Medicine and Health Sciences Commons^™

Implicating Genes, Pleiotropy, And Sexual Dimorphism At Blood Lipid Loci Through Multi-Ancestry Meta-Analysis, Stavroula Kanoni, Sarah E Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, Qiping Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A Yousri, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F Mcdaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, Ewarwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Miguel Vazquez-Moreno, Mary F Feitosa, Mary K Wojczynski, Zhe Wang, Michael H Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Noah L Tsao, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Phuong Le, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Swati Bayyana, Heather M Stringham, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J Van Der Most, Niina Pitkänen, Brian E Cade, Sander W Van Der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica Van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique De Kleijn, Gert J De Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L R Kardia, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka De Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Steven C Hunt, Mark Walker, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Maria C Costanzo, Dongkeun Jang, Noël P Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, Eshyong Tai, Rob M Van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne Mcknight, Frank Kee, Karl-Heinz Jöckel, Mark I Mccarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M Van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M 'T Hart, Petra J M Elders, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim Van Der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus A L M Kiemeney, Jacqueline De Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems Van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Allegonda H M Willemsen, Ladrienne Cupples, Joyce B J Van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S De Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A Van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Yeugene Chen, Yuk-Lam Ho, Julie A Lynch, Daniel J Rader, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter W F Wilson, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Karen L Mohlke, Yan V Sun, Andrew P Morris, Michael Boehnke, Christopher D Brown, Pradeep Natarajan, Panos Deloukas, Cristen J Willer, Themistocles L Assimes, Gina M Peloso

Faculty, Staff and Student Publications

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases …

Comparison Of Machine-Learning And Deep-Learning Methods For The Prediction Of Osteoradionecrosis Resulting From Head And Neck Cancer Radiation Therapy, Brandon Reber, Lisanne Van Dijk, Brian Anderson, Abdallah Sherif Radwan Mohamed, Clifton Fuller, Stephen Lai, Kristy Brock

Faculty, Staff and Student Publications

PURPOSE: Deep-learning (DL) techniques have been successful in disease-prediction tasks and could improve the prediction of mandible osteoradionecrosis (ORN) resulting from head and neck cancer (HNC) radiation therapy. In this study, we retrospectively compared the performance of DL algorithms and traditional machine-learning (ML) techniques to predict mandible ORN binary outcome in an extensive cohort of patients with HNC.

METHODS AND MATERIALS: Patients who received HNC radiation therapy at the University of Texas MD Anderson Cancer Center from 2005 to 2015 were identified for the ML (n = 1259) and DL (n = 1236) studies. The subjects were followed for ORN …

Sentiment Analysis Of Insomnia-Related Tweets Via A Combination Of Transformers Using Dempster-Shafer Theory: Pre- And Peri-Covid-19 Pandemic Retrospective Study, Arash Maghsoudi, Sara Nowakowski, Ritwick Agrawal, Amir Sharafkhaneh, Mark E Kunik, Aanand D Naik, Hua Xu, Javad Razjouyan

Faculty, Staff and Student Publications

BACKGROUND: The COVID-19 pandemic has imposed additional stress on population health that may result in a change of sleeping behavior.

OBJECTIVE: In this study, we hypothesized that using natural language processing to explore social media would help with assessing the mental health conditions of people experiencing insomnia after the outbreak of COVID-19.

METHODS: We designed a retrospective study that used public social media content from Twitter. We categorized insomnia-related tweets based on time, using the following two intervals: the prepandemic (January 1, 2019, to January 1, 2020) and peripandemic (January 1, 2020, to January 1, 2021) intervals. We performed a …

Anti-Cancer Mechanisms Of Action Of Therapeutic Alternating Electric Fields (Tumor Treating Fields [Ttfields]), Shadi Shams, Chirag B Patel

Faculty, Staff and Student Publications

Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outcomes in patients. Although the pre-clinical and clinical data are promising, the mechanisms of TTFields are not fully elucidated. Many …

