Medicine and Health Sciences Commons^™

Physical And Stressful Psychological Impacts Of Prolonged Personal Protective Equipment Use During The Covid-19 Pandemic: A Cross-Sectional Survey Study, Giuseppe Candido, Costanza Tortù, Chiara Seghieri, Riccardo Tartaglia, Chiara Baglioni, Paolo Citti, Ida Marina Raciti, Micaela La Regina, Silvia Simonini, Moira Urbani, Chiara Parretti, Paul Barach

College of Population Health Faculty Papers

BACKGROUND: Healthcare workers (HCWs) caring for COVID-19 infected patients are exposed to stressful and traumatic events with potential for severe and sustained adverse mental and physical health consequences. Our aim was to assess the magnitude of physical and mental health outcomes of HCWs due to the prolonged use of personal protective equipment (PPE) treating COVID-19 patients.

METHODS: This cross-sectional study assessed the symptoms of stress, anxiety, insomnia, and psychological resilience using the Stress and Anxiety to Viral Epidemics (SAVE) scale, Insomnia Severity Index (ISI), and Resilience Scale (RS), respectively, in Italy between 1st February and 31st March 2022. The physical …

Variant Spectrum Of Von Hippel-Lindau Disease And Its Genomic Heterogeneity In Japan, Kenji Tamura, Yuki Kanazashi, Chiaki Kawada, Yuya Sekine, Kazuhiro Maejima, Shingo Ashida, Takashi Karashima, Shohei Kojima, Nickolas F Parrish, Shunichi Kosugi, Chikashi Terao, Shota Sasagawa, Masashi Fujita, Todd A Johnson, Yukihide Momozawa, Keiji Inoue, Taro Shuin, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one …

Autolysosomal Exocytosis Of Lipids Protect Neurons From Ferroptosis, Isha Ralhan, Jinlan Chang, Matthew J Moulton, Lindsey D Goodman, Nathanael Y J Lee, Greg Plummer, H Amalia Pasolli, Doreen Matthies, Hugo J Bellen, Maria S Ioannou

Faculty, Staff and Students Publications

During oxidative stress neurons release lipids that are internalized by glia. Defects in this coordinated process play an important role in several neurodegenerative diseases. Yet, the mechanisms of lipid release and its consequences on neuronal health are unclear. Here, we demonstrate that lipid-protein particle release by autolysosome exocytosis protects neurons from ferroptosis, a form of cell death driven by lipid peroxidation. We show that during oxidative stress, peroxidated lipids and iron are released from neurons by autolysosomal exocytosis which requires the exocytic machinery VAMP7 and syntaxin 4. We observe membrane-bound lipid-protein particles by TEM and demonstrate that these particles are …

The Role Of Native Cysteine Residues In The Oligomerization Of Kcnq1 Channels, Alison Bates, Rebecca B Stowe, Elizabeth M Travis, Lauryn E Cook, Carole Dabney-Smith, Gary A Lorigan

Faculty, Staff and Student Publications

KCNQ1, the major component of the slow-delayed rectifier potassium channel, is responsible for repolarization of cardiac action potential. Mutations in this channel can lead to a variety of diseases, most notably long QT syndrome. It is currently unknown how many of these mutations change channel function and structure on a molecular level. Since tetramerization is key to proper function and structure of the channel, it is likely that mutations modify the stability of KCNQ1 oligomers. Presently, the C-terminal domain of KCNQ1 has been noted as the driving force for oligomer formation. However, truncated versions of this protein lacking the C-terminal …

Mitotrace: A Computational Framework For Analyzing Mitochondrial Variation In Single-Cell Rna Sequencing Data, Mingqiang Wang, Wankun Deng, David C Samuels, Zhongming Zhao, Lukas M Simon

Faculty, Staff and Student Publications

Genetic variation in the mitochondrial genome is linked to important biological functions and various human diseases. Recent progress in single-cell genomics has established single-cell RNA sequencing (scRNAseq) as a popular and powerful technique to profile transcriptomics at the cellular level. While most studies focus on deciphering gene expression, polymorphisms including mitochondrial variants can also be readily inferred from scRNAseq. However, limited attention has been paid to investigate the single-cell landscape of mitochondrial variants, despite the rapid accumulation of scRNAseq data in the community. In addition, a diploid context is assumed for most variant calling tools, which is not appropriate for …

Intrinsic Tgf-Β Signaling Attenuates Proximal Tubule Mitochondrial Injury And Inflammation In Chronic Kidney Disease, Merve Kayhan, Judith Vouillamoz, Daymé Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H Wenger, Stellor Nlandu Khodo

2020-Current year OA Pubs

Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in …

Clinical Characteristics And Treatment Patterns Of Pregnant Women With Hypertension In Primary Care In The Federal Capital Territory Of Nigeria: Cross-Sectional Results From The Hypertension Treatment In Nigeria Program, Zainab Mahmoud, Ikechukwu A Orji, Gabriel L Shedul, Kasarachi Aluka-Omitiran, Nanna Ripiye, Blessing Akor, Helen Eze, Tunde Ojo, Guhan Iyer, Abigail S Baldridge, Lisa R Hirschhorn, Mark D Huffman, Dike B Ojji

2020-Current year OA Pubs

BACKGROUND: Hypertensive disorders of pregnancy, including hypertension, are a leading cause of maternal mortality in Nigeria. However, there is a paucity of data on pregnant women with hypertension who receive care in primary health care facilities. This study presents the results from a cross-sectional analysis of pregnant women enrolled in the Hypertension Treatment in Nigeria Program which is aimed at integrating and strengthening hypertension care in primary health care centres.

METHODS: A descriptive analysis of the baseline results from the Hypertension Treatment in Nigeria Program was performed. Baseline blood pressures, treatment and control rates of pregnant women were analysed and …

Digital Health Technologies For Peripartum Depression Management Among Low-Socioeconomic Populations: Perspectives From Patients, Providers, And Social Media Channels, Alexandra Zingg, Tavleen Singh, Amy Franklin, Angela Ross, Sudhakar Selvaraj, Jerrie Refuerzo, Sahiti Myneni

Faculty, Staff and Student Publications

BACKGROUND: Peripartum Depression (PPD) affects approximately 10-15% of perinatal women in the U.S., with those of low socioeconomic status (low-SES) more likely to develop symptoms. Multilevel treatment barriers including social stigma and not having appropriate access to mental health resources have played a major role in PPD-related disparities. Emerging advances in digital technologies and analytics provide opportunities to identify and address access barriers, knowledge gaps, and engagement issues. However, most market solutions for PPD prevention and management are produced generically without considering the specialized needs of low-SES populations. In this study, we examine and portray the information and technology needs …

Cfp1 Governs Uterine Epigenetic Landscapes To Intervene In Progesterone Responses For Uterine Physiology And Suppression Of Endometriosis, Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J Demayo, John P Lydon, David G Skalnik, Hyunjung J Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Haengseok Song

Faculty, Staff and Students Publications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent …

Sex Differences In The Clinical Presentation Of Early Psychosis In A Primary Care Setting, Brooke Carter, Rebecca Rodrigues, Jennifer Reid, Suzanne Archie, Amanda L Terry, Lena Palaniyappan, Arlene G Macdougall, Aristotle Voineskos, Saadia Hameed Jan, Liisa Jaakkimainen, Branson Chen, Neo Sawh, Kelly K. Anderson

Epidemiology and Biostatistics Publications

Primary care is an important part of the help-seeking pathway for young people experiencing early psychosis, but sex differences in clinical presentation in these settings are unexplored. We aimed to identify sex differences in clinical presentation to primary care services in the 1-year period prior to a first diagnosis of psychotic disorder. We identified first-onset cases of non-affective psychotic disorder over a 10-year period (2005-2015) using health administrative data linked with electronic medical records (EMRs) from primary care (n = 465). Detailed information on encounters in the year prior to first diagnosis was abstracted, including psychiatric symptoms, other relevant behaviours, …

