Digital Commons Network^™

Amphotericin B Resistance In Leishmania Mexicana: Alterations To Sterol Metabolism And Oxidative Stress Response, Edubiel A Alpizar-Sosa, Nur Raihana Binti Ithnin, Wenbin Wei, Andrew W Pountain, Stefan K Weidt, Anne M Donachie, Ryan Ritchie, Emily A Dickie, Richard J S Burchmore, Paul W Denny, Michael P Barrett

Faculty, Staff and Student Publications

Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of …

Rates Of Laboratory Adverse Events By Course In Paediatric Leukaemia Ascertained With Automated Electronic Health Record Extraction: A Retrospective Cohort Study From The Children’S Oncology Group, Tamara P Miller, Kelly D Getz, Yimei Li, Biniyam G Demissei, Peter C Adamson, Todd A Alonzo, Evanette Burrows, Lusha Cao, Sharon M Castellino, Marla H Daves, Brian T Fisher, Robert Gerbing, Robert W Grundmeier, Edward M Krause, Judy Lee, Philip J Lupo, Karen R Rabin, Mark Ramos, Michael E Scheurer, Jennifer J Wilkes, Lena E Winestone, Douglas S Hawkins, M Monica Gramatges, Richard Aplenc

Center for Medical Ethics and Health Policy Staff Publications

Background: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia.

Methods: For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia …

Cisplatin And Gemcitabine Exert Opposite Effects On Immunotherapy With Pd-1 Antibody In K-Ras-Driven Cancer, Christophe Glorieux, Xiaojun Xia, Xin You, Zining Wang, Yi Han, Jing Yang, Gauthier Noppe, Christophe De Meester, Jianhua Ling, Annie Robert, Hui Zhang, Sheng-Ping Li, Huamin Wang, Paul J Chiao, Li Zhang, Xiaobing Li, Peng Huang

Faculty, Staff and Student Publications

INTRODUCTION: Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome.

OBJECTIVES: The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1.

METHODS: Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in …

Addressing Patient Heterogeneity In Disease Predictive Model Development, Xu Gao, Weining Shen, Jing Ning, Ziding Feng, Jianhua Hu

Faculty, Staff and Student Publications

This paper addresses patient heterogeneity associated with prediction problems in biomedical applications. We propose a systematic hypothesis testing approach to determine the existence of patient subgroup structure and the number of subgroups in patient population if subgroups exist. A mixture of generalized linear models is considered to model the relationship between the disease outcome and patient characteristics and clinical factors, including targeted biomarker profiles. We construct a test statistic based on expectation maximization (EM) algorithm and derive its asymptotic distribution under the null hypothesis. An important computational advantage of the test is that the involved parameter estimates under the complex …

Associations Between Maternal Reports Of Periconceptional Fever From Miscellaneous Causes And Structural Birth Defects, Nithya Lakshmi Mohan Dass, Lorenzo D Botto, Sarah C Tinker, Mark A Canfield, Richard H Finnell, Michael Shayne Gallaway, Syed Shahrukh Hashmi, Adrienne T Hoyt, Wendy N Nembhard, Dorothy K Waller, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

BACKGROUND: Associations between birth defects and fevers attributed to colds, influenza, and urinary tract infections (UTIs) have been observed in previous studies. Our aim was to study associations between birth defects and fevers attributed to other causes.

METHODS: We analyzed data from 34,862 participants in the National Birth Defects Prevention Study, a multistate case-control study of major structural birth defects. Using multivariable logistic regression, we assessed the association between maternal report of fever during early pregnancy due to causes other than colds, influenza, or UTI and 36 categories of birth defects.

RESULTS: Maternal reports of fever due to other causes …

Factors Associated With Severe Illness In Patients Aged <21 Years Hospitalized For Covid-19, Rewa Choudhary, Bryant J Webber, Lindsay S Womack, Hannah K Dupont, Sophia K Chiu, Valentine Wanga, Megan E Gerdes, Sophia Hsu, Dallas S Shi, Theresa M Dulski, Osatohamwen I Idubor, Arthur M Wendel, Nickolas T Agathis, Kristi Anderson, Tricia Boyles, Eleanor S Click, Juliana Da Silva, Mary E Evans, Jeremy A W Gold, Julia C Haston, Pamela Logan, Susan A Maloney, Marisol Martinez, Pavithra Natarajan, Kevin B Spicer, Mark Swancutt, Valerie A Stevens, Jessica Rogers-Brown, Gyan Chandra, Megan Light, Frederick E Barr, Jessica Snowden, Larry K Kociolek, Matthew Mchugh, David L Wessel, Joelle N Simpson, Kathleen C Gorman, Kristen A Breslin, Roberta L Debiasi, Aaron Thompson, Mark W Kline, Julie A Boom, Ila R Singh, Michael Dowlin, Mark Wietecha, Beth Schweitzer, Sapna Bamrah Morris, Emilia H Koumans, Jean Y Ko, David A Siegel, Anne A Kimball