Kidney Proximal Tubule Glut2-More Than Meets The Eye, Majdoleen Ahmad, Ifat Abramovich, Bella Agranovich, Alina Nemirovski, Eyal Gottlieb, Liad Hinden, Joseph Tam

Faculty, Staff and Student Publications

Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion …

Mechanical Ventilation In Patients With Cardiogenic Pulmonary Edema: A Sub-Analysis Of The Lung Safe Study, Laura Amado-Rodríguez, Raquel Rodríguez-Garcia, Giacomo Bellani, Tài Pham, Eddy Fan, Fabiana Madotto, John G Laffey, Guillermo M Albaiceta, Lung Safe Investigators

Faculty, Staff and Student Publications

BACKGROUND: Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality.

METHODS: Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model.

RESULTS: From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59-78], 40% female) were included. ICU and hospital mortality were 34% and 40%, …

Exome Array Analysis Of 9721 Ischemic Stroke Cases From The Sign Consortium, Huichun Xu, Kevin Nguyen, Brady J Gaynor, Hua Ling, Wei Zhao, Patrick F Mcardle, Timothy D O'Connor, O Colin Stine, Kathleen A Ryan, Megan Lynch, Jennifer A Smith, Jessica D Faul, Yao Hu, Jeffrey W Haessler, Myriam Fornage, Charles Kooperberg, On Behalf Of The Trans-Omics For Precision Medicine Topmed Stroke Working Group, James A Perry, Charles C Hong, John W Cole, Elizabeth Pugh, Kimberly Doheny, Sharon L R Kardia, David R Weir, Steven J Kittner, Braxton D Mitchell, Sign Consortium

Faculty, Staff and Student Publications

Recent genome wide association studies have identified 89 common genetic variants robustly associated with ischemic stroke and primarily located in non-coding regions. To evaluate the contribution of coding variants, which are mostly rare, we performed an exome array analysis on 106,101 SNPs for 9721 ischemic stroke cases from the SiGN Consortium, and 12,345 subjects with no history of stroke from the Health Retirement Study and SiGN consortium. We identified 15 coding variants significantly associated with all ischemic stroke at array-wide threshold (i.e., p < 4.7 × 10-7), including two common SNPs in ABO that have previously been associated with stroke. Twelve of the remaining 13 variants were extremely rare …

Glutamine Produces Ammonium To Tune Lysosomal Ph And Regulate Lysosomal Function, Jian Xiong, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du, Michael X Zhu

Faculty, Staff and Student Publications

Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino …

Collaborative Interprofessional Health Science Student Led Realistic Mass Casualty Incident Simulation, Deborah L Mccrea, Robert C Coghlan, Tiffany Champagne-Langabeer, Stanley Cron

Faculty, Staff and Student Publications

In collaboration, a health science university and a fire department offered a mass casualty incident (MCI) simulation. The purpose of this study was to evaluate a cross-section of student health care providers to determine their working knowledge of an MCI. Students were given a pretest using the Emergency Preparedness Information Questionnaire (EPIQ) and the Simple Triage and Rapid Transport (START) Quiz. The EPIQ instrument related to knowledge of triage, first aid, bio-agent detection, critical reporting, incident command, isolation/quarantine/decontamination, psychological issues, epidemiology, and communications. The START Quiz gave 10 scenarios. Didactic online content was given followed by the simulation a few …

Risk Factors For Sars-Cov-2 Transmission In Close Contacts Of Adults At High Risk Of Infection Due To Occupation: Results From The Contact Tracing Strategy Of The Covida Epidemiological Surveillance Study In Bogotá, Colombia, In 2020-2021, Andrea Ramírez Varela, Sandra Contreras-Arrieta, Guillermo Tamayo-Cabeza, Leonardo Salas Zapata, Yuldor Caballero-Díaz, Luis Jorge Hernández Florez, Andrés Patiño Benavidez, Rachid Laajaj, Fernando De La Hoz, Giancarlo Buitrago Gutierrez, Silvia Restrepo, Eduardo Behrentz

Faculty, Staff and Student Publications

OBJECTIVES: To estimate the risk factors for SARS-CoV-2 transmission in close contacts of adults at high risk of infection due to occupation, participants of the CoVIDA study, in Bogotá D.C., Colombia.

SETTING: The CoVIDA study was the largest COVID-19 intensified sentinel epidemiological surveillance study in Colombia thus far, performing over 60 000 RT-PCR tests for SARS-CoV-2 infection. The study implemented a contact tracing strategy (via telephone call) to support traditional surveillance actions performed by the local health authority.

PARTICIPANTS: Close contacts of participants from the CoVIDA study.

PRIMARY AND SECONDARY OUTCOME MEASURES: SARS-CoV-2 testing results were obtained (RT-PCR with CoVIDA …

Multiomics Characterization Of Methicillin-Resistant Staphylococcus Aureus (Mrsa) Isolates With Heterogeneous Intermediate Resistance To Vancomycin (Hvisa) In Latin America, Betsy E Castro, Rafael Rios, Lina P Carvajal, Mónica L Vargas, Mónica P Cala, Lizeth León, Blake Hanson, An Q Dinh, Oscar Ortega-Recalde, Carlos Seas, Jose M Munita, Cesar A Arias, Sandra Rincon, Jinnethe Reyes, Lorena Diaz

Faculty, Staff and Student Publications

BACKGROUND: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms.

OBJECTIVE: To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches.

METHODS: 39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and …

Successful Treatment Of Myofascial Pain Syndrome (Mps) With Surgical Cauterization Of Temporalis Muscle Trigger Points: A Case Report, Craig Pearl, Brendan Moxley, Andrew Perry, Nagi Demian

Faculty, Staff and Student Publications

For patients suffering from myofascial pain syndrome (MPS) affecting muscles of mastication, traditional trigger point therapy treatment regimens can prove inconvenient, due to the short duration of pain relief after each injection and expense of repeated visits which are often not covered by insurance. We present a case of a patient treated using an alternative technique that could develop into an additional modality for treating MPS patients who are refractory to conservative treatment. This technique involves identifying and marking the patient's trigger points and surgically cauterizing each location using a Bovie electrosurgical unit. While traditional trigger point injection therapy for …

Control Of Sars-Cov-2 Infection By Mt1-Mmp-Mediated Shedding Of Ace2, Xuanming Guo, Jianli Cao, Jian-Piao Cai, Jiayan Wu, Jiangang Huang, Pallavi Asthana, Sheung Kin Ken Wong, Zi-Wei Ye, Susma Gurung, Yijing Zhang, Sheng Wang, Zening Wang, Xin Ge, Hiu Yee Kwan, Aiping Lyu, Kui Ming Chan, Nathalie Wong, Jiandong Huang, Zhongjun Zhou, Zhao-Xiang Bian, Shuofeng Yuan, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung …

Clinical Cancer And Direct-To-Consumer Genetic Test Result-Sharing Behavior: Findings From Hints 2020, Sukh Makhnoon, Robert Yu, Susan K Peterson, Sanjay Shete

Faculty, Staff and Student Publications

INTRODUCTION: Sharing genetic test results with different stakeholders such as family members, healthcare providers and genetic counselors (HCP/GCs), spouses/partners, and friends is a health behavior of clinical importance in genomic medicine.

METHODS: Using nationally representative population-based data collected from the Health Information National Trends Survey (HINTS 5, cycle 4), we identified the prevalence and factors associated with genetic test result-sharing behavior for high-risk cancer tests, genetic health risk tests, and ancestry tests within four groups: HCP/GCs, first-degree relatives (FDRs), spouse/partner, and friend/other.

