, Stephen D Cederbaum, Joshua L Deignan, Joseph Glessner, Wayne W Grody, Hakon Hakonarson

Faculty, Staff and Students Publications

Purpose: Clinical next-generation sequencing is an effective approach for identifying pathogenic sequence variants that are medically actionable for participants and families but are not associated with the participant's primary diagnosis. These variants are called secondary findings (SFs). According to the literature, there is no report of the types and frequencies of SFs in a large pediatric cohort that includes substantial African-American participants. We sought to investigate the types (including American College of Medical Genetics and Genomics [ACMG] and non-ACMG-recommended gene lists), frequencies, and rates of SFs, as well as the effects of SF disclosure on the participants and families of …

A Phase 1 Study Of Abi-009 (Nab-Sirolimus) In Combination With Temozolomide And Irinotecan In Pediatric Patients With Recurrent Or Refractory Solid Tumors, Including Cns Tumors-A Children's Oncology Group Pediatric Early Phase Clinical Trial Network Study Advl1514, Stuart L Cramer, Alyssa Terry Reddy, Charles Gene Minard, Stephan Voss, Elizabeth Fox, Xiaowei Liu, Kristina Denic, Joel M Reid, Brenda J Weigel

Faculty, Staff and Students Publications

BACKGROUND: Nab-sirolimus (ABI-009, nab-rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin-bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose-limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab-sirolimus in combination with temozolomide and irinotecan.

METHODS: Using a rolling 6 design, Nab-sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab-sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m

RESULTS: Thirty-three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median …

Burden Re-Analysis Of Neurodevelopmental Disorder Cohorts For Prioritization Of Candidate Genes, Noor Smal, Fatma Majdoub, Katrien Janssens, Edwin Reyniers, Marije E C Meuwissen, Berten Ceulemans, Hope Northrup, Jeremy B Hill, Lingying Liu, Edoardo Errichiello, Simone Gana, Alanna Strong, Luis Rohena, Rachel Franciskovich, Chaya N Murali, An Huybrechs, Telma Sulem, Run Fridriksdottir, Patrick Sulem, Kari Stefansson, Yan Bai, Jill A Rosenfeld, Seema R Lalani, Haley Streff, Undiagnosed Diseases Network, R Frank Kooy, Sarah Weckhuysen

Faculty, Staff and Students Publications

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden …

Family Lore, A Variant Of Uncertain Significance, And Cadasil, Rhys Duarte, Liesbeth Vossaert, Sandra A Darilek, Chelsi Rose, Evan Schauer, Christian Parobek, Emily Bland, Keren Machol, Elizabeth Mizerik, Chaya N Murali

Faculty, Staff and Students Publications

An infant presents in extremis. After the medical team stabilizes him, the race is on to figure out why he got so sick in the first place. The consulting genetics team thinks that it is unlikely his problems are due to a genetic cause, but his extreme, confounding presentation is enough to justify trio exome sequencing. When the results reveal an unexpected, paternally inherited variant of uncertain significance (VUS) in NOTCH3, fresh questions arise. The infant's presenting symptoms and descriptive diagnoses, including hematemesis, epistaxis, and gastric ulcers, certainly do not fit the mold of CADASIL. However, closer inspection of his …

Yield Of Skeletal Surveys In National Network Of Child Abuse Pediatricians: Age Is Key, Caitlin R Mcnamara, Joanne N Wood, Daniel Lindberg, Kristine A Campbell, Spencer Poston, Matthew Valente, Maria Antonucci, Jennifer Wolford, Carmen Coombs, Hannah Sahud, Jennifer Clarke, Farah W Brink, Angela Bachim, Lori D Frasier, Nancy S Harper, John D Melville, Natalie Laub, James Anderst, Rachel P Berger

Faculty, Staff and Students Publications

Background: Skeletal surveys (SS) are recommended for the evaluation of suspected physical abuse in children < 2 years old. No guidelines exist for SS completion in children between 2 and 5 years old.

Objective: To determine rates of SS completion by age and examine variables associated with occult fracture identification in older children.

Participants and setting: Observational cross-sectional multi-center study of 10 US pediatric centers 2/2021-9/2022 including children < 6 years old evaluated for physical child abuse.

Methods: The principal outcome is occult fracture identified on SS. Non-parametric tests were conducted from comparison between age groups and those with and without occult fractures.

Results: The rate of SS completion declined with increasing age from a high of 91 % in infants < 6 months old to 7 % in children 5-5.9 years old. The proportion of SS with occult fractures also decreased with age. Of 450 children 2-5 years old with a SS, 20 [4 % (95 % CI: 3-8 %)] had an occult fracture. The rate of occult fractures among children 2-5 years old who were diagnosed with abuse and not admitted to the hospital was 0.3 % (95 % CI 0-0.6 %)]. Over 30 % of children 2-5 years old were diagnosed with child abuse by a child abuse pediatrician without completion of a SS.

Conclusion: In children 2-5 years of …

Perivascular Epithelioid Cell-Family Tumors In Children, Adolescents, And Young Adults: Clinicopathologic Features In 70 Cases, Phoebe M Hammer, Angus Toland, Muhammad Shaheen, Archana Shenoy, Ashwini Esnakula, M John Hicks, Mikako Warran, Alyaa Al-Ibraheemi, Jessica L Davis, Serena Y Tan

Faculty, Staff and Students Publications

Context.—: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented.

Objective.—: To describe a multi-institutional series of PEComas in children, adolescents, and young adults.

Design.—: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and the authors' files.

Results.—: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominantly in the kidney (53 of 70), followed by the …

National Liver Cancer Screening Trial (Tracer) Study Protocol, Amit G Singal, Neehar D Parikh, Fasiha Kanwal, Jorge A Marrero, Sneha Deodhar, Stephanie Page-Lester, Camden Lopez, Ziding Feng, Nabihah Tayob

Faculty, Staff and Students Publications

BACKGROUND: Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. …

Serum Levels Of Total Bile Acids Are Associated With An Increased Risk Of Hcc In Patients With Cirrhosis, Hashem B El-Serag, Aaron P Thrift, Hao Duong, Jing Ning, Saira Khaderi, Amit G Singal, Sumeet K Asrani, Jorge A Marrero, Hannah Powell, Kinza Rizwan, Omar Najjar, Christopher I Amos, Michelle Luster, Abeer Al-Sarraj, Emad Salem, Michael E Scheurer, Jagpreet Chhatwal, Salma Kaochar, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND: Previous studies have reported higher circulating bile acid levels in patients with HCC compared to healthy controls. However, the association between prediagnostic bile acid levels and HCC risk among patients with cirrhosis is unclear.

METHODS: We measured total BA (TBA) concentration in serum samples collected from a prospective cohort of patients with cirrhosis who were followed until the development of HCC, death, or last study date. Competing risk proportional hazard-adjusted models were used to estimate the association between tertiles of serum TBA levels and the risk of developing HCC. We quantified the incremental predictive value of serum bile acid …

Macrophage Iron Dyshomeostasis Promotes Aging-Related Renal Fibrosis, Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular …