Medicine and Health Sciences Commons^™

Leveraging Pretrained Language Models For Seizure Frequency Extraction From Epilepsy Evaluation Reports, Rashmie Abeysinghe, Shiqiang Tao, Samden D Lhatoo, Guo-Qiang Zhang, Licong Cui

Faculty, Staff and Student Publications

Seizure frequency is essential for evaluating epilepsy treatment, ensuring patient safety, and reducing risk for Sudden Unexpected Death in Epilepsy. As this information is often described in clinical narratives, this study presents an approach to extracting structured seizure frequency details from such unstructured text. We investigated two tasks: (1) extracting phrases describing seizure frequency, and (2) extracting seizure frequency attributes. For both tasks, we fine-tuned three BERT-based models (bert-large-cased, biobert-large-cased, and Bio_ClinicalBERT), as well as three generative large language models (GPT-4, GPT-3.5 Turbo, and Llama-2-70b-hf). The final structured output integrated the results from both tasks. GPT-4 attained the best performance …

Long-Read Single-Cell Rna Sequencing Enables The Study Of Cancer Subclone-Specific Genotypes And Phenotypes In Chronic Lymphocytic Leukemia, Gage S Black, Xiaomeng Huang, Yi Qiao, Philip Moos, Deepa Sampath, Deborah M Stephens, Jennifer A Woyach, Gabor T Marth

Faculty, Staff and Student Publications

Bruton tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK's role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate cancer subclones harboring a BTKC481S mutation and identify cells with co-occurring CLL driver mutations. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we use scBayes, which integrates bulk DNA sequencing and single-cell …

Results Of The Phase I/Ii Study And Preliminary B-Cell Gene Signature Of Combined Inhibition Of Glutamine Metabolism And Egfr In Colorectal Cancer, Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning

Faculty, Staff and Student Publications

Purpose: EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and methods: We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET …

Germline Pathogenic Drosha Variants Are Linked To Pineoblastoma And Wilms Tumor Predisposition, Peter N Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y Lin, Angshumoy Roy, Allison Pribnow, Melissa R Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A Jackson, Mark M Sasaki, Trent Fowler, Anita Ng, Ryan J Corbett, Rebecca S Kaufman, Jeremy S Haley, David J Carey, Kuan-Lin Huang, Sharon J Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B Mcgee, Joshua D Schiffman, Kenneth S Chen, Douglas R Stewart, D Williams Parsons, Sharon E Plon, Kris Ann P Schultz, Kenan Onel

Center for Medical Ethics and Health Policy Staff Publications

Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported.

Experimental design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts.

Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a …

Surgical Mitral Valve Repair Vs Replacement After Failed Mitral Transcatheter Edge-To-Edge Repair: The Cutting-Edge Registry., Mateo Marin-Cuartas, Jagdip Kang, Thilo Noack, Manuela De La Cuesta, Markus Krane, Volkmar Falk, Lenard Conradi, Christian Hagl, Maurizio Taramasso, Tom C Nguyen, D Scott Lim, Gorav Ailawadi, Michael J Mack, Robert L Smith, Anita W Asgar, Kendra J Grubb, Luigi Pirelli, Paolo Denti, Thomas Modine, Michael J Reardon, Tamim M Nazif, Vinayak N Bapat, Tsuyoshi Kaneko, Philipp Kiefer, Michael A Borger, Gilbert H L Tang, Syed Zaid

Faculty, Staff and Students Publications

Background: The impact of mitral valve (MV) surgery type after failed mitral transcatheter edge-to-edge repair (M-TEER) has not been well studied.

Objectives: The aim of this study was to compare the outcomes of MV repair vs replacement after failed M-TEER.

Methods: From 2009 to 2020, a total of 332 patients across 34 centers from the CUTTING-EDGE registry underwent MV surgery after M-TEER. Outcomes were compared between MV repair and replacement. Primary outcomes included 30-day mortality and 1-year survival after MV surgery.