RESULTS: Overall, 68.4% of those who underwent high-risk cancer genetic testing shared their results with FDRs, whereas 89.9% …

White Matter Correlates Of Domain-Specific Working Memory, Autumn Horne, Junhua Ding, Tatiana T Schnur, Randi C Martin

Faculty, Staff and Student Publications

Prior evidence suggests domain-specific working memory (WM) buffers for maintaining phonological (i.e., speech sound) and semantic (i.e., meaning) information. The phonological WM buffer's proposed location is in the left supramarginal gyrus (SMG), whereas semantic WM has been related to the left inferior frontal gyrus (IFG), the middle frontal gyrus (MFG), and the angular gyrus (AG). However, less is known about the white matter correlates of phonological and semantic WM. We tested 45 individuals with left hemisphere brain damage on single word processing, phonological WM, and semantic WM tasks and obtained T1 and diffusion weighted neuroimaging. Virtual dissections were performed for …

Hif1a-Dependent Induction Of Alveolar Epithelial Pfkfb3 Dampens Acute Lung Injury, Christine U Vohwinkel, Nana Burns, Ethan Coit, Xiaoyi Yuan, Eszter K Vladar, Christina Sul, Eric P Schmidt, Peter Carmeliet, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during …

Human Health During Space Travel: State-Of-The-Art Review, Chayakrit Krittanawong, Nitin Kumar Singh, Richard A Scheuring, Emmanuel Urquieta, Eric M Bershad, Timothy R Macaulay, Scott Kaplin, Carly Dunn, Stephen F Kry, Thais Russomano, Marc Shepanek, Raymond P Stowe, Andrew W Kirkpatrick, Timothy J Broderick, Jean D Sibonga, Andrew G Lee, Brian E Crucian

Faculty, Staff and Student Publications

The field of human space travel is in the midst of a dramatic revolution. Upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX, Virgin Galactic) have already started the process of preparing for long-distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s. With the emergence of space tourism, space travel has materialized as a potential new, exciting frontier of business, hospitality, …

Activation Of Basal Forebrain-To-Lateral Habenula Circuitry Drives Reflexive Aversion And Suppresses Feeding Behavior, Jessica L Swanson, Joshua Ortiz-Guzman, Snigdha Srivastava, Pey-Shyuan Chin, Sean W Dooling, Elizabeth Hanson Moss, Mikhail Y Kochukov, Patrick J Hunt, Jay M Patel, Brandon T Pekarek, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related …

Molecular Markers In Maternal Blood Exosomes Allow Early Detection Of Fetal Alcohol Spectrum Disorders, Nune Darbinian, Armine Darbinyan, John Sinard, Gabriel Tatevosian, Nana Merabova, Faith D'Amico, Tarek Khader, Ahsun Bajwa, Diana Martirosyan, Alina K Gawlinski, Richa Pursnani, Huaqing Zhao, Shohreh Amini, Mary Morrison, Laura Goetzl, Michael E Selzer

Faculty, Staff and Student Publications

Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions. Banked human fetal brains and eyes at 9−22 weeks’ gestation were paired with maternal blood samples, analyzed for morphometry, protein, and RNA expression, and apoptotic signaling. Alcohol (EtOH)-exposed (maternal self-report) fetuses were compared with unexposed controls matched for fetal age, sex, and maternal race. Fetal brain-derived exosomes (FB-E) were isolated from maternal blood and analyzed for protein, RNA, and apoptotic …

Dissecting The Recruitment And Self-Organization Of Αsma-Positive Fibroblasts In The Foreign Body Response, Maria Parlani, Matthew L Bedell, Antonios G Mikos, Peter Friedl, Eleonora Dondossola

Faculty, Staff and Student Publications

The foreign body response (FBR) is a clinically relevant issue that can cause malfunction of implanted medical devices by fibrotic encapsulation. Whereas inflammatory aspects of the FBR have been established, underlying fibroblast-dependent mechanisms remain unclear. We here combine multiphoton microscopy with ad hoc reporter mice expressing α-smooth muscle actin (αSMA) protein to determine the locoregional fibroblast dynamics, activation, and fibrotic encapsulation of polymeric materials. Fibroblasts invaded as individual cells and established a multicellular network, which transited to a two-compartment fibrotic response displaying an αSMA cold external capsule and a long-lasting, inner αSMA hot environment. The recruitment of fibroblasts and extent …