Long-Term Outcomes Of Bevacizumab And Chemoradiation For Locoregionally Advanced Nasopharyngeal Carcinoma: A Nonrandomized Controlled Trial, Nancy Y. Lee, Jonathan Harris, John Kim, Adam Garden, James Mechalakos, David G. Pfister, Anthony T.C. Chan, Kenneth Hu, A. Dimitrios Colevas, Steven Frank, George Shenouda, Voichita Bar-Ad, John N. Waldron, Paul M. Harari, Adam Raben, Pedro Torres-Saavedra, Quynh-Thu Le

Department of Radiation Oncology Faculty Papers

IMPORTANCE: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC).

OBJECTIVE: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC.

DESIGN, SETTING, AND PARTICIPANTS: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. …

Combinatorial Bcl2 Family Expression In Acute Myeloid Leukemia Stem Cells Predicts Clinical Response To Azacitidine/Venetoclax, Alexander Waclawiczek, Darja Karpova, Et Al.

2020-Current year OA Pubs

UNLABELLED: The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based "Mediators of …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, C Charles Gu, Et Al.

2020-Current year OA Pubs

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

Real-World Utilization Of The Pill-In-The-Pocket Method For Terminating Episodes Of Atrial Fibrillation: Data From The Multinational Antiarrhythmic Interventions For Managing Atrial Fibrillation (Aim-Af) Survey, James A Reiffel, Carina Blomström-Lundqvist, Giuseppe Boriani, Andreas Goette, Peter R Kowey, Jose L Merino, Jonathan P Piccini, Sanjeev Saksena, A John Camm

Department of Medicine Faculty Papers

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Episodes may stop spontaneously (paroxysmal AF); may terminate only via intervention (persistent AF); or may persist indefinitely (permanent AF) (see European and American guidelines, referenced below, for more precise definitions). Recently, there has been renewed interest in an approach to terminate AF acutely referred to as 'pill-in-the-pocket' (PITP). The PITP is recognized in both the US and European guidelines as an effective option using an oral antiarrhythmic drug for acute conversion of acute/recent-onset AF. However, how PITP is currently used has not been systematically evaluated.

METHODS …

Phylogenomic Analyses Provide Insights Into Primate Evolution, Yong Shao, Long Zhou, Fang Li, Lan Zhao, Bao-Lin Zhang, Feng Shao, Jia-Wei Chen, Chun-Yan Chen, Xupeng Bi, Xiao-Lin Zhuang, Hong-Liang Zhu, Jiang Hu, Zongyi Sun, Xin Li, Depeng Wang, Iker Rivas-González, Sheng Wang, Yun-Mei Wang, Wu Chen, Gang Li, Hui-Meng Lu, Yang Liu, Lukas F K Kuderna, Kyle Kai-How Farh, Peng-Fei Fan, Li Yu, Ming Li, Zhi-Jin Liu, George P Tiley, Anne D Yoder, Christian Roos, Takashi Hayakawa, Tomas Marques-Bonet, Jeffrey Rogers, Peter D Stenson, David N Cooper, Mikkel Heide Schierup, Yong-Gang Yao, Ya-Ping Zhang, Wen Wang, Xiao-Guang Qi, Guojie Zhang, Dong-Dong Wu

Faculty, Staff and Students Publications

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our …

Curated And Harmonized Gut Microbiome 16s Rrna Amplicon Data From Dietary Fiber Intervention Studies In Humans, Cynthia I Rodriguez, Ali Keshavarzian, Bruce R Hamaker, Feitong Liu, Genelle R Lunken, Heather Rasmussen, Hongwei Zhou, Julien Tap, Kelly S Swanson, Maria Ukhanova, Marion Leclerc, Martin Gotteland, Paola Navarrete, Petia Kovatcheva-Datchary, Wendy J Dahl, Jennifer B H Martiny