Results: Among enrolled patients (mean age 73.8 ± 10.1 years, median Society of Thoracic Surgeons Predicted Risk of Mortality …

Somatodendritic Orientation Determines Tdcs-Induced Neuromodulation Of Purkinje Cell Activity In Awake Mice, Carlos A Sánchez-León, Guillermo Sánchez-Garrido Campos, Marta Fernández, Álvaro Sánchez-López, Javier F Medina, Javier Márquez-Ruiz

Faculty, Staff and Students Publications

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n=9) were prepared for the chronic recording of local field potentials (LFPs) to assess the actual electric field gradient imposed by …

Diagnosis And Management Of Esophageal Perforation With Necrotizing Fasciitis In Traumatic Cervical Spine Injuries: Illustrative Case, Arman Kavoussi, Ashley Ricciardelli, Alex Flores, Alexander Brenner, Nelson Eddie Liou, Alexander E Ropper, Cyrus King

Faculty, Staff and Students Publications

Background: Esophageal perforation is a rare but deadly complication of cervical spine fractures. Early identification can be difficult but is imperative for proper treatment and prevention of life-threatening infection. Once diagnosed, surgical drainage and broad-spectrum antibiotics can yield positive outcomes. The authors present a successfully managed case of cervical spine fracture with associated esophageal perforation and necrotizing fasciitis as well as an extensive literature review.

Observations: An 87-year-old male with a previous cervical laminectomy presented to the emergency department with shortness of breath after a ground-level fall. Initial CT imaging of the cervical spine was noted to have no abnormalities …

Spreading Depolarization And Seizures: End Of The Beginning, Or Beginning Of The End?, Isamu Aiba, Jeffrey L Noebels

Faculty, Staff and Students Publications

Like Janus, the Roman god of beginnings, transitions, and endings, spreading depolarizations (SDs) can be depicted with two faces: one looking backward, waving a symbolic farewell to the end of a cortical seizure; the other forward looking, opening a darker door for a fatal wave in the brainstem that ends life. There is good agreement on the distinct electrical nature of both events, but neither role is yet proven in patients. SD is a slow-moving wave of cellular depolarization that steadily silences neuronal networks and depresses EEG amplitude, whereas seizures represent fast, intermittent synchronization of neural networks with highly variable …

Region-Specific Roles Of Oviductal Motile Cilia In Oocyte/Embryo Transport And Fertility†, Deirdre M Scully, Tian Xia, Guzel R Musina, Michaela A Mccown, Kohei Umezu, Bonnie K Kircher, Richard R Behringer, Irina V Larina

Faculty, Staff and Students Publications

The physiological and clinical importance of motile cilia in reproduction is well recognized; however, the specific role they play in transport through the oviduct and how ciliopathies lead to subfertility and infertility are still unclear. The contribution of cilia beating, fluid flow, and smooth muscle contraction to overall progressive transport within the oviduct remains under debate. Therefore, we investigated the role of cilia in the oviduct transport of preimplantation eggs/embryos using a combination of genetic and advanced imaging approaches. We show that the region of the oviduct where cumulus-oocyte complex circling occurs, around the time of fertilization, is correlated with …

Lipoprotein(A) And Risk Of Incident Atherosclerotic Cardiovascular Disease: Impact Of High-Sensitivity C-Reactive Protein And Risk Variability Among Human Clinical Subgroups, Ron C Hoogeveen, Margaret R Diffenderfer, Elise Lim, Ching-Ti Liu, Hiroaki Ikezaki, Weihua Guan, Michael Y Tsai, Christie M Ballantyne

Faculty, Staff and Students Publications

No abstract provided.