Concurrent Mutations In Sf3b1 And Phf6 In Myeloid Neoplasms, Zhuang Zuo, L Jeffrey Medeiros, Sofia Garces, Mark J Routbort, Chi Young Ok, Sanam Loghavi, Rashmi Kanagal-Shamanna, Fatima Zahra Jelloul, Guillermo Garcia-Manero, Kelly S Chien, Keyur P Patel, Rajyalakshmi Luthra, C Cameron Yin

Faculty, Staff and Student Publications

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the …

Ototoxicity Of Topical Antibiotic Ear Drops In Chronic Suppurative Otitis Media In Humans: A Review Of The Literature, Syed Zohaib Maroof Hussain, Syed S Hashmi, Asad Qayyum

Faculty, Staff and Student Publications

An electronic search of the literature was performed for reported cases of ototoxicity associated with the use of topical antibiotic ear drops in humans. The dosage, duration, and type of ototoxic preparations involved were recorded. Due to the scant quantity of low-quality information that is currently available, there was uncertainty about the usefulness of topical antibiotics in enhancing the resolution of ear discharge in patients with chronic suppurative otitis media. However, despite this uncertainty, there are some data to show that using topical antibiotics in comparison to a placebo or in conjunction with a systemic antibiotic may be useful. Additionally, …

Kras Inhibitor That Simultaneously Inhibits Nucleotide Exchange Activity And Effector Engagement, Cynthia V Pagba, Amit K Gupta, Ali K Naji, Dharini Van Der Hoeven, Kelly Churion, Xiaowen Liang, Jacob Jakubec, Magnus Hook, Yan Zuo, Marisela Martinez De Kraatz, Jeffrey A Frost, Alemayehu A Gorfe

Faculty, Staff and Student Publications

We describe a small molecule ligand ACA-14 (2-hydroxy-5-{[(2-phenylcyclopropyl) carbonyl] amino} benzoic acid) as an initial lead for the development of direct inhibitors of KRAS, a notoriously difficult anticancer drug target. We show that the compound binds to KRAS near the switch regions with affinities in the low micromolar range and exerts different effects on KRAS interactions with binding partners. Specifically, ACA-14 impedes the interaction of KRAS with its effector Raf and reduces both intrinsic and SOS-mediated nucleotide exchange rates. Likely as a result of these effects, ACA-14 inhibits signal transduction through the MAPK pathway in cells expressing mutant KRAS and …

Total Transfemoral Percutaneous Endovascular Aortic Arch Repair Using 3-Vessel Inner Branch Stent-Graft, Emanuel R Tenorio, Thanila A Macedo, Laura Ocasio, Marina Dias Neto, Guilherme B Barbosa Lima, Aidin Baghbani-Oskouei, Anthony L Estrera, Abhijeet Dhoble, Shao Feng Zhou, Gustavo S Oderich

Faculty, Staff and Student Publications

Endovascular repair has been introduced to decrease the morbidity and mortality associated with open surgical repair of aortic arch pathology. We illustrate total percutaneous transfemoral approach with a 3-vessel inner branch stent-graft to treat aortic arch aneurysm. (Level of Difficulty: Advanced.).

Author Correction: A Nanoengineered Topical Transmucosal Cisplatin Delivery System Induces Anti-Tumor Response In Animal Models And Patients With Oral Cancer, Manijeh Goldberg, Aaron Manzi, Amritpreet Birdi, Brandon Laporte, Peter Conway, Stefanie Cantin, Vasudha Mishra, Alka Singh, Alexander T Pearson, Eric R Goldberg, Sam Goldberger, Benjamin Flaum, Rifat Hasina, Nyall R London, Gary L Gallia, Chetan Bettegowda, Simon Young, Vlad Sandulache, James Melville, Jonathan Shun, Sonya E O'Neill, Erkin Aydin, Alex Zhavoronkov, Anxo Vidal, Atenea Soto, Maria Jose Alonso, Ari J Rosenberg, Mark W Lingen, Anil D'Cruz, Nishant Agrawal, Evgeny Izumchenko

Faculty, Staff and Student Publications

No abstract provided.