Faculty, Staff and Student Publications

Next generation amplicon sequencing has created a plethora of data from human microbiomes. The accessibility to this scientific data and its corresponding metadata is important for its reuse, to allow for new discoveries, verification of published results, and serving as path for reproducibility. Dietary fiber consumption has been associated with a variety of health benefits that are thought to be mediated by gut microbiota. To enable direct comparisons of the response of the gut microbiome to fiber, we obtained 16S rRNA sequencing data and its corresponding metadata from 11 fiber intervention studies for a total of 2,368 samples. We provide …

An Epidemic Model With Time Delays Determined By The Infectivity And Disease Durations, Masoud Saade, Samiran Ghosh, Malay Banerjee, Vitaly Volpert

Faculty, Staff and Student Publications

We propose an epidemiological model with distributed recovery and death rates. It represents an integrodifferential system of equations for susceptible, exposed, infectious, recovered and dead compartments. This model can be reduced to the conventional ODE model under the assumption that recovery and death rates are uniformly distributed in time during disease duration. Another limiting case, where recovery and death rates are given by the delta-function, leads to a new point-wise delay model with two time delays corresponding to the infectivity period and disease duration. Existence and positiveness of solutions for the distributed delay model and point-wise delay model are proved. …

A Global Catalog Of Whole-Genome Diversity From 233 Primate Species\, Lukas F K Kuderna, Hong Gao, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idrissa S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Jeffrey Rogers, Kyle Kai-How Farh, Tomas Marques Bonet

Faculty, Staff and Students Publications

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families …

Rare Penetrant Mutations Confer Severe Risk Of Common Diseases, Petko P Fiziev, Jeremy Mcrae, Jacob C Ulirsch, Jacqueline S Dron, Tobias Hamp, Yanshen Yang, Pierrick Wainschtein, Zijian Ni, Joshua G Schraiber, Hong Gao, Dylan Cable, Yair Field, Francois Aguet, Marc Fasnacht, Ahmed Metwally, Jeffrey Rogers, Tomas Marques-Bonet, Heidi L Rehm, Anne O'Donnell-Luria, Amit V Khera, Kyle Kai-How Farh

Faculty, Staff and Students Publications

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared …

Machine Learning Reveals Lipidome Remodeling Dynamics In A Mouse Model Of Ovarian Cancer, Olatomiwa O Bifarin, Samyukta Sah, David A Gaul, Samuel G Moore, Ruihong Chen, Murugesan Palaniappan, Jaeyeon Kim, Martin M Matzuk, Facundo M Fernández

Faculty, Staff and Students Publications

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. …

The Landscape Of Tolerated Genetic Variation In Humans And Primates, Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G Schraiber, Jeremy Mcrae, Moriel Singer-Berk, Yanshen Yang, Anastasia S D Dietrich, Petko P Fiziev, Lukas F K Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi Do Amaral, Mariluce Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Monkol Lek, Shamil Sunyaev, Anne O'Donnell-Luria, Heidi L Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

INTRODUCTION:

Millions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.

RATIONALE:

As a result of the short evolutionary distance between humans and nonhuman primates, …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, Matthew O Goodman, Alyna T Khan, Jiongming Wang, Elena Feofanova, Joshua C Bis, Kerri L Wiggins, Jennifer E Huffman, Tanika Kelly, Tali Elfassy, Xiuqing Guo, Walter Palmas, Henry J Lin, Shih-Jen Hwang, Yan Gao, Kendra Young, Gregory L Kinney, Jennifer A Smith, Bing Yu, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Xiaofeng Zhu, Yii-Der Ida Chen, I-Te Lee, C Charles Gu, Donald M Lloyd-Jones, Sebastian Zöllner, Myriam Fornage, Charles Kooperberg, Adolfo Correa, Bruce M Psaty, Donna K Arnett, Carmen R Isasi, Stephen S Rich, Robert C Kaplan, Susan Redline, Braxton D Mitchell, Nora Franceschini, Daniel Levy, Jerome I Rotter, Alanna C Morrison, Tamar Sofer