Faculty, Staff and Students Publications

OBJECTIVES: To describe coronavirus disease 2019 (COVID-19)-related pediatric hospitalizations during a period of B.1.617.2 (Δ) variant predominance and to determine age-specific factors associated with severe illness.

METHODS: We abstracted data from medical charts to conduct a cross-sectional study of patients agedchildren's hospitals from July to August 2021 for COVID-19 or with an incidental positive severe acute respiratory syndrome coronavirus 2 test. Among patients with COVID-19, we assessed factors associated with severe illness by calculating age-stratified prevalence ratios (PR). We defined severe illness as receiving high-flow nasal cannula, positive airway pressure, or invasive mechanical ventilation.

RESULTS: Of 947 hospitalized patients, 759 …

Tertiary Syphilis Masquerading As Oropharyngeal Cancer, Caroline R Christmann, Wesley D Figg, Ritodhi Chatterjee, Philip F Lavere, Niraj Mehta

Faculty, Staff and Students Publications

Syphilis is re-emerging in the United States. Treponema pallidum, the spirochete bacterium responsible for syphilis, has immunoevasive properties that facilitate pathogenesis and widespread tissue involvement. Host immune status, particularly the presence of HIV/AIDS, can influence the presentation and severity of the disease. Patients co-infected with HIV and syphilis may develop atypical lesions, including those involving the oropharynx. Any immunocompromised patient with tongue lesions and lymphadenopathy is presumed to have a wide differential diagnosis, and tissue sampling with histopathologic analysis is indicated. We present a patient with gumma of the tongue as the initial manifestation of tertiary syphilis.

Efficacy And Safety Of Ensovibep For Adults Hospitalized With Covid-19 : A Randomized Controlled Trial, Christina Barkauskas, Eleftherios Mylonakis, Garyfallia Poulakou, Barnaby E Young, David M Vock, Lianne Siegel, Nicole Engen, Greg Grandits, Nilima R Mosaly, Andrew M Vekstein, Ralph Rogers, Fadi Shehadeh, Matthew Kaczynski, Evangelia K Mylona, Konstantinos N Syrigos, Vasiliki Rapti, David C Lye, Diong Shiau Hui, Lindsay Leither, Kirk U Knowlton, Mamta K Jain, Rubria Marines-Price, Alice Osuji, J Scott Overcash, Ioannis Kalomenidis, Zafeiria Barmparessou, Michael Waters, Karla Zepeda, Peter Chen, Sam Torbati, Francis Kiweewa, Nicholus Sebudde, Eyad Almasri, Alyssa Hughes, Sanjay R Bhagani, Alison Rodger, Uriel Sandkovsky, Robert L Gottlieb, Eriobu Nnakelu, Barbara Trautner, Vidya Menon, Joseph Lutaakome, Michael Matthay, Philip Robinson, Konstantinos Protopapas, Nikolaos Koulouris, Ivan Kimuli, Amiran Baduashvili, Dominique L Braun, Huldrych F Günthard, Srikanth Ramachandruni, Robert Kidega, Kami Kim, Timothy J Hatlen, Andrew N Phillips, Daniel D Murray, Tomas O Jensen, Maria L Padilla, Evan X Accardi, Katy Shaw-Saliba, Robin L Dewar, Marc Teitelbaum, Ven Natarajan, Sylvain Laverdure, Helene C Highbarger, M Tauseef Rehman, Susan Vogel, David Vallée, Page Crew, Negin Atri, Adam J Schechner, Sarah Pett, Fleur Hudson, Jonathan Badrock, Giota Touloumi, Samuel M Brown, Wesley H Self, Crystal M North, Adit A Ginde, Christina C Chang, Anthony Kelleher, Stephanie Nagy-Agren, Shikha Vasudeva, David Looney, Hien H Nguyen, Adriana Sánchez, Amy C Weintrob, Birgit Grund, Shweta Sharma, Cavan S Reilly, Roger Paredes, Agnieszka Bednarska, Norman P Gerry, Abdel G Babiker, Victoria J Davey, Annetine C Gelijns, Elizabeth S Higgs, Virginia Kan, Gail Matthews, B Taylor Thompson, Philippe Legenne, Richa Chandra, H Clifford Lane, James D Neaton, Jens D Lundgren

Faculty, Staff and Students Publications

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.

OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.

DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978).

SETTING: Multinational, multicenter trial.

PARTICIPANTS: Adults hospitalized with COVID-19.

INTERVENTION: Intravenous ensovibep, 600 mg, or placebo.

MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day …

Short Signature Rpob Gene Sequence To Differentiate Species In Mycobacterium Abscessus Group, Jian R Bao, Kileen L Shier, Ronald N Master, Robert S Jones, Richard B Clark

Faculty, Staff and Student Publications

Mycobacterium abscessus group (MAG) are rapidly growing acid-fast bacteria that consist of three closely related species: M. abscessus (Ma), M. bolletii (Mb), and M. massiliense (Mm). Differentiation of these species can be difficult but is increasingly requested owing to recent infectious outbreaks and their differential drug resistance. We developed a novel and rapid pyrosequencing method using short signature sequences (35 to 45 bp) at a hypervariable site in the rpoB gene to differentiate the three MAG species, along with M. chelonae (Mc), and M. immunogenum (Mi). This method was evaluated …

Virtual Global Health In Graduate Medical Education: A Systematic Review, Lisa Umphrey, Nora Lenhard, Suet Kam Lam, Nathaniel E Hayward, Shaina Hecht, Priya Agrawal, Amy Chambliss, Jessica Evert, Heather Haq, Stephanie M Lauden, George Paasi, Mary Schleicher, Megan Song Mchenry

Faculty, Staff and Students Publications

OBJECTIVES: To synthesize recent virtual global health education activities for graduate medical trainees, document gaps in the literature, suggest future study, and inform best practice recommendations for global health educators.

METHODS: We systematically reviewed articles published on virtual global health education activities from 2012-2021 by searching MEDLINE, EMBASE, Cochrane Library, ERIC, Scopus, Web of Science, and ProQuest Dissertations & Theses A&I. We performed bibliography review and search of conference and organization websites. We included articles about primarily virtual activities targeting for health professional trainees. We collected and qualitatively analyzed descriptive data about activity type, evaluation, audience, and drivers or barriers. …

Years Of Life Lost Associated With Covid-19 Deaths In The Usa During The First 2 Years Of The Pandemic, Troy Quast, Ross Andel, Sean Gregory, Eric A Storch

Center for Medical Ethics and Health Policy Staff Publications

Background: Prior estimates of the years of life lost (YLLs) in the USA associated with coronavirus disease 2019 (COVID-19) were 1.2 million through 11 July 2020 and 3.9 million through 31 January 2021 (which roughly coincides with the first full year of the pandemic). The aim of this study is to update YLL estimates through the first 2 years of the pandemic.

Methods: We employed data regarding COVID-19 deaths through 5 February 2022 by jurisdiction, gender and age group. We used actuarial life expectancy tables by gender and age to estimate YLLs.

Results: We estimated roughly 9.7 million YLLs due …

The Need For Sexual Health Clinics, Their Future Role, And Contribution To Public Health, Meena S. Ramchandani, Christopher Bourne, Lindley A. Barbee, Elske Hoornenborg, Preeti Pathela, Stephanie N. Taylor, Henry De Vries

School of Medicine Faculty Publications

Specialised sexual health clinics (SHCs) play an important role in addressing the staggering rates of STIs seen in many high-income nations. Despite increasing healthcare coverage in the US and nationalised health care in some countries, there is a continued need for SHCs to meet the needs of patients and the community, especially for high-priority populations: those at high risk of STI acquisition and/or groups historically marginalised and underserved in the traditional healthcare system. We need to mobilise resources to support a stronger clinical infrastructure in specialised SHCs. This review describes the importance of SHCs, their future role, and some of …