Large-Scale Multi-Omics Analyses In Hispanic/Latino Populations Identify Genes For Cardiometabolic Traits, Lauren E Petty, Hung-Hsin Chen, Elizabeth G Frankel, Wanying Zhu, Carolina G Downie, Mariaelisa Graff, Phillip Lin, Priya Sharma, Xinruo Zhang, Alyssa C Scartozzi, Rashedeh Roshani, Joshua M Landman, Michael Boehnke, Donald W Bowden, John C Chambers, Anubha Mahajan, Mark I Mccarthy, Maggie C Y Ng, Xueling Sim, Cassandra N Spracklen, Weihua Zhang, Michael Preuss, Erwin P Bottinger, Girish N Nadkarni, Ruth J F Loos, Yii-Der Ida Chen, Jingyi Tan, Eli Ipp, Pauline Genter, Leslie S Emery, Tin Louie, Tamar Sofer, Adrienne M Stilp, Kent D Taylor, Anny H Xiang, Thomas A Buchanan, Kathryn Roll, Chuan Gao, Nicholette D Palmer, Jill M Norris, Lynne E Wagenknecht, Darryl Nousome, Rohit Varma, Roberta Mckean-Cowdin, Xiuqing Guo, Yang Hai, Willa Hsueh, Kevin Sandow, Esteban J Parra, Miguel Cruz, Adan Valladares-Salgado, Niels Wacher-Rodarte, Jerome I Rotter, Mark O Goodarzi, Stephen S Rich, Alain Bertoni, Leslie J Raffel, Jerry L Nadler, Fouad R Kandeel, Ravindranath Duggirala, John Blangero, Donna M Lehman, Ralph A Defronzo, Farook Thameem, Yujie Wang, Sheila Gahagan, Estela Blanco, Raquel Burrows, Alicia Huerta-Chagoya, Jose C Florez, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Christopher A Haiman, Craig L Hanis, Rebecca Rohde, Eric A Whitsel, Alexander P Reiner, Charles Kooperberg, Yun Li, Qing Duan, Miryoung Lee, Paulina Correa-Burrows, Susan K Fried, Kari E North, Joseph B Mccormick, Susan P Fisher-Hoch, Eric R Gamazon, Andrew P Morris, Josep M Mercader, Heather M Highland, Jennifer E Below

Faculty, Staff and Student Publications

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L Demeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael Lenoir, Changwei Li, Loic Le Marchand, Merry-Lynn N Mcdonald, Caitlin P Mchugh, Alanna C Morrison, Take Naseri, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-Der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice

Faculty, Staff and Student Publications

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

Global And Regional Disparities In Access To Specialist Sarcoma Services, Tomas Zamora, Eduardo Botello, Thomas Jenkins, Charlotte Jeys, Minna Laitinen, Ajay Puri, Lee Jeys, Boom Consensus Meeting Participants, Santiago Abad Repiso, Hesham Abdelbary, Alejandro Abiad Mejia, Ahmed Abood, Juan C Abril Martin, Adesegun Abudu, Ayman Abu Elhamd, Marthelena Acosta, Keisuke Ae, Manish Agarwal, Vivek Ajit Singh, Toru Akiyama, Ibrahim Alshaygy, Jose I Albergo, John Alexander, Patricio A Alfaro, Bugra Alpan, Jose Amaya-Valero, Megan Anderson, Dimosthenis Andreou, Lucas Annabell, Christopher Anthony, Ahmed Aoude, William Aston, Libe Asua Mentxaka, Christine Azzopardi, Thomas Baad-Hansen, Ismail T Badr, Francisco Baixauli-Garcia, Gavin Baker, Tessa Balach, Giacomo G Baldi, Janie Barry, Georges Basile, Stefano Bastoni, Mohammad H Basuki, Henrik Bauer, Lee Bayliss, Ricardo G Becker, Angad Bedi, Joseph Benevenia, Francisco Bengoa, Peter Bergh, Marko Bergovec, Nicholas Bernthal, Odion Binitie, David Boddie, Michele Boffano, Patricia Bonilla Huertas, Anna B Borgognoni, Rajesh Botchu, Richard A Boyle, Jos Bramer, Rahat Brar, Harriet Branford-White, Demien Broekhuis, Samuel E Broida, Tymoteusz Budny, Zachary D Burke, Jorge Cabrolier, Jose A Calvo-Haro, Jorge R Calvo-Tapies, Domenico A Campanacci, Rodrigo Cardoso, Richard Carey Smith, Pedro I Carvallo, Nicolas Casales Fresenga, Jose M Casanova, Oscar Ceballos, Juan L Cebrian Parra, Laura K Certain, Sara Chancon Cartaya, Chung M Chan, Yoon Joo Cho, Peter Choong, Yang-Guk Chung, David Ciechanowicz, David Clever, Sebastian Colina, Luis Consuegra, Cory Couch, Gillian Cribb, Carlos Cuervo, Laurence A Cusick, Solomon Dadia, Tanios Dagher, Dietmar Dammerer, Mark Davies, Nerys Davies, Luis P De La Rosa Martino, Francisco J De Santos De La Fuente, Marieke De Vaal, Claudia Deckers, Javier Delgado Obando, Shaneel Deo, Niklas Deventer, Claudia Di Bella, Gregory Domson, Davide M Donati, Desiree M Dorleijn, Jacques Du Toit, Debra Dunne, Rodolfo Duran Ciarrochi, Walid Ebeid, Elina Ekman, Ahmed M El Ghoneimy, Makoto Endo, Levent Eralp, Mahmoud Etaiwi, Scott Evans, Robin Evrard, Will Eward, Alberto Farese, Peter C Ferguson, Pedro F Ferreira Cardoso, Fabrice Fiorenza, Michael Flint, Hector Flores, Joao Freitas, Bruno Fuchs, Tomohiro Fujiwara, Philipp T Funovics, Marcos Galli Serra, Zakareya Gamie, Carlos Garces-Zarzalejo, Aaron Gazendam, Carsten Gebert, Jasper G Gerbers, Craig Gerrand, Ghaith Abou-Nouar, Michelle Ghert, Kanishka M Ghosh, Max Gibbons, Luis C Gomez-Mier, Jesus Gomez-Vallejo, Anne Gomez-Mascard, Marcos R Gonzalez, Fausto Gonzalez-Lizan, Georg Gosheger, Stuart Goudie, Krista Goulding, Stavros D Goumenos, Anthony Griffin, Ashish Gulia, Sanjay Gupta, Amit Gupta, Maurice Guzman, Mohammed Haitham, Jendrik Hardes, Francisco Hardoy, Yusuf Hasan, Georg Hauer, Helard Havard, Rex Haydon, John Healey, Nerea Hernandez Gonzalez, Adriana Hernandez-Lopez, Asle Hesla, Matthew Hess, Chindanai Hongsaprabhas, Francis Hornicek, Keith Hosking, Matthew T Houdek, Eleanor Houghton, Oluwaseyi K Idowu, Joseph Ippolito, Marc Isler, Shintaro Iwata, Jake Jagiello, Neil Jenkins, Tom Jeys, Luke Johnson, Andy Johnston, Min Wook Joo, Paul C Jutte, Kadri Kaldas, Amar Kamat, Sudhir Kannan, Bilal Kapanci, Zeeshan Khan, Hiroshi Kobayashi, Yehuda Kollender, Sebastian Koob, Daniel Kotrych, Vineet Kurisunkal, Richard Kyte, Jose M Lamo De Espinosa, Alexander L Lazarides, Louis-Romee Le Nail, Pawel Legosz, Burkhard Lehner, Andreas Leithner, Maryse Lejoly, Valerae O Lewis, Peng Lin, Francisco Linares, Santiago A Lozano-Calderon, Ashish Mahendra, Ferdiansyah Mahyudin, Fermin J Mandia Mancebo, Sara Martos Torrejon, Christian Marx, Eric Mascard, Jean-Camille Mattei, Louise Mccullough, Sam Mcmahon, Manuel R Medellin Rincon, Benjamin Miller, Shinji Miwa, Gustavo Molina Uribe, Bryan Moon, Thomas Hilton, Diego J Moriel Garcesco, Carol Morris, Guy Morris, Steward Morrison, Sophie Mottard, Marcio Moura, Linde Muster, Robert Nakayama, Prashant Narhari, Ana Navas, Prakash Nayak, Johannes Neugebauer, Erik T Newman, Jyrki Nieminen, Emmy Nyqvist, Lukas Nystrom, Sarah O'Reilly-Harbidge, Gary O'Toole, Vania Oliveira, André Olivier, Mohamed Omar, Eduardo J Ortiz-Cruz, Harzem Ozger, Korhan Ozkan, Elisa Pala, Emanuela Palmerini, Grant Pang, Panayiotis Papagelopoulos, Giovanni Paraliticci, Michael C Parry, Sam Patton, David Peake, Ana Peiro Ibanez, Israel Perez Munoz, Ganapathy R Perianayagam, Michael M Petersen, Joris Ploegmakers, Robin Pollock, Gerard Powell, Juan Pretell, Jan Puetzler, Faisal Qamar, Anand Raja, Raja B Rajasekaran, Dipak Ramkumar, R L Randall, Kenneth Rankin, Kevin A Raskin, Kumaran Rassppan, Lauris Repsa, Mickael Ropars, Peter Rose, Pietro Ruggieri, Wael Sadek, German Salcedo, Aasim Saleemi, Andrea Sambri, Hartej Sar, Roberto Scanferla, Thomas Schubert, Jan Schwarze, Guido Scoccianti, Ashley Scrimshire, Tetsuya Sekita, Ahmad Shehadeh, Ahmed Shoaib, Bhim Shreemal, Felix Shumelinsky, Geoffrey Siegel, Claudio Silveri, Robert Silverwood, Friedl Sinnaeve, Jerome Sison, Andrea Slade, Maria A Smolle, Franz Snyman, Scott Sommerville, Sahil Sood, Andre Spiguel, Hugo St-Yves, Eric L Staals, Silvia Stacchiotti, Nikolas Stavropoulos, Peter Steadman, Jonathan D Stevenson, Mikaela Sullivan, Gwen Sys, Bartlomiej Szostakowski, Angela Tamburini, Yuta Taniguchi, Thomas Temple, Christoph Theil, Joachim Thorkildsen, Meagan Tibbo, Roger Tillman, Yu Toda, Kaspar Tootsi, Ferran Torner-Rubies, Frank Traub, Ioannis Trikoupis, Panagiotis Tsagkozis, Kim Tsoi, Hiroyuki Tsuchiya, Veli-Matti Vainio, Antonio Valcarcel, Juan Valencia, Annelies Van Beeck, Michiel Van De Sande, Thomas Van Den Berghe, Ingrid Van Der Geest, Lizz Van Der Heijden, Robert Van Der Wal, Kirsten Van Langevelde, Gualter Vaz, Roberto Velez Villa, Floortje Verspoor, Koenraad Verstraete, Julia Visgauss, Oleg Vyrva, Hazem Wafa, Sebastian Walter, Wan F Wan Ismail, Edward Wang, Patrick Q Wang, David Warnock, Joel Werier, Wolfram Weschenfelder, Kwok-Chuen Wong, Marjan Wouthuyzen-Bakker, Jay Wunder, Indica Wysinghe, Norio Yamamoto, Zhaoming Ye, Seung-Jae Yoon, Suraya Zainul Abidin, Pierluca Zecchetto, Liuzhe Zhang, Juan P Zumarraga, Miguel A Clara-Altamirano

