Medicine and Health Sciences Commons^™

Seasonality, Clinical Characteristics, And Outcomes Of Respiratory Syncytial Virus Disease By Subtype Among Children Aged <5 Years: New Vaccine Surveillance Network, United States, 2016-2020., Ariana P. Toepfer, Justin Z. Amarin, Andrew J. Spieker, Laura S. Stewart, Mary Allen Staat, Elizabeth P. Schlaudecker, Geoffrey A. Weinberg, Peter G. Szilagyi, Janet A. Englund, Eileen J. Klein, Marian G. Michaels, John V. Williams, Rangaraj Selvarangan, Christopher J. Harrison, Joana Y. Lively, Pedro A. Piedra, Vasanthi Avadhanula, Brian Rha, James Chappell, Meredith Mcmorrow, Heidi Moline, Natasha B. Halasa

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illnesses in children. RSV can be broadly categorized into 2 major subtypes: A and B. RSV subtypes have been known to cocirculate with variability in different regions of the world. Clinical associations with viral subtype have been studied among children with conflicting findings such that no conclusive relationships between RSV subtype and severity have been established.

METHODS: During 2016-2020, children aged/guardian interviews, chart reviews, and collection of midturbinate nasal plus/minus throat swabs for RSV (RSV-A, RSV-B, and untyped) using reverse transcription polymerase chain reaction.

RESULTS: Among 6398 RSV-positive …

The Dementia Care Study (D-Care): Recruitment Strategies And Demographic Characteristics Of Participants In A Pragmatic Randomized Trial Of Dementia Care, Mia Yang, Rafael Samper-Ternent, Elena Volpi, Aval-Na'ree Green, Maya Lichtenstein, Katy Araujo, Pamela Borek, Peter Charpentier, James Dziura, Thomas M Gill, Rebecca Galloway, Erich J Greene, Kristin Lenoir, Peter Peduzzi, Can Meng, Jordan Reese, Amy Shelton, Eleni A Skokos, Jenny Summapund, Erin Unger, David B Reuben, Jeff D Williamson, Alan B Stevens

Journal Articles

INTRODUCTION: Pragmatic research studies that include diverse dyads of persons living with dementia (PLWD) and their family caregivers are rare.

METHODS: Community-dwelling dyads were recruited for a pragmatic clinical trial evaluating three approaches to dementia care. Four clinical trial sites used shared and site-specific recruitment strategies to enroll health system patients.

RESULTS: Electronic health record (EHR) queries of patients with a diagnosis of dementia and engagement of their clinicians were the main recruitment strategies. A total of 2176 dyads were enrolled, with 80% recruited after the onset of the pandemic. PLWD had a mean age of 80.6 years (SD 8.5), …

Accuracy Of Influenza Icd-10 Diagnosis Codes In Identifying Influenza Illness In Children., James W. Antoon, Tess Stopczynski, Justin Z. Amarin, Laura S. Stewart, Julie A. Boom, Leila C. Sahni, Marian G. Michaels, John V. Williams, Janet A. Englund, Eileen J. Klein, Mary A. Staat, Elizabeth P. Schlaudecker, Rangaraj Selvarangan, Jennifer E. Schuster, Geoffrey A. Weinberg, Peter G. Szilagyi, Ariana Perez, Heidi L. Moline, Andrew J. Spieker, Carlos G. Grijalva, Samantha M. Olson, Natasha B. Halasa

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Studies of influenza in children commonly rely on coded diagnoses, yet the ability of International Classification of Diseases, Ninth Revision codes to identify influenza in the emergency department (ED) and hospital is highly variable. The accuracy of newer International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to identify influenza in children is unknown.

OBJECTIVE: To determine the accuracy of ICD-10 influenza discharge diagnosis codes in the pediatric ED and inpatient settings.