Phase 2 Of Extracellular Rna Communication Consortium Charts Next-Generation Approaches For Extracellular Rna Research, Bogdan Mateescu, Jennifer C Jones, Roger P Alexander, Eric Alsop, Ji Yeong An, Mohammad Asghari, Alex Boomgarden, Laura Bouchareychas, Alfonso Cayota, Hsueh-Chia Chang, Al Charest, Daniel T Chiu, Robert J Coffey, Saumya Das, Peter De Hoff, Andrew Demello, Crislyn D'Souza-Schorey, David Elashoff, Kiarash R Eliato, Jeffrey L Franklin, David J Galas, Mark B Gerstein, Ionita H Ghiran, David B Go, Stephen Gould, Tristan R Grogan, James N Higginbotham, Florian Hladik, Tony Jun Huang, Xiaoye Huo, Elizabeth Hutchins, Dennis K Jeppesen, Tijana Jovanovic-Talisman, Betty Y S Kim, Sung Kim, Kyoung-Mee Kim, Yong Kim, Robert R Kitchen, Vaughan Knouse, Emily L Laplante, Carlito B Lebrilla, L James Lee, Kathleen M Lennon, Guoping Li, Feng Li, Tieyi Li, Tao Liu, Zirui Liu, Adam L Maddox, Kyle Mccarthy, Bessie Meechoovet, Nalin Maniya, Yingchao Meng, Aleksandar Milosavljevic, Byoung-Hoon Min, Amber Morey, Martin Ng, John Nolan, Getulio P De Oliveira Junior, Michael E Paulaitis, Tuan Anh Phu, Robert L Raffai, Eduardo Reátegui, Matthew E Roth, David A Routenberg, Joel Rozowsky, Joseph Rufo, Satyajyoti Senapati, Sigal Shachar, Himani Sharma, Anil K Sood, Stavros Stavrakis, Alessandra Stürchler, Muneesh Tewari, Juan P Tosar, Alexander K Tucker-Schwartz, Andrey Turchinovich, Nedyalka Valkov, Kendall Van Keuren-Jensen, Kasey C Vickers, Lucia Vojtech, Wyatt N Vreeland, Ceming Wang, Kai Wang, Zeyu Wang, Joshua A Welsh, Kenneth W Witwer, David T W Wong, Jianping Xia, Ya-Hong Xie, Kaichun Yang, Mikołaj P Zaborowski, Chenguang Zhang, Qin Zhang, Angela M Zivkovic, Louise C Laurent

Faculty, Staff and Student Publications

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, …

A Case Series Of Children With Acute Hepatitis And Human Adenovirus Infection, L Helena Gutierrez Sanchez, Henry Shiau, Julia M Baker, Stephanie Saaybi, Markus Buchfellner, William Britt, Veronica Sanchez, Jennifer L Potter, L Amanda Ingram, David Kelly, Xiaoyan Lu, Stephanie Ayers-Millsap, Wesley G Willeford, Negar Rassaei, Julu Bhatnagar, Hannah Bullock, Sarah Reagan-Steiner, Ali Martin, Michael E Rogers, Anna M Banc-Husu, Sanjiv Harpavat, Daniel H Leung, Elizabeth A Moulton, Daryl M Lamson, Kirsten St George, Aron J Hall, Umesh Parashar, Adam Macneil, Jacqueline E Tate, Hannah L Kirking

Faculty, Staff and Students Publications

BACKGROUND: Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia.

METHODS: We used International Classification of Diseases, 10th Revision, codes to identify all children (<18 years of age) with hepatitis who were admitted to Children’s of Alabama hospital between October 1, 2021, and February 28, 2022; those with acute hepatitis who also tested positive for human adenovirus by whole-blood quantitative polymerase chain reaction (PCR) were included in our case series. Demographic, clinical, laboratory, and treatment data were obtained from medical records. Residual blood specimens were sent for diagnostic confirmation and human adenovirus typing.