Faculty, Staff and Student Publications

Aims: Cancer care guidelines have been developed in many subspecialities, usually in advanced health systems. However, there are notable global disparities in healthcare access, which can impact sarcoma care. Unfortunately, there is a lack of global data on this subject. Our aim was to describe access to sarcoma care based on a comprehensive global survey among orthopaedic oncologists, and assess for global as well as regional differences.

Methods: A 25-question survey was emailed to the attendees of the 2024 Birmingham Orthopaedic Oncology Meeting and included questions about the respondents' training and practice, access to sarcoma centres, and specific items for …

Natural Killer Cells’ Functional Impairment Drives The Immune Escape Of Pre-Malignant Clones In Early-Stage Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome Mcallen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla

Faculty, Staff and Student Publications

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is …

Do Patients Want Their Spirituality Addressed During Their Hospital Journey; A Cross-Sectional Study At A Tertiary Care Center In Lebanon, Mohammad Assaf, Ali Ahmad, Hanine Atwi, Joseph Habib, Magda Haj, Reham Yehia, Amal C Rahi, Marianne Majdalani

Faculty, Staff and Student Publications

Background: Spirituality (including religiosity) is a powerful concept in Middle Eastern populations for members of all religious affiliations. This study aims to assess the desire of cancer and critically ill adult inpatients to be asked about their spiritual history, the impact their religious and spiritual beliefs have on their medical decisions, and if such beliefs help them cope with their illnesses.

Methods: A questionnaire consisting of demographics and spirituality questions was developed and administered to 100 patients in a cross-sectional study. We performed psychometric analysis of the questionnaire through reliability and validity testing including construct validity using PCA with a …

A Cluster Randomized Trial Of Xylitol Chewing Gum For Prevention Of Preterm Birth: The Ppax Trial, Gregory C Valentine, Kathleen M Antony, Haleh Sangi-Haghpeykar, Alexis C Wood, Rose Chirwa, Saukani Petro, Mary Dumba, Deborah Nanthuru, Cynthia Shope, Jesse Mlotha-Namarika, Jeffrey Wilkinson, Joshua Aagaard, Ellen J Aagaard, Maxim D Seferovic, Judy Levison, Peter Kazembe, Kjersti M Aagaard

Children’s Nutrition Research Center Staff Publications

Background: Maternal periodontal disease is associated with preterm and low-birthweight deliveries, but randomized trials of likely efficacious treatments (e.g., dental scaling and root planing) during pregnancy have not reduced these adverse outcomes. As an alternative, we hypothesized that periconception initiation of xylitol chewing gum would reduce the occurrence of preterm or low-birthweight deliveries among a historical high-prevalence population in Malawi.

Methods: We conducted an open-label, parallel-enrollment, matched-pair, cluster-randomized, controlled clinical trial across eight health centers (sites) in and around Lilongwe, Malawi. Sites were paired by anticipated delivery volume and randomized to prenatal and oral health education alone (active control) or …

Histone H3 Cysteine 110 Enhances Iron Metabolism And Modulates Replicative Life Span In Saccharomyces Cerevisiae, Chen Cheng, Brenna S Mccauley, Nedas Matulionis, Maria Vogelauer, Dimitrios Camacho, Heather R Christofk, Weiwei Dang, Nicholas A T Irwin, Siavash K Kurdistani

Center on Aging Staff Publications

The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu2+) ion binding and its reduction to the cuprous (Cu1+) form. However, this residue is absent in Saccharomyces cerevisiae, raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into S. cerevisiae increased intracellular Cu1+ levels and ameliorated the iron …

Strong Support Systems Foster Positive Self-Image In Patients With Scoliosis, Megan Glahn Castille, Susan Resendiz Ortega

Faculty, Staff and Students Publications

Purpose: Friend support and social support have been suggested to be beneficial for adolescents facing medical challenges; however, there is little research to identify who is providing emotional support for children and adolescents with scoliosis. Therefore, the purpose of this study was to investigate the sources of emotional support and to analyze a program designed to encourage social support, the Scolios-us Mentor Program (Mentor Program).

Methods: This study consisted of a cross-sectional survey. The survey included the SRS-22r, BSSQ-Brace, and questions about demographics, mental health, the Scolios-us Mentor Program, and general scoliosis experience. The survey was distributed via email to …

Time Required To Implement A Computerized Patient Decision Aid For Lupus In Outpatient Visits, Nathan W Carroll, Aizhan Karabukayeva, Larry R Hearld, Diane Kamen, Alfred H J Kim, Sonali Narain, Narender Annapureddy, Zineb Aouhab, Maureen Mcmahon, Vikas Majithia, Cathy Lee Ching, Winn Chatham, Jasvinder A Singh

Faculty, Staff and Students Publications

BACKGROUND: Patient decision aids have the potential to lower decision conflict for patients and to improve patient-physician communication. However, uptake of decision aids has been poor, in part because the time required to incorporate these into clinical practice is not well understood.

OBJECTIVE: To estimate the time required for a rheumatology clinic to implement a validated decision aid for patients with lupus.