DESIGN, SETTING, AND PARTICIPANTS: Children younger than 18 years presenting to the ED or inpatient settings with fever and/or respiratory symptoms at 7 …

Granulocytic Myeloid-Derived Suppressor Cell Activity During Biofilm Infection Is Regulated By A Glycolysis/Hif1a Axis, Christopher M. Horn, Prabhakar Arumugam, Zachary Van Roy, Cortney E. Heim, Rachel W. Fallet, Blake P. Bertrand, Dhananjay Shinde, Vinai Chittezham Thomas, Svetlana Romanova, Tatiana K. Bronich, Curtis Hartman, Kevin Garvin, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. …

Notes From The Field: Reemergence Of Mycoplasma Pneumoniae Infections In Children And Adolescents After The Covid-19 Pandemic, United States, 2018-2024., Chris Edens, Benjamin R. Clopper, Jourdan Devies, Alvaro Benitez, Erin R. Mckeever, Dylan Johns, Bernard Wolff, Rangaraj Selvarangan, Jennifer E. Schuster, Geoffrey A. Weinberg, Peter G. Szilagyi, Fatimah S. Dawood, Lakshmi Radhakrishnan, Christina Quigley, Leila C. Sahni, Natasha Halasa, Laura S. Stewart, Meredith L. Mcmorrow, Brett Whitaker, Danielle M. Zerr, Vasanthi Avadhanula, John V. Williams, Marian G. Michaels, Aaron Kite-Powell, Janet A. Englund, Mary Allen Staat, Kathleen Hartnett, Heidi L. Moline, Adam L. Cohen, Maureen Diaz

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Metabolism Shapes Immune Responses To Staphylococcus Aureus., Prabhakar Arumugam, Tammy Kielian

Journal Articles: Pathology and Microbiology

BACKGROUND: Staphylococcus aureus (S. aureus) is a common cause of hospital- and community-acquired infections that can result in various clinical manifestations ranging from mild to severe disease. The bacterium utilizes different combinations of virulence factors and biofilm formation to establish a successful infection, and the emergence of methicillin- and vancomycin-resistant strains introduces additional challenges for infection management and treatment.

SUMMARY: Metabolic programming of immune cells regulates the balance of energy requirements for activation and dictates pro- versus anti-inflammatory function. Recent investigations into metabolic adaptations of leukocytes and S. aureus during infection indicate that metabolic crosstalk plays a crucial role in …

Metabolic Diversity Of Human Macrophages: Potential Influence On Staphylococcus Aureus Intracellular Survival, Blake P. Bertrand, Dhananjay Shinde, Vinai C. Thomas, Marvin Whiteley, Carolyn B. Ibberson, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of medical device-associated biofilm infections. This is influenced by the ability of S. aureus biofilm to evade the host immune response, which is partially driven by the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that treatment of human monocyte-derived macrophages (HMDMs) with IL-10 enhanced biofilm formation, suggesting that macrophage anti-inflammatory programming likely plays an important role during the transition from planktonic to biofilm growth. To identify S. aureus genes that were important for intracellular survival in HMDMs and how this was affected by IL-10, transposon sequencing was performed. The size of the S. aureus …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …

Ifit2 Restricts Murine Coronavirus Spread To The Spinal Cord White Matter And Its Associated Myelin Pathology, Madhav Sharma, Debanjana Chakravarty, Afaq Hussain, Ajay Zalavadia, Amy Burrows, Patricia Rayman, Nikhil Sharma, Lawrence C. Kenyon, Cornelia Bergmann, Ganes C. Sen, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection. To understand this, RSA59 infected Ifit2-/- and Ifit2+/+ (WT) were observed for neuropathological outcomes at day 5 (acute phase) and 30 …

Sars-Cov-2 Screening Testing Programs For Safe In-Person Learning In K-12 Schools., Ibukunoluwa C. Kalu, Kanecia O. Zimmerman, Jennifer Goldman, Dana Keener Mast, Ashley M. Blakemore, Ganga Moorthy, Angelique E. Boutzoukas, Melissa M. Campbell, Diya Uthappa, Jesse Delarosa, Jessica M. Potts, Laura J. Edwards, Rangaraj Selvarangan, Daniel K. Benjamin, Tara K. Mann, Jennifer E. Schuster

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening testing is a recommended mitigation strategy for schools, although few descriptions of program implementation are available.