RESULTS: A total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 …

Structure-Based Design Of Stapled Peptides That Bind Gabarap And Inhibit Autophagy, Hawley Brown, Mia Chung, Alina Üffing, Nefeli Batistatou, Tiffany Tsang, Samantha Doskocil, Weiqun Mao, Dieter Willbold, Robert C Bast, Zhen Lu, Oliver H Weiergräber, Joshua A Kritzer

Faculty, Staff and Student Publications

The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized …

Intrinsic Cardiac Effects Of Severe Acute Respiratory Syndrome Coronavirus 2 In Coronavirus Disease 2019, Brittany Danielle Brumback

McKelvey School of Engineering Graduate Student Theses & Dissertations

Cardiac arrhythmias, particularly ventricular arrhythmias, can be life-threatening and caused by both congenital genetic mutations and acquired cardiac injury. My thesis work was originally focused on delineating the effects of genetic mutation-driven dysregulation of a protein called Hey2 in Brugada Syndrome, a complex disease characterized by a predisposition to dangerous arrhythmias originating in the right ventricular outflow tract. In response to the pandemic, my thesis work shifted toward understanding the mechanisms of cardiovascular injury in Coronavirus disease 2019 (COVID-19), which is associated with serious cardiovascular complications, including ventricular arrhythmias and sudden cardiac death as well as endothelial dysfunction and coagulopathies. …

Improved Sars-Cov-2 Sequencing Surveillance Allows The Identification Of New Variants And Signatures In Infected Patients, Antonio Grimaldi, Francesco Panariello, Patrizia Annunziata, Teresa Giuliano, Michela Daniele, Biancamaria Pierri, Chiara Colantuono, Marcello Salvi, Valentina Bouché, Anna Manfredi, Maria Concetta Cuomo, Denise Di Concilio, Claudia Tiberio, Mariano Fiorenza, Giuseppe Portella, Ilaria Cimmino, Antonio Sorrentino, Giovanna Fusco, Maria Rosaria Granata, Pellegrino Cerino, Antonio Limone, Luigi Atripaldi, Andrea Ballabio, Davide Cacchiarelli

Duncan NRI Faculty and Staff Publications

Background: Genomic surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the only approach to rapidly monitor and tackle emerging variants of concern (VOC) of the COVID-19 pandemic. Such scrutiny is crucial to limit the spread of VOC that might escape the immune protection conferred by vaccination strategies or previous virus exposure. It is also becoming clear now that efficient genomic surveillance would require monitoring of the host gene expression to identify prognostic biomarkers of treatment efficacy and disease progression. Here we propose an integrative workflow to both generate thousands of SARS-CoV-2 genome sequences per week and analyze host …

Optimizing Antiretroviral Therapy With Modern Rifapentine Containing Tb Treatment, Anthony T. Podany

Theses & Dissertations

In the past decade there has been a multitude of phase 3 clinical trials targeting treatment shortening for tuberculosis (TB). The synthetic rifamycin derivative rifapentine (RPT) has been at the forefront of many of the treatment shortening approaches. RPT possesses greater potency and a longer pharmacokinetic (PK) half-life (t_1/2) as compared with the long used rifamycin, rifampin (RIF). For TB preventative treatment, a 3-month, once weekly regimen of RPT and isoniazid (INH; 3HP) was shown to be as effective as 9-months of daily INH therapy in the PREVENT TB trial. Similarly, a 4-week course of daily RPT and …

Evaluation The Role Of Conventional And Xpert Mtb/Rif Assays As Point-Of-Care Tests Of Mycobacterium Tuberculosis Infections, Especially During The Covid-19 Pandemic In Menoufia, Egypt, Asmaa M. Soliman, Elham T. Awad, Mariam A. Fouad, Moatz M. Elhefnay

Journal of Medicine in Scientific Research

Background Tuberculosis (TB) is a destructive pulmonary disease, which was the most fatal infectious disease in the world for many years before the COVID-19 outbreak. During pandemic, COVID-19 was the main concern in every clinic and there were overlapping respiratory diseases resulting in delaying of the diagnosis and treatment of TB. Xpert MTB/RIF assay and Ziehl–Neelsen (ZN) stain are the most commonly used point-of-care test (POCT) assays for TB that were endorsed by WHO allowing a quick treatment turnaround time of a few minutes or hours, hence avoiding patient loss to follow-up. The aim of the study was to evaluate …

The Prevalence Of Pulmonary Aspergillosis In Coronavirus Disease 19 (Covid-19) Patients In Shebin El-Kom Teaching Hospital In Egypt, Asmaa M. Soliman, Elham T. Awad, Mariam A. Fouad