Faculty, Staff and Student Publications

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

Association Of Circulating Markers With Cognitive Decline After Radiation Therapy For Brain Metastasis, Kristin Huntoon, S Keith Anderson, Karla V Ballman, Erin Twohy, Katharine Dooley, Wen Jiang, Yi An, Jing Li, Christina Von Roemeling, Yaqing Qie, Owen A Ross, Jane H Cerhan, Anthony C Whitton, Jeffrey N Greenspoon, Ian F Parney, Jonathan B Ashman, Jean-Paul Bahary, Constantinos Hadjipanayis, James J Urbanic, Elana Farace, Deepak Khuntia, Nadia N Laack, Paul D Brown, David Roberge, Betty Y S Kim

Faculty, Staff and Student Publications

BACKGROUND: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.

METHODS: In this retrospective analysis of prospectively collected …

Modeling The Longitudinal Changes Of Ancestry Diversity In The Million Veteran Program, Frank R Wendt, Gita A Pathak, Jacqueline Vahey, Xuejun Qin, Dora Koller, Brenda Cabrera-Mendoza, Angela Haeny, Kelly M Harrington, Nallakkandi Rajeevan, Linh M Duong, Daniel F Levey, Flavio De Angelis, Antonella De Lillo, Tim B Bigdeli, Saiju Pyarajan, John Michael Gaziano, Joel Gelernter, Mihaela Aslan, Dawn Provenzale, Drew A Helmer, Elizabeth R Hauser, Renato Polimanti, Department Of Veteran Affairs Cooperative Study Program (#2006)

Center for Medical Ethics and Health Policy Staff Publications

Background: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]).

Results: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and …

Long-Term Outcomes Of Dual Vs Single Her2-Directed Neoadjuvant Therapy In Nsabp B-41., Priya Rastogi, Gong Tang, Saima Hassan, Charles E Geyer, Catherine A Azar, Gustav C Magrinat, J Marie Suga, Harry D Bear, Luis Baez-Diaz, Shakir Sarwar, Jean-Francois Boileau, Adam M Brufsky, Henry R Shibata, Hanna Bandos, Soonmyung Paik, Greg Yothers, Sandra M Swain, Eleftherios P Mamounas, Norman Wolmark

Oncology Articles

BACKGROUND: The primary aim of this randomized neoadjuvant trial in operable, HER2-positive breast cancer, was to determine the efficacy on pathologic complete response (pCR) of substituting lapatinib (L) for trastuzumab (T) or adding L to T, in combination with weekly paclitaxel (WP) following AC. Results on pCR were previously reported. Here, we report data on planned secondary endpoints, recurrence-free interval (RFI) post-surgery, and overall survival (OS).

METHODS: All patients received standard AC q3 weeks × 4 cycles followed by WP (80 mg/m

RESULTS: RFI at 4.5 years was 87.2%, 79.4% (p = 0.34; HR = 1.37; 95% CI 0.80, 2.34), …

Resident Perspectives On The Value Of Rural General Surgery Rotations: It's Not Just About The Cases, Dorothy Hughes, Rebekah Wood, Randy Woods, Michael Sarap

Department of Surgery Faculty Publications

Purpose: Understand the scope of cases that residents participate in during rural general surgery rotations and the value residents and program directors find in such rotations. In turn, our goal is to add to the ongoing conversation the value exposure to rural surgery brings to surgery training. Methods: Qualitative study analyzed reviews of residents' self-reported case lists and field notes from exit interviews with the site director. Results: Trainees participated in an average of 105 cases during the rotation, including basic and advanced endoscopy along with exposure to a wide array of surgical cases. Residents had exposure to the rural …

Innovative Strategy To Improve Enteral Nutrition In Prone Positioning With Patients With Covid-19., Jan Powers Phd, Rn, Ccrn, Janette Richardson, Jennifer Rechter Msn, Rn-Bc, Agcns-Bc

Nursing Publications, Posters, & Presentations

BACKGROUND: Enteral nutrition is essential to improve outcomes in patients who are critically ill. Patients in the prone position, including those diagnosed with coronavirus disease 2019 (COVID-19) present additional challenges for enteral nutrition initiation.