METHODS: Kindergarten through 12th grade (K-12) students and staff practicing universal masking during the delta and omicron variant waves from five schools in Durham, North Carolina and eight schools in Kansas City, Missouri participated; Durham's program was structured as a public health initiative facilitated by school staff, and Kansas City's as a research study facilitated by a research team. Tests included school-based rapid antigen or polymerase chain reaction testing, at-home rapid antigen testing, and off-site …

Circulation Of Rhinoviruses And/Or Enteroviruses In Pediatric Patients With Acute Respiratory Illness Before And During The Covid-19 Pandemic In The Us., Danielle A. Rankin, Andrew J. Spieker, Ariana Perez, Anna L. Stahl, Herdi K. Rahman, Laura S. Stewart, Jennifer E. Schuster, Joana Y. Lively, Zaid Haddadin, Varvara Probst, Marian G. Michaels, John V. Williams, Julie A. Boom, Leila C. Sahni, Mary A. Staat, Elizabeth P. Schlaudecker, Monica M. Mcneal, Christopher J. Harrison, Geoffrey A. Weinberg, Peter G. Szilagyi, Janet A. Englund, Eileen J. Klein, Susan I. Gerber, Meredith Mcmorrow, Brian Rha, James D. Chappell, Rangaraj Selvarangan, Claire M. Midgley, Natasha B. Halasa, Nvsn Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Rhinoviruses and/or enteroviruses, which continued to circulate during the COVID-19 pandemic, are commonly detected in pediatric patients with acute respiratory illness (ARI). Yet detailed characterization of rhinovirus and/or enterovirus detection over time is limited, especially by age group and health care setting.

OBJECTIVE: To quantify and characterize rhinovirus and/or enterovirus detection before and during the COVID-19 pandemic among children and adolescents seeking medical care for ARI at emergency departments (EDs) or hospitals.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective surveillance platform, for pediatric patients who sought …

Autophagy Requirements For Eye Lens Differentiation And Transparency, Lisa Brennan, M Joseph Costello, J Fielding Hejtmancik, A. Menko, S Amer Riazuddin, Alan Shiels, Marc Kantorow

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Recent evidence points to autophagy as an essential cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens. Collective evidence from multiple laboratories using chick, mouse, primate, and human model systems provides evidence that classic autophagy structures, ranging from double-membrane autophagosomes to single-membrane autolysosomes, are found throughout the lens in both undifferentiated lens epithelial cells and maturing lens fiber cells. Recently, key autophagy signaling pathways have been identified to initiate critical steps in the lens differentiation program, including the elimination of organelles to form the core lens organelle-free zone. Other recent studies using ex vivo lens culture …

An Intravenous Pancreatic Cancer Therapeutic: Characterization Of Crispr/Cas9n-Modified Clostridium Novyi-Non Toxic, Kaitlin M. Dailey, James M. Small, Jessica E. Pullan, Seth Winfree, Krysten E. Vance, Megan Orr, Sanku Mallik, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E Brooks

Journal Articles: Pathology and Microbiology

Clostridium novyi has demonstrated selective efficacy against solid tumors largely due to the microenvironment contained within dense tumor cores. The core of a solid tumor is typically hypoxic, acidic, and necrotic-impeding the penetration of current therapeutics. C. novyi is attracted to the tumor microenvironment and once there, can both lyse and proliferate while simultaneously re-activating the suppressed immune system. C. novyi systemic toxicity is easily mitigated by knocking out the phage DNA plasmid encoded alpha toxin resulting in C. novyi-NT; but, after intravenous injection spores are quickly cleared by phagocytosis before accomplishing significant tumor localization. C. novyi-NT could be designed …