Journal of Medicine in Scientific Research

Background A high rate of invasive fungal infection has been demonstrated among critically COVID-19 ill patients admitted to the ICU, with high odds of mortality. Simple and rapid risk stratification methods are mandatory to recognize severe patients. Objectives The aims was to study the prevalence of invasive fungal infection in Corona virus disease 19 (COVID-19) patients, the effect of some inflammatory markers that lead to the development and progression of invasive fungal infection and to assess the value of PCR in early and rapid detection of invasive fungal infection in immune compromised patients with COVID-19. Methods This study was conducted …

Ankle2-Related Microcephaly: A Variable Microcephaly Syndrome Resembling Zika Infection, Ajay X Thomas, Nichole Link, Laurie A Robak, Gail Demmler-Harrison, Emily C Pao, Audrey E Squire, Savannah Michels, Julie S Cohen, Anne Comi, Paolo Prontera, Alberto Verrotti Di Pianella, Giuseppe Di Cara, Livia Garavelli, Stefano Giuseppe Caraffi, Carlo Fusco, Roberta Zuntini, Kendall C Parks, Elliott H Sherr, Mais O Hashem, Sateesh Maddirevula, Fowzan S Alkuraya, Isphana A F Contractar, Jennifer E Neil, Christopher A Walsh, Hugo J Bellen, Hsiao-Tuan Chao, Robin D Clark, Ghayda M Mirzaa

Duncan NRI Faculty and Staff Publications

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.

Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster.

Results: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, …

The Media Discourses On Organ Donation And Transplantation In Spain (1954-2020) And Their Implications For Spanish Nationalism, Rebeca Herrero Sáenz

Legacy Theses & Dissertations (2009 - 2024)

Spain has been the global leader in organ donation and transplantation since 1992, an achievement that has become a source of national pride, in a country where national symbols are heavily contested. In this dissertation I examine the changing meanings that organ donation and transplantation have acquired in contemporary Spain, focusing specifically on their implications for different aspects of Spanish nationalism. To do so, I employ a modified version computational grounded theory, a mixed-methods approach that combines topic modeling with interpretive analysis, to identify and interpret the narratives around organ donation and transplantation circulated by the Spanish press between 1954 …

Homeostasis Of Cell Wall Integrity Pathway Phosphorylation Is Required For The Growth And Pathogenicity Of Magnaporthe Oryzae, Yongchao Cai, Xinyu Liu, Lingbo Shen, Nian Wang, Yangjie He, Haifeng Zhang, Ping Wang, Zhengguang Zhang

School of Graduate Studies Faculty Publications

The cell wall provides a crucial barrier to stress imposed by the external environment. In the rice blast fungus Magnaporthe oryzae, this stress response is mediated by the cell wall integrity (CWI) pathway, consisting of a well-characterized protein phosphorylation cascade. However, other regulators that maintain CWI phosphorylation homeostasis, such as protein phosphatases (PPases), remain unclear. Here, we identified two PPases, MoPtc1 and MoPtc2, that function as negative regulators of the CWI pathway. MoPtc1 and MoPtc2 interact with MoMkk1, one of the key components of the CWI pathway, and are crucial for the vegetative growth, conidial formation, and virulence of M. …

A Systematic Review And Meta-Analysis On Prevalence Of And Risk Factors Associated With Depression, Anxiety And Insomnia In Infectious Diseases, Including Covid-19: A Call To Action, Kai Yuan, Yong-Bo Zheng, Yi-Jie Wang, Yan-Kun Sun, Yi-Miao Gong, Yue-Tong Huang, Xuan Chen, Xiao-Xing Liu, Yi Zhong, Si-Zhen Su, Nan Gao, Yi-Long Lu, Zhe Wang, Wei-Jian Liu, Jian-Yu Que, Ying-Bo Yang, An-Yi Zhang, Meng-Ni Jing, Chen-Wei Yuan, Na Zeng, Michael V Vitiello, Vikram Patel, Seena Fazel, Harry Minas, Graham Thornicroft, Teng-Teng Fan, Xiao Lin, Wei Yan, Le Shi, Jie Shi, Thomas Kosten, Yan-Ping Bao, Lin Lu