METHODS: Using a cohort of eight implementation sites, study investigators identified the activities required to administer a decision aid. Site coordinators embedded within the clinics timed the duration of each activity. To estimate the effect of viewing the …

Early Nintedanib Deployment In Covid-19 Interstitial Lung Disease (Endcov-I): Study Protocol Of A Randomised, Double-Blind, Placebo-Controlled Trial, Valeria Santibanez, Aditi Mathur, Jigna Zatakia, Nicole Ng, Michele Cohen, Emilia Bagiella, Stacey-Ann Brown, Ivan O Rosas, Nina M Patel, Amy Olson, Peide Li, Maria Padilla

Faculty, Staff and Students Publications

Introduction: In December 2019, the novel SARS-CoV-2 triggered a global pneumonia outbreak, leading to millions of deaths worldwide. A subset of survivors faces increased morbidity and mortality, particularly due to subacute lung injury evolving to chronic fibrosing interstitial lung disease. While nintedanib, a tyrosine-kinase inhibitor, shows promise in treating progressive fibrotic lung disease, limited randomised trial data exists for post-COVID-19-induced lung injury. We hypothesise that treatment with nintedanib may attenuate advancement to the fibrotic stages, offering a potential avenue for improving outcomes in this specific patient subset.

Methods and analysis: We describe the design of a multicentre, randomised, double-blind, placebo-controlled …

Allosteric Targeted Drug Delivery For Enhanced Blood-Brain Barrier Penetration Via Mimicking Transmembrane Domain Interactions, Kaicheng Tang, Zhongjie Tang, Miaomiao Niu, Zuyin Kuang, Weiwei Xue, Xinyu Wang, Xinlong Liu, Yang Yu, Seongdong Jeong, Yifan Ma, Annette Wu, Betty Y S Kim, Wen Jiang, Zhaogang Yang, Chong Li

Faculty, Staff and Student Publications

Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin α

Effects Of Metformin Use On Aneurysmal Subarachnoid Hemorrhage Outcomes, Angel Bueno, Andrea Becerril-Gaitan, Collins Mokua, Kristina Ramirez-Garcia, Justin Nguyen, Faris Shaker, Tien Nguyen, Antonio Dono, Spiros Blackburn, Peng Roc Chen, Mark Dannenbaum, H Alex Choi, Arthur L Day, Jacques J Morcos, Ching-Jen Chen

Faculty, Staff and Student Publications

Background: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.

Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.

Results: A total of 900 patients …

Her2-Selective Tyrosine Kinase Inhibitor, Zongertinib (Bi 1810631), In Patients With Advanced/Metastatic Solid Tumors With Her2 Alterations: A Phase Ia Dose-Escalation Study, John V Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto

Faculty, Staff and Student Publications

Purpose: Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non-small cell lung cancer (NSCLC). Beamion LUNG-1 (ClinicalTrials.gov identifier: NCT04886804) is assessing the safety/efficacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors.

Materials and methods: Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); …

The Zbtb24-Cdca7-Hells Axis Suppresses The Totipotent 2c-Like Reprogramming By Maintaining Dux Methylation And Repression, Dan Guo, Zeling Du, Youqi Liu, Meiqi Lin, Yue Lu, Swanand Hardikar, Yanna Xue, Jinghong Zhang, Taiping Chen, Jiameng Dan

Faculty, Staff and Student Publications

Two-cell-like cells (2CLCs), a rare population (∼0.5%) in mouse embryonic stem cell (mESC) cultures, are in a transient totipotent-like state resembling that of 2C-stage embryos, and their discovery and characterization have greatly facilitated the study of early developmental events, such as zygotic genome activation. However, the molecular determinants governing 2C-like reprogramming remain to be elucidated. Here, we show that ZBTB24, CDCA7, and HELLS, components of a molecular pathway that is involved in the pathogenesis of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, function as negative regulators of 2C-like reprogramming by maintaining DNA methylation of the Dux cluster, a master …

Cognitive Correlates Of Borderline Personality Disorder Features In Youth With Bipolar Spectrum Disorders And Bipolar Offspring, Alessio Simonetti, Sherin Kurian, Evelina Bernardi, Antonio Restaino, Francesca Bardi, Claudia Calderoni, Gabriele Sani, Jair C Soares, Kirti Saxena

Faculty, Staff and Student Publications

Background: Bipolar disorder (BD) and borderline personality disorder (BPD) share common cognitive impairments. These deficits are also shared by bipolar offspring (BD-OFF). Nevertheless, little is known regarding the association between cognitive impairments and BPD features in youth with BD and BD-OFF. Objectives: This study aimed to investigate the association between BPD features and cognitive impairments in youth with BD and BD-OFF.