Androgen Receptor Inhibition Suppresses Anti-Tumor Neutrophil Response Against Bone Metastatic Prostate Cancer Via Regulation Of Tβri Expression, Massar Alsamraae, Diane Costanzo-Garvey, Benjamin A. Teply, Shawna Boyle, Gary Sommerville, Zachary T. Herbert, Colm Morrissey, Alicia J. Dafferner, Maher Y. Abdalla, Rachel W. Fallet, Tammy Kielian, Heather Jensen Smith, Edson I. Deoliveira, Keqiang Chen, Ian A. Bettencourt, Ji Ming Wang, Daniel W. Mcvicar, Tyler Keeley, Fang Yu, Leah M. Cook

Journal Articles: Pathology and Microbiology

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that …

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …

Respiratory Virus Surveillance Among Children With Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021., Ariana Perez, Joana Y. Lively, Aaron Curns, Geoffrey A. Weinberg, Natasha B. Halasa, Mary Allen Staat, Peter G. Szilagyi, Laura S. Stewart, Monica M. Mcneal, Benjamin Clopper, Yingtao Zhou, Brett L. Whitaker, Elizabeth Lemasters, Elizabeth Harker, Janet A. Englund, Eileen J. Klein, Rangaraj Selvarangan, Christopher J. Harrison, Julie A. Boom, Leila C. Sahni, Marian G. Michaels, John V. Williams, Gayle E. Langley, Susan I. Gerber, Angela Campbell, Aron J. Hall, Brian Rha, Meredith Mcmorrow, New Vaccine Surveillance Network Collaborators

Manuscripts, Articles, Book Chapters and Other Papers

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN …

Covid-19 And Blood Clots: A Report Of Massive Pulmonary Embolism In Covid-19 Patient Supported On Veno-Venous Ecmo And The Utility Of Thrombolysis, Bindu Akkanti, Joseph Zwischenberger, Mark T Warner, Kha Dinh, Rahat Hussain, Farah Kazzaz, Pascal Kingah, Lisa M Janowiak, Biswajit Kar, Igor D Gregoric

Journal Articles

COVID-19 morbidity and mortality are not equivalent to other etiologies of acute respiratory distress syndrome (ARDS) as fulminant activation of coagulation can occur, thereby resulting in widespread microvascular thrombosis and consumption of coagulation factors. A 53-year-old female presented to an emergency center on two occasions with progressive gastrointestinal and respiratory symptoms. She was diagnosed with COVID-19 pneumonia and admitted to a satellite intensive care unit with hypoxemic respiratory failure. She was intubated and mechanically ventilated, but her ARDS progressed over the next 48 hours. The patient was emergently cannulated for veno-venous extracorporeal membrane oxygenation (V-V ECMO) and transferred to our …

A Single Dose Of The Deactivated Rabies-Virus Vectored Covid-19 Vaccine, Coravax, Is Highly Efficacious And Alleviates Lung Inflammation In The Hamster Model, Drishya Kurup, Christoph Wirblich, Leila Zabihi Diba, Rachael Lambert, Megan Watson, Noor Shaikh, Holly Ramage, Charalambos Solomides, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

Without sufficient herd immunity through either vaccination or natural infection, the coronavirus disease 2019 pandemic is unlikely to be controlled. Waning immunity with the currently approved vaccines suggests the need to evaluate vaccines causing the induction of long-term responses. Here, we report the immunogenicity and efficacy of our adjuvanted single-dose Rabies-vectored SARS-CoV-2 S1 vaccine, CORAVAX, in hamsters. CORAVAX induces high SARS-CoV-2 S1-specific and virus-neutralizing antibodies (VNAs) that prevent weight loss, viral loads, disease, lung inflammation, and the cytokine storm in hamsters. We also observed high Rabies VNA titers. In summary, CORAVAX is a promising dual-antigen vaccine candidate for clinical evaluation …

Reduced Er-Mitochondria Connectivity Promotes Neuroblastoma Multidrug Resistance., Jorida Çoku, David M. Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, György Hajnóczky, Michael D Hogarty

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive …

Rare Occurrence Of Pseudomyxoma Peritonei (Pmp) Syndrome Arising From A Malignant Transformed Ovarian Primary Mature Cystic Teratoma Treated By Cytoreductive Surgery And Hipec: A Case Report, Francesca Ponzini, Luke Kowal, Mariam Ghafoor, Allison F Goldberg, Joanna Chan, Ryan Lamm, Shawnna Cannaday, Scott D. Richard, Avinoam Nevler, Harish Lavu, Wilbur Bowne, Norman G Rosenblum

Department of Surgery Faculty Papers

Background: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered.