A Flexible-Hazards Cure Model With Application To Patients With Soft Tissue Sarcoma, Can Xie, Xuelin Huang, Ruosha Li, Peter W T Pisters

Faculty, Staff and Student Publications

In medical research, it is often of great interest to have an accurate estimation of cure rates by different treatment options and for different patient groups. If the follow-up time is sufficiently long and the sample size is large, the proportion of cured patients will make the Kaplan-Meier estimator of survival function have a flat plateau at its tail, whose value indicates the overall cure rate. However, it may be difficult to estimate and compare the cure rates for all the subsets of interest in this way, due to the limit of sample sizes and curse of dimensionality. In the …

Correlations Between Complex Human Phenotypes Vary By Genetic Background, Gender, And Environment, Michael Elgart, Matthew O Goodman, Carmen Isasi, Han Chen, Alanna C Morrison, Paul S De Vries, Huichun Xu, Ani W Manichaikul, Xiuqing Guo, Nora Franceschini, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Donald M Lloyd-Jones, Myriam Fornage, Adolfo Correa, Nancy L Heard-Costa, Ramachandran S Vasan, Ryan Hernandez, Robert C Kaplan, Susan Redline, Tamar Sofer

Faculty, Staff and Student Publications

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we …

Labial Frenotomy For Symptomatic Isolated Upper Lip Tie, Cecilia G Freeman, Jason F Ohlstein, Nicholas A Rossi, John B Mcintire, Luis D Neve, Shiva Daram, Harold S Pine

Faculty, Staff and Student Publications

BACKGROUND: The benefits and challenges of successful breastfeeding for both mother and child have been well-established in the literature. While ankyloglossia, or tongue tie, alone or in combination with upper lip tie has been the focus of several previous studies, very few have directly addressed isolated symptomatic upper lip tie and the role of surgical correction for breastfeeding difficulties.

MATERIALS AND METHODS: Seven infants with isolated upper lip tie and breastfeeding difficulty were taken to the operating room for labial frenotomy. These infants were assessed at their follow-up visits for their degree of weight gain since their procedure. Their mothers …

Spatial Heterogeneity Of Infiltrating T Cells In High-Grade Serous Ovarian Cancer Revealed By Multi-Omics Analysis, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Yong Zhou, Wenting Li, Jingjing Yin, Xiaohang Yang, Ensong Guo, Xi Li, Yu Fu, Si Liu, Dianxing Hu, Xu Qin, Yingyu Dou, Rourou Xiao, Funian Lu, Zizhuo Wang, Tianyu Qin, Wei Wang, Qinghua Zhang, Shuaicheng Li, Ding Ma, Gordon B Mills, Gang Chen, Chaoyang Sun

Faculty, Staff and Student Publications

Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T …

Structural Insights Into Cardiolipin Replacement By Phosphatidylglycerol In A Cardiolipin-Lacking Yeast Respiratory Supercomplex, Elena G Govorunova, Oleg A Sineshchekov, Leonid S Brown, Ana-Nicoleta Bondar, John L Spudich

Faculty, Staff and Student Publications

Potassium-selective channelrhodopsins (KCRs) are light-gated K+ channels recently found in the stramenopile protist Hyphochytrium catenoides. When expressed in neurons, KCRs enable high-precision optical inhibition of spiking (optogenetic silencing). KCRs are capable of discriminating K+ from Na+ without the conventional K+ selectivity filter found in classical K+ channels. The genome of H. catenoides also encodes a third paralog that is more permeable for Na+ than for K+. To identify structural motifs responsible for the unusual K+ selectivity of KCRs, we systematically analyzed a series of chimeras and mutants of this protein. We found that mutations of three critical residues in the …