Methods: Thirty-nine participants (7-17 years) with BD, 18 BD-OFF, and 50 healthy controls (HCs) were recruited. BPD features were assessed using the Borderline Personality Features Scale for Children (BPFS-C). Deficits in executive functions and affective processing were assessed using …

An Open-Label Study Evaluating The Safety And Efficacy Of Amo-01 For The Treatment Of Seizures In Phelan-Mcdermid Syndrome, Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison Mcmorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon

Duncan NRI Faculty and Staff Publications

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion …

Association Of Clonal Hematopoiesis Of Indeterminate Potential With Cardiovascular Events In Patients With Ckd, Yang Pan, Caitlyn Vlasschaert, Varun Rao, Elvis A Akwo, James E Hixson, Md Mesbah Uddin, Zhi Yu, Do-Kyun Kim, Alexander Bick, Bryan Kestenbaum, Michael Chong, Guillaume Paré, Michael Rauh, Adeera Levin, James P Lash, Manjula Kurella Tamura, Debbie L Cohen, Jiang He, Lee Hamm, Rajat Deo, Zeenat Bhat, Panduranga Rao, Dawei Xie, Pradeep Natarajan, Tanika N Kelly, Cassianne Robinson-Cohen, Matthew B Lanktree

Faculty, Staff and Student Publications

Key Points:

1. In patients with CKD, non-DNMT3A clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events.

2. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race.

3. The protective effect of IL6R p.Asp358Ala on non-DNMT3A CHIP cardiovascular risk was similar to the general population.

Background: Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of …

Can Endothelin-1 Help Address The Diagnostic And Prognostic Challenges In Multimorbid Acute Heart Failure Patients?, Bianca-Ana Dmour, Minerva Codruta Badescu, Cristina Tuchiluș, Corina Maria Cianga, Daniela Constantinescu, Nicoleta Dima, Ștefania Teodora Duca, Awad Dmour, Alexandru Dan Costache, Maria-Ruxandra Cepoi, Adrian Crișan, Sabina Andreea Leancă, Cătălin Loghin, Ionela-Lăcrămioara Șerban, Irina Iuliana Costache-Enache

Faculty, Staff and Student Publications

The management of acute heart failure (AHF) is becoming increasingly complex, especially in patients with multiple comorbidities. Endothelin-1 (ET-1), a vasoconstrictive peptide, is an important mediator of neurohormonal activation, endothelial dysfunction, and cardiac remodeling-key processes involved in the pathogenesis of AHF. The aim of our study was to evaluate the diagnostic and prognostic performance of ET-1 in multimorbid AHF patients, compared to established markers such as amino terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI). We conducted a single-center prospective study including 76 patients; 54 with AHF and 22 serving as controls. Upon admission, all patients …

Cell Type-Specific Multi-Omics Analysis Of Cocaine Use Disorder In The Human Caudate Nucleus, Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja P Völker, Svenja Müller, Anita C Hansson, Thomas D Meyer, Marcella Rietschel, Julia Ladewig, Rainer Spanagel, Ana M M Oliveira, Consuelo Walss-Bass, Rick E Bernardi, Philipp Koch, Stephanie H Witt

Faculty, Staff and Student Publications

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, …

Impact Of Perioperative Organ Injury On Morbidity And Mortality In 28 Million Surgical Patients, Felix Kork, Yafen Liang, Adit A Ginde, Xiaoyi Yuan, Rolf Rossaint, Hongfang Liu, Alex S Evers, Holger K Eltzschig

Faculty, Staff and Student Publications

Perioperative organ injury contributes to morbidity and mortality of surgical patients. This cohort study included all elective and emergent surgeries in Germany over 4 years to address the impact of perioperative organ injuries on outcomes. We analyzed 28,350,953 cases. In-hospital mortality was 1.4% (n = 393,157), and 4.4% of cases (n = 1,245,898) experienced perioperative organ injury. Perioperative organ injury was associated with 9-fold higher odds of death and prolonged hospital stay by 11.2 days. Acute kidney injury had the highest incidence (2.0%) and was associated with 25.0% mortality. While delirium had the second highest incidence (1.5%), it was associated …