Case presentation: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian …

Clinical Influenza Testing Practices In Hospitalized Children At United States Medical Centers, 2015-2018., Mark W. Tenforde, Angela P. Campbell, Marian G. Michaels, Christopher J. Harrison, Eileen J. Klein, Janet A. Englund, Rangaraj Selvarangan, Natasha B. Halasa, Laura S. Stewart, Geoffrey A. Weinberg, John V. Williams, Peter G. Szilagyi, Mary A. Staat, Julie A. Boom, Leila C. Sahni, Monica N. Singer, Parvin H. Azimi, Richard K. Zimmerman, Monica M. Mcneal, H Keipp Talbot, Arnold S. Monto, Emily T. Martin, Manjusha Gaglani, Fernanda P. Silveira, Donald B. Middleton, Jill M. Ferdinands, Melissa A. Rolfes

Manuscripts, Articles, Book Chapters and Other Papers

At nine US hospitals that enrolled children hospitalized with acute respiratory illness (ARI) during 2015-2016 through 2017-2018 influenza seasons, 50% of children with ARI received clinician-initiated testing for influenza and 35% of cases went undiagnosed due to lack of clinician-initiated testing. Marked heterogeneity in testing practice was observed across sites.

Insect Cell Expression And Purification Of Recombinant Sars-Cov-2 Spike Proteins That Demonstrate Ace2 Binding, Lucas R. Struble, Audrey L. Smith, William E. Lutz, Gabrielle Grubbs, Satish Sagar, Kenneth W. Bayles, Prakash Radhakrishnan, Surender Khurana, Dalia El-Gamal, Gloria E. O. Borgstahl

Journal Articles: Pathology and Microbiology

The COVID-19 pandemic caused by SARS-CoV-2 infection has led to socio-economic shutdowns and the loss of over 5 million lives worldwide. There is a need for the identification of therapeutic targets to treat COVID-19. SARS-CoV-2 spike is a target of interest for the development of therapeutic targets. We developed a robust SARS-CoV-2 S spike expression and purification protocol from insect cells and studied four recombinant SARS-CoV-2 spike protein constructs based on the original SARS-CoV-2 sequence using a baculovirus expression system: a spike protein receptor-binding domain that includes the SD1 domain (RBD) coupled to a fluorescent tag (S-RBD-eGFP), spike ectodomain coupled …

Type I Ifn Signaling Protects Mice From Lethal Sars-Cov-2 Neuroinvasion., Md Bashir Uddin, Yuejin Liang, Shengjun Shao, Sunil Palani, Michael Mckelvey, Scott C. Weaver, Keer Sun

Journal Articles: Pathology and Microbiology

Multiple organ damage is common in patients with severe COVID-19, even though the underlying pathogenic mechanisms remain unclear. Acute viral infection typically activates type I IFN (IFN-I) signaling. The antiviral role of IFN-I is well characterized in vitro. However, our understanding of how IFN-I regulates host immune response to SARS-CoV-2 infection in vivo is incomplete. Using a human ACE2-transgenic mouse model, we show in the present study that IFN-I receptor signaling is essential for protection against the acute lethality of SARS-CoV-2 in mice. Interestingly, although IFN-I signaling limits viral replication in the lung, the primary infection site, it is dispensable …

Ifn-Γ Transforms The Transcriptomic Landscape And Triggers Myeloid Cell Hyperresponsiveness To Cause Lethal Lung Injury, Atul K. Verma, Michael Mckelvey, Md Bashir Uddin, Sunil Palani, Meng Niu, Christopher Bauer, Shengjun Shao, Keer Sun

Journal Articles: Pathology and Microbiology

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes …

Clinical Laboratory Testing Practices In Diffuse Gliomas Prior To Publication Of 2021 World Health Organization Classification Of Central Nervous System Tumors, Shakti H. Ramkissoon, Helen Fernandes, Dolores H. Lopez-Terrada, Meera R. Hameed, Dimitri G. Trembath, Julia A. Bridge, Neal I. Lindeman, Rhona J. Souers, Patricia Vasalos, Daniel J Brat, Joel T. Moncur

Journal Articles: Pathology and Microbiology

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear.

OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors.

DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers …

Inhibition Of Nadph Oxidase Blocks Netosis And Reduces Thrombosis In Heparin-Induced Thrombocytopenia, Halina H L Leung, Jose Perdomo, Zohra Ahmadi, Feng Yan, Steven E. Mckenzie, Beng H Chong

Department of Medicine Faculty Papers

Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis …

Global Trends In Norovirus Genotype Distribution Among Children With Acute Gastroenteritis., Jennifer L. Cannon, Joseph Bonifacio, Filemon Bucardo, Javier Buesa, Leesa Bruggink, Martin Chi-Wai Chan, Tulio M. Fumian, Sidhartha Giri, Mark D. Gonzalez, Joanne Hewitt, Jih-Hui Lin, Janet Mans, Christian Muñoz, Chao-Yang Pan, Xiao-Li Pang, Corinna Pietsch, Mustafiz Rahman, Naomi Sakon, Rangaraj Selvarangan, Hannah Browne, Leslie Barclay, Jan Vinjé

Manuscripts, Articles, Book Chapters and Other Papers

Noroviruses are a leading cause of acute gastroenteritis (AGE) among adults and children worldwide. NoroSurv is a global network for norovirus strain surveillance among children(genotype and polymerase type) and uploaded 1,325 dual-typed sequences to the NoroSurv web portal during 2016-2020. More than 50% of submitted sequences were GII.4 Sydney[P16] or GII.4 Sydney[P31] strains. Other common strains included GII.2[P16], GII.3[P12], GII.6[P7], and GI.3[P3] viruses. In total, 22 genotypes and 36 dual types, including GII.3 and GII.20 viruses with rarely reported polymerase types, were detected, reflecting high strain diversity. Surveillance data captured in NoroSurv enables the monitoring of trends in norovirus strains …

Clinical Performance Of The Point-Of-Care Cobas Liat For Detection Of Sars-Cov-2 In 20 Minutes: A Multicenter Study., Glen Hansen, Jamie Marino, Zi-Xuan Wang, Kathleen G Beavis, John Rodrigo, Kylie Labog, Lars F Westblade, Run Jin, Nedra Love, Karen Ding, Sachin Garg, Alan Huang, Joanna Sickler, Nam K Tran

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with …

Genomic Characterization Of Malignant Progression In Neoplastic Pancreatic Cysts, Michaël Noë, Noushin Niknafs, Catherine G Fischer, Wenzel M Hackeng, Violeta Beleva Guthrie, Waki Hosoda, Marija Debeljak, Eniko Papp, Vilmos Adleff, James R White, Claudio Luchini, Antonio Pea, Aldo Scarpa, Giovanni Butturini, Giuseppe Zamboni, Paola Castelli, Seung-Mo Hong, Shinichi Yachida, Nobuyoshi Hiraoka, Anthony J Gill, Jaswinder S Samra, G Johan A Offerhaus, Anne Hoorens, Joanne Verheij, Casper Jansen, N Volkan Adsay, Wei Jiang, Jordan Winter, Jorge Albores-Saavedra, Benoit Terris, Elizabeth D Thompson, Nicholas J Roberts, Ralph H Hruban, Rachel Karchin, Robert B Scharpf, Lodewijk A A Brosens, Victor E Velculescu, Laura D Wood

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three …