Children’s Nutrition Research Center Staff Publications

Infectious disease epidemics have become more frequent and more complex during the 21st century, posing a health threat to the general public and leading to psychological symptoms. The current study was designed to investigate the prevalence of and risk factors associated with depression, anxiety and insomnia symptoms during epidemic outbreaks, including COVID-19. We systematically searched the PubMed, Embase, Web of Science, OVID, Medline, Cochrane databases, bioRxiv and medRxiv to identify studies that reported the prevalence of depression, anxiety or insomnia during infectious disease epidemics, up to August 14th, 2020. Prevalence of mental symptoms among different populations including the general public, …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Infection And Transmission Determinants Of Flea-Borne Rickettsioses, Hanna J. Laukaitis

Graduate Theses and Dissertations (2019 - present)

The genus Rickettsia is comprised of Gram-negative, obligate intracellular bacteria that are spread by hematophagous arthropods. Elucidating the factors conferring rickettsial virulence has perplexed investigators for decades, complicated by the lack of efficient genetic tools necessary to uncover rickettsial- and vector-specific factors contributing to persistence. The advent of transposon mutagenesis has enabled the field to make vast developments in uncovering novel rickettsial mechanisms utilized in various host backgrounds. Thus, the aim of this study was to generate Rickettsia felis transposon mutants and characterize novel phenotypes associated with genetic disruption in an arthropod background. Distribution of rickettsiae is reliant on the …

The Intricate Interplay Between Cancer Stem Cells And Cell-Of-Origin Of Cancer: Implications For Therapeutic Strategies, Luis Alberto Vega, Misu A Sanson, María Belén Cubria, Shrijana Regmi, Brittany J Shah, Samuel A Shelburne, Anthony R Flores

Faculty, Staff and Student Publications

Antimicrobial resistance-encoding mobile genetic elements (MGEs) may contribute to the disease potential of bacterial pathogens. We previously described the association of Group A Streptococcus (GAS) derived from invasive disease with increasingly frequent antimicrobial resistance (AMR). We hypothesized that a 65-kb AMR-encoding MGE (ICESpyM92), highly conserved among closely related emergent invasive emm92 GAS, contributes to GAS disease potential. Here, we provide evidence that a combination of ICESpyM92- and core genome-dependent differential gene expression (DGE) contributes to invasive disease phenotypes of emergent emm92 GAS. Using isogenic ICESpyM92 mutants generated in distinct emm92 genomic backgrounds, we determined the presence of ICESpyM92 enhances GAS …

Acylcarnitines And Genetic Variation In Fat Oxidation Genes In Hiv-Infected, Antiretroviral-Treated Children With And Without Myopathy, Brian Kirmse, Charlotte Hobbs, Lisa Aaron, Grace Montepiedra, Marshall Summar, Paige L Williams, Caitlin J Smith, Russell Van Dyke, Chunli Yu, Kelli K Ryckman, William Borkowsky

Faculty, Staff and Student Publications

BACKGROUND: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO).

METHODS: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated.

RESULTS: Abnormal ACP …

Genome-Wide Bidirectional Crispr Screens Identify Mucins As Host Factors Modulating Sars-Cov-2 Infection, Scott B Biering, Sylvia A Sarnik, Eleanor Wang, James R Zengel, Sarah R Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R Jangid, Connor V Duffy, Jin Wei, Rodney C Gilmore, Mia Madel Alfajaro, Madison S Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H Yamashiro, Julia A Belk, Adam Begeman, Jessica C Stark, D Judy Shon, Douglas M Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C Aguilar, Andreas S Puschnik, Brian Button, Benjamin A Pinsky, Catherine A Blish, Ralph S Baric, Wanda K O'Neal, Carolyn R Bertozzi, Craig B Wilen, Richard C Boucher, Jan E Carette, Sarah A Stanley, Eva Harris, Silvana Konermann, Patrick D Hsu

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a …

Pulmonary Fibrosis Model Using Micro-Ct Analyzable Human Psc-Derived Alveolar Organoids Containing Alveolar Macrophage-Like Cells, Seri Choi, Jiwoong Choi, Seongmin Cheon, Jihong Song, Seung-Yeon Kim, Ji-Eun Kim, Dae-Hwan Nam, Gohar Manzar, Su-Man Kim, Hyung-Sik Kang, Kee K Kim, Sang Hoon Jeong, Ju-Han Lee, Eun-Kee Park, Minseob Lee, Hyang-Ae Lee, Ki-Suk Kim, Han-Jin Park, Won Keun Oh, Chungoo Park, Chang Hyun Lee, Eun-Mi Kim

Faculty, Staff and Student Publications

Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)-like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68