METHODS: A novel technique for placing feeding tubes while in the prone position was developed using an electromagnetic placement device and specialty trained clinical nurse specialists. Data were assessed retrospectively to determine effectiveness of this new practice.

RESULTS: Sixty-eight patients had feeding tubes placed while in the prone position; 75% were able to be placed through the postpyloric route, 22% were placed through the gastric route, …

A Shared Decision-Making Process Utilizing A Decision Coach In Pediatric Epilepsy Surgery, Michelle Kregel, Natalie Evans, Bonnie Wooten, Craig Campbell, Sandrine De Ribaupierre, Andrea Andrade

Paediatrics Publications

BACKGROUND & RATIONALE: The process to evaluate candidacy for epilepsy surgery is lengthy and stressful for caregivers, therefore the decision can be challenging. There is not a lot of information in regard to how families of a child living with epilepsy navigate the stressful decision during surgical candidacy evaluation. With difficult decisions comes the possibility of increased decisional conflict in both the child and the family.

METHODS: A project designed to provide greater knowledge to the family was conducted utilizing the shared decision-making (SDM) process to assist families in the decision-making during surgical candidacy evaluation; this was done using a …

A Novel Integrated Approach To Predicting Cancer Immunotherapy Efficacy, Ruihan Luo, Jacqueline Chyr, Jianguo Wen, Yanfei Wang, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint …

A Guide To The Brain Initiative Cell Census Network Data Ecosystem, Michael Hawrylycz, Maryann E Martone, Giorgio A Ascoli, Jan G Bjaalie, Hong-Wei Dong, Satrajit S Ghosh, Jesse Gillis, Ronna Hertzano, David R Haynor, Patrick R Hof, Yongsoo Kim, Ed Lein, Yufeng Liu, Jeremy A Miller, Partha P Mitra, Eran Mukamel, Lydia Ng, David Osumi-Sutherland, Hanchuan Peng, Patrick L Ray, Raymond Sanchez, Aviv Regev, Alex Ropelewski, Richard H Scheuermann, Shawn Zheng Kai Tan, Carol L Thompson, Timothy Tickle, Hagen Tilgner, Merina Varghese, Brock Wester, Owen White, Hongkui Zeng, Brian Aevermann, David Allemang, Seth Ament, Thomas L Athey, Cody Baker, Katherine S Baker, Pamela M Baker, Anita Bandrowski, Samik Banerjee, Prajal Bishwakarma, Ambrose Carr, Min Chen, Roni Choudhury, Jonah Cool, Heather Creasy, Florence D'Orazi, Kylee Degatano, Benjamin Dichter, Song-Lin Ding, Tim Dolbeare, Joseph R Ecker, Rongxin Fang, Jean-Christophe Fillion-Robin, Timothy P Fliss, James Gee, Tom Gillespie, Nathan Gouwens, Guo-Qiang Zhang, Yaroslav O Halchenko, Nomi L Harris, Brian R Herb, Houri Hintiryan, Gregory Hood, Sam Horvath, Bingxing Huo, Dorota Jarecka, Shengdian Jiang, Farzaneh Khajouei, Elizabeth A Kiernan, Huseyin Kir, Lauren Kruse, Changkyu Lee, Boudewijn Lelieveldt, Yang Li, Hanqing Liu, Lijuan Liu, Anup Markuhar, James Mathews, Kaylee L Mathews, Chris Mezias, Michael I Miller, Tyler Mollenkopf, Shoaib Mufti, Christopher J Mungall, Joshua Orvis, Maja A Puchades, Lei Qu, Joseph P Receveur, Bing Ren, Nathan Sjoquist, Brian Staats, Daniel Tward, Cindy T J Van Velthoven, Quanxin Wang, Fangming Xie, Hua Xu, Zizhen Yao, Zhixi Yun, Yun Renee Zhang, W Jim Zheng, Brian Zingg

Faculty, Staff and Student Publications